PAGENO="0001" FDA ISSUES ~,S(o ~ HEARINGS BEFORE THE STIBOOMIMTTTEE ON IIIEALTH AND TIIIE ENVIRONMIENT OF THE COMIMITTEE ON ENERGY AN]) COM1\[ERCE HOUSE OF REPRESENTATIVES NINETY-NINTH CONGRESS FIRST SESSION RISKS AND BENEFITS OF RAW MILK FEBRUARY 13, 1985 EMERGENCY REYE'S SYNDROME PREVENTION ACT OF 1985 MARCH 15, 1985 ORPHAN DRUG ACT REAUTHORIZATION MARCH 20, 1985 Serial No. 99-26 Printed for the use of the Committee on Energy and Commerce U.S. GOVERNMENT PRINTING OFFICE 52-2660 WASHINGTON : 1985 PAGENO="0002" COMMITTEE ON ENERGY AND COMMERCE JOHN D. DINGELL, Michigan, Chairman JAMES H. SCHEUER, New York HENRY A. WAXMAN, California TIMOTHY E. WIRTH, Colorado PHILIP R. SHARP, Indiana JAMES J. FLORIO, New Jersey EDWARD J. MARKEY, Massachusetts THOMAS A. LUKEN, Ohio DOUG WALGREN, Pennsylvania BARBARA A. MIKULSKI, Maryland AL SWITT, Washington MICKEY LELAND, Texas RICHARD C. SHELBY, Alabama CARDISS COLLINS, Illinois MIKE SYNAR, Oklahoma W.J. "BILLY" TAUZIN, Louisiana RON WYDEN, Oregon RALPH M. HALL, Texas DENNIS E. ECKART, Ohio WAYNE DOWDY, Mississippi BILL RICHARDSON, New Mexico JIM SLATTERY, Kansas GERRY SIKORSKI, Minnesota JOHN BRYANT, Texas JIM BATES, California WM. MICHAEL KITZMILLER, Staff Director SHARON E. DAVIS, Chief Clerk/Administrative Assistant DONALD A. WA~rr, Printing Editor ARNOLD I. HAVENS, Minority Counsel SUBCOMMITTEE ON HEALTH AND THE ENVIRONMENT HENRY A. WAXMAN, California, Chairman JAMES H. SCHEUER, New York EDWARD R. MADIGAN, Illinois DOUG WALGREN, Pennsylvania WILLIAM E. DANNEMEYER, California RICHARD C. SHELBY, Alabama BOB WHITTAKER, Kansas RON WYDEN, Oregon THOMAS J. TAUKE, Iowa GERRY SIKORSKI, Minnesota DON RITTER, Pennsylvania TIMOTHY E. WIRTH, Colorado THOMAS J. BLILEY, JR., Virginia JAMES J. FLORIO, New Jersey HOWARD C. NIELSON, Utah THOMAS A. LUKEN, Ohio MICHAEL BILIRAKIS, Florida BARBARA A. MIKULSKI, Maryland FRED J. ECKERT, New York MICKEY LELAND, Texas JAMES T. BROYHILL, North Carolina CARDISS, COLLINS, Illinois (Ex Officio) BILL RICHARDSON, New Mexico JIM BATES, California JOHN D. DINGELL, Michigan (Ex Officio) KAREN NELSON, Staff Director E. RIPLEY FORBES, Special Assistant WILLIAM V. CORE, Counsel MICHAEL J. MASON, Associate Minority Counsel EDWIN H. AuliN, Associate Minority Counsel JAMES T. BROYHILL, North Carolina NORMAN F. LENT, New York EDWARD R. MADIGAN, Illinois CARLOS J. MOORHEAD, California MATTHEW J. RINALDO, New Jersey WILLIAM E. DANNEMEYER, California BOB WHITTAKER, Kansas THOMAS J. TAUKE, Iowa DON RITTER, Pennsylvania DAN COATS, Indiana THOMAS J. BLILEY, JR., Virginia JACK FIELDS, Texas MICHAEL G. OXLEY, Ohio HOWARD C. NIELSON, Utah MICHAEL BILIRAKIS, Florida DAN SCHAEFER, Colorado FRED J. ECKERT, New York (H) PAGENO="0003" CONTENTS RISKS AND BENEFITS OF RAW MILK Page Hearing held on February 13, 1985 1 Testimony of: Adams, John, director, Milk Regulatory and Animal Health Affairs, Na- tional Milk Producers Federation 138 Bolton, John, M.D., on behalf of American Academy of Pediatrics 18 Chin, James, M.D., chief, Infectious Disease Section, California Depart- ment of Health Services 152 Fierer, Joshua, M.D., professor of medicine and pathology, University of California, San Diego School of Medicine, and director of microbiology at the VA Medicial Center, San Diego 24 Fleiss, Paul M., M.D., secretary-treasurer, American Association of Medi- cal Milk Commissions 32 Gooch, Sandy, owner, Mrs. Gooch's Natural Foods Ranch Market 241 Hesser, Pat and William 4 Novell, Raymond A., counsel, Alta-Dena Certified Dairy 224 Okamura, Larry 3 Orsborn, John, DVM, chief, Veterinarian Laboratory Services, California Department of Food and Agriculture 152 Potter, Morris E., DVM, veterinary epidemiologist, Center for Infectious Diseases, Centers for Disease Control 161 Smith, Patton, DVM, assistant director, California Department of Food and Agriculture 209 Stueve, Harold J., owner-partner, Alta-Dena Certified Dairy 224 Telford, Paul 9 Thomas, R. Dean, president, Delst Chemical & Research, Inc 171 Material submitted for the record by: American Medical Association 266 Binz, Evelyn B 273 Danish Creamery Association 265 Delst Chemical & Research, Inc., letter dated February 14, 1985, from Dean Thomas to Chairman Waxman re further clarification to ques- tions asked during the hearing 223 Health and the Environment Subcommittee: Letter, dated February 12, 1985, from S. Benson Werner to Chairman Waxman re false and misleading propaganda distributed by Alta Dena Dairy 127 Two sets of standards from American Association of Medical Milk Commissions, revised 1976 and 1984, also a letter dated February 15, 1985, from Paul Fleiss to Chairman Waxman 49 EMERGENCY REYE'S SYNDROME PREVENTION ACT OF 1985 Hearing held on March 15 275 Text of H.R. 1381 277 Testimony of: Chayet, Neil L., legal counsel, Committee on the Care of Children 540 Cope, James D., president, the Proprietary Asociation 518 Dickson, R. Bruce, counsel, Aspirin Foundation of America 462 Dumigan, George and Diane, New Haven, CT 307 Freudenberger, John E. and Terry, president, National Reye's Syndrome Foundation 286 Happle, Jimmy and Gail, Florence, SC 306 (III) PAGENO="0004" lv Page Testimony of-Continued Jennison, Dr. M. Harry, executive director, American Academy of Pediat- rics 316 Metzenbaum, Howard H., a U.S. Senator from the State of Ohio 281 Michels, Dan, Director, Office of Compliance, Public Health Service, De- partment of Health and Human Services 326 Pruitt, Albert, M.D., FAAP, chairman, Committee on Drugs, American Academy of Pediatrics 319 Taubin, Joel M., M.D., vice president, National Reye's Syndrome Founda- tion 285 White, Joseph M., M.D., president, Aspirin Foundation of America 462 Wolfe, Sidney, M., M.D., director, Public Citizen Health Research Group... 316 Young, Frank E., M.D., Ph.D., Commissioner, Food and Drug Administra- tion, Public Health Service, Department of Health and Human Services 326 Material submitted for the record by: American Advertising Federation 672 American Aspirin Association: Dickson, Bruce, letter dated April 10, 1985, enclosing requested mate- rials 464 Reye Syndrome awareness research final report 465 Voluntary precautionary program progress report 454 American Association of Advertising Agencies, Inc 679 American Newspaper Publishers Association 683 American Pharmaceutical Association 659 American Reye's Syndrome Association 651 Association of National Advertisers, Inc 689 Chayet, Neil L., letter dated March 28, 1985 644 Health and Human Services Department: Aspirin Foundation of America 364 Estrogenic drugs-patient package inserts 346 Heckler, Hon. Margaret, statement 377 Industry initiatives other than Aspirin Foundation on Reye Syn- drome Warnings 383 Letter, dated March 8, 1985, entitled Dear Drug Establishment Regis- trant 373 Letter, dated April 11, 1985, from Frank Young to Chairman Waxman re response to January 11, 1985 letter to Secretary Heck- ler 365 Retail survey-Reye Syndrome warning statement posters 372 Reye Syndrome public education materials 418 Reye Syndrome PSA 364 Magazine Publishers Association 683 National Association of Broadcasters 693 National Association of Chain Drug Stores, Inc 669 National Association of Truck Stop Operators 649 Outdoor Advertising Association of America, Inc 702 Wignhoff, Edwin D 704 ORPHAN DRUG ACT REAUTHORIZATION Hearing held on March 20, 1985 709 Testimony of: Baird, William, president, American Narcolepsy Association 749 Finkel, Marion, M.D., Director, Office of Orphan Products Development, Food and Drug Administration, Public Health Service, Department of Health and Human Services 710 Martin, Larry H., president, Florida Medical Device Association and gen- eral counsel, Neuromed, Inc 764 Meyers, Abbey S., chairperson, government-industry liaison committee, director, family and professional services, Tourette Syndrome Associa- tion Scarlett, Tom, general counsel, Food and Drug Administration, Public Health Service, Department of Health and Human Services 710 Shaw, Dilip P., Ph.D., vice president, Regulatory Affairs, Lyphomed, Inc ... 747 Simon, John W., on behalf of American Academy of Ophthalmology 752 Thoene, Jess G., M.D., president-elect, National Organization for Rare Disorders PAGENO="0005" V Testimony of-Continued Page Young, Frank E., M.D., Ph.D, Commissioner, Food and Drug Adminis- tration, Public Health Service, Department of Health and Human Services 710 Material submitted for the record by: American Pharmaceutical Association 776 Health and Human Services Department, letter, dated March 21, 1985, from Henry Dausch to Chairman Waxman re additional materials in response to questions during the hearing 726 PMA Commission on Drugs for Rare Diseases 780 PAGENO="0006" PAGENO="0007" RISKS AND BENEFITS OF RAW MILK WEDNESDAY, FEBRUARY 13, 1985 HOUSE OF REPRESENTATIVES, COMMITTEE ON ENERGY AND COMMERCE, SUBCOMMITTEE ON HEALTH AND THE ENVIRONMENT, Los Angeles, CA. The Subcommittee met, pursuant to notice, at 9:35 a.m., in the Moss Auditorium, room A2-342 of the Marion Davies Children's Clinic, University of California, Los Angeles, CA, Hon. Henry A. Waxman (chairman) presiding. Mr. WAXMAN. I would like to call the meeting to order. Welcome to all of our guests for this discussion of the question of raw unpasteurized milk. We convene this morning's session to re- ceive testimony on the health effects of raw, unpasteurized milk. There is a lot of advertising about the benefits of raw milk. It is said to be the safest, purest milk one can buy. The advertisements and testimonials seem persuasive. Who would not want to do what is best for one's health and that of one's family? But now there is growing concern among some public health ex- perts about an association between contaminated raw milk and a variety of life-threatening illnesses. Many medical experts tell us that some raw milk consumers have been exposed to dangerous levels of bacteria with names such as salmonella, campylobacter, and brucella. State regulations may not adequately protect the public from the risk of contaminated raw milk. If this situation is true, there is cause for alarm. In view of the reports of illness and death associated with con- taminated raw milk, the Federal Food and Drug Administration is currently considering a proposal to ban raw milk sales. This com- mittee has legislative and oversight jurisdiction over the FDA and is interested in a full and complete discussion of this issue. I am particularly interested in knowing how raw milk could become contaminated. Are existing State and industry quality con- trol procedures adequate to prevent bacterial contamination? Second, do consumers who drink raw milk have a good under- standing of not only the claimed benefits, but also the possible risks? Further, are there any groups for whom contaminated raw milk presents a particular risk? Our witnesses this morning represent both sides of this often controversial and emotional issue. Our roster of witnesses includes a representative from the Nation's largest raw milk producer, health officials and physicians with direct experience in assessing (1) PAGENO="0008" 2 the risks and benefits of drinking raw milk, and ordinary citizens who have experienced personal tragedies with this product. Before we call our first witness panel, I would like to recognize a distinguished Member of Congress also from the Southern Califor- nia area, Congressman Dannemeyer, for some opening comments he may wish to make. Mr. DANNEMEYER. Thank you, Mr. Waxman. Ladies and gentlemen, it is my understanding that the principal reason for this hearing being held is that in the continuing contro- versy over the availability of certified raw milk in California in these United States, certain people in the public health world are claiming that the continued availability should be stopped because allegedly salmonella is sometimes found in certified raw milk. That is the claim, that it is unfit for human consumption because on occasion it contains salmonella. I would like to publicly congratulate officials of the Department of Public Health of the State of California and of the County of Los Angeles because it is my understanding that they are prepared to say this morning on the public record that they are going to de- clare war on salmonella in California and in the United States if they can get that action taken. That is to say, in their view, salmo- nella in any food available to a consumer in California, is so inimi- cal to the health of such a person that it is public policy that we should stop this availability of any food product that contains sal- monella. I commend them for this judgment and wish them well in their effàrts to eliminate salmonella from the table of consumers in our State. This will mean, my friends, that the following foods, consistent with this war on salmonella, will be eliminated by edict of the State Department of Public Health of California: pork, turkey, po- tatoes, tacos, beef, water, ice cream, milk, goat, chicken, cake, Mexican food, mayonnaise, and egg nog. Those are the food products from the records of the Centers for Disease Control in Atlanta, GA that were implicated by way of con- sumption of food products that manifested illness in humans caus- ing salmonella food poisoning. In 1979, the following products produced the same result: pork, turkey, hospitals, chicken, green beans, beef, eggs, canned soda, baked goods, hollandaise sauce, crab meat, egg noodles, casserole, watermelon, meat, stuffed shells with cheese, ice cream, raw milk. In 1980, turkey, beef, bakery products, eggs, ham, Chinese food, chicken salad, pork, ice cream, fruits and vegetables, egg nog, potato salad, milk, salad sauce, and Mexican food. In 1981, chicken, pork, egg nog, shell fish, milk, ice cream, baked foods, turkey, beef, cheese, and Mexican food. The records for 1982 and 1983 and 1984 were not available for this hearing today. When they are available, we will likewise make reference to them. Of the cases that the CDC has reported-that is attributable to the food, part of an outbreak, in the 4 years to which I have made reference, 1978, 1979, 1980, and 1981-11,255 cases were made. Of those associated with milk were 65-roughly 0.5 of 1 percent. In other words, of all the cases reported to CDC in that 4-year span, PAGENO="0009" 3 0.5 of 1 percent are related to milk from salmonella food poisoning. The others came from the food products I have indicated. So I think it is commendable that the health authorities of Cali- fornia in pursuit of this declaration of war which is being an- nounced today, to my understanding, to eliminate salmonella from the tables of consumers in California, you know, we are going to have to just get by in our eating with less foods than are presently available, but that is all the price we have to pay in terms of reach- ing this world where our public health officials say we can no longer tolerate the presence of food products containing salmonella. It is interesting to note that of the association of food products with milk, in 1978, pasteurized milk-I repeat, pasteurized milk- was responsible for 25 cases of salmonella food poisoning. In 1978, 7 cases of raw milk; in 1979, 8; 1980, 7; 1981, 26, a half a percent out of the total of 11,255. So when the public health offi- cials testify today, I look forward to them stating today their decla- ration of war on salmonella so we Californians can live in a salmo- nella-free environment in order to protect the public health. I would also expect since we are banning water from the use of consumers in California that the public health officials will recom- mend that we establish an army of inspectors that will station themselves in residential neighborhoods of California for the pur- pose of making sure that the domestic water supply does not find its way into the drinking habits of the consumers of our State. I believe it is reasonable to suggest that we will be able to use the domestic water supply for plumbing purposes, that is, for toi- lets and for bathing, but certainly we do not want to permit water from the domestic supply to be available for consumption for drink- ing because history shows that this is a source of salmonella food poisoning and in the pursuit of our war against salmonella we should not tolerate continued availability of domestic water sup- plies for the citizens of our State. Thank you, Mr. Chairman. I look forward to today's testimony. Mr. WAXMAN. Thank you, Mr. Dannemeyer. Our first witnesses this morning are individuals who have had a personal experience with an illness associated with unpasteurized raw milk. I want to express the committee's appreciation for their willingness to come forward and tell about what must be intensely personal events in their lives. I would ask Mr. Larry Okamura, Mr. Paul Telford and Mr. and Mrs. Hesser to come forward and take chairs at the table. Let me thank each of you for coming to present your testimony. We are looking forward to hearing what you have to say and would like you to summarize what you have in your statements, what you think is important for us to know in a period of time that would give you the ability to tell us what happened, but not take long be- cause we have many witnesses today. STATEMENTS OF LARRY OKAMURA, PAT AND WILLIAM HESSER, AND PAUL TELFORD Mr. OKAMURA. Thank you, Mr. Chairman. It was back in May that my daughter went on a field trip to Alta-Dena Dairy with her school class. They gave her raw milk, ice PAGENO="0010" 4 cream, and kefir. She consumed the raw milk and the ice cream. We were not told she would be given anything on this outing. This was on a Thursday. It was roughly Sunday when we were told in passing that she had been given these products and that Sunday night she looked strange, just not herself. On Monday, my wife called me at work and told me she woke up with a 103-degree-plus temperature and she called the doctor and she said we should bring her in that afternoon. After I came home, we took her to the doctor and he as- sumed that it was some sort of stomach flu or food poisoning. On Tuesday-that Monday evening, she started diarrhea and on Tues- day she had at least 34 movements. That is when our pediatrician said he wanted to keep an eye on her. He wanted to see her daily until this cleared up. We told him that she had consumed raw milk. He then asked for a stool sample which he had taken to some lab and they tested it for salmonella and whatever. The salmonella came back negative, but it came back positive on the campylobacter of which he said was very dangerous in her condition. She kept the diarrhea going, I guess, until Friday, but it contin- ually got decreasingly less but the only reason my daughter was not hospitalized was the fact that she was cooperative for the fact that we had kept feeding her two or three quarters of Gatorade, plus other liquids and in that 3½-day period, she lost over 2½ pounds. Our pediatrician said that the campylobacter only came from the raw milk because he got in touch with Public Health. They told him that this is the direct derivative of raw milk. I don't believe that other people should be submitted to some- thing like this. Mr. WAXMAN. Thank you very much. We will ask each of the witnesses to talk first and then ask ques- tions. Mr. and Mrs. Hesser. STATEMENT OF WILLIAM AND PAT HESSER Mrs. HESSER. Thank you. My personal experience with salmonella is I was drinking the raw milk for about 10 years on and off throughout the 10 years, during which time I had diarrhea and nausea and not knowing what it came from. In April of 1984, I got extremely sick and I had all of the symp- toms of salmonella, not knowing what it was. I was pregnant carrying twins that were very healthy at the time. Through my suffering, they did suffer and they died. Two weeks after-we knew they were dead for 2 weeks. We gave birth- I gave birth to them and they were stillborn at the time. They were autopsied and found to have had the infection of salmonella. They died from the mother's infection which is what the autopsy says, and that was salmonella dublin. The milk in our refrigerator was tested and it had salmonella dublin. It was all confirmed. Everything was just tested and proven. PAGENO="0011" 5 The suffering on my own part, I know, was severe, and as for the children, I know they suffered. They were born here at UCLA and in talking with nurses and doctors, it was the concern of how much suffering they went through and they did. Mr. HESSER. During my wife's illness, she suffered severe abdomi- nal cramps in addition to severe back pain and chest pain and be- cause she was carrying twins, it was believed that she was having trouble, carrying them high, and that that was causing breathing difficulty. During her 2½ week illness, she would intermittently be sick, every other day, violently sick, and on the other day, she would be moderately ill. She experienced vomiting, nausea, extreme pain in her back particularly and chest, and stomach. She was not able to sleep most of this time nor eat. The concern was she would dehy- drate in carrying the twins and also the need for nourishment and protein was a problem. So our concern was to get nourishment into her and we contin- ued to give her additional raw milk products which we were using at the time, which was probably the worst thing she could have continued to consume because it had salmonella dublin in it. The suffering was very severe on my wife's part. The emotional suffering that both my wife and I endured and continue to endure since that time has been severe. We believed as consumers and felt we were well informed and well read, that the benefits of raw milk were substantial and that raw milk was good for our health. We believed every time there was a recall, what the dairies involved would say strictly, that the recall was a matter of harassment by the State and, therefore, we did continue toconsume raw milk products. We do believe because of the readings we have done since then, medically and scientific readings, that there is a serious concern re- garding salmonella dublin in particular in raw milk and we do urge that there would be consideration for the banning of sales of raw milk. Thank you. [The statement of Mr. and Mrs. Hesser follows:] PAGENO="0012" 6 William and Patricia Hesser February 11, 1985 Rep. Henry A. Waxman U.S. House of R?presentativeS Subcommittee on Health and the Environment 8425 W. 3rd Street Los Angeles, CA 90048 RE: Personal statement submitted to the Subcommittee on Health and the Environment for their hearing on the risks and benefits of unpasteurized milk. Dear Rep. Waxman: I, William Hesser, began using certified raw milk products in 1972 when I moved to Southern California. My interest in nutrition and natural foods started in 1970 when I read Adelle Davis' Let's Eat Right To Keep Fit and was intro- duced to Prevention magazine. Raw milk products were un- available in the state where I lived in 1970, so I was happy to be able to~purchase raw milk products when I moved to California. I believed raw milk,products were nutritionally superior to pasteurized milk. I believed pasteurization destroyed essential enzymes, vitamins, minerals, and, in conjunction with homogenization, altered the fat content of *the milk. Health-food industry literature urged the importance of using certified raw milk products to beassured of its safety. Pro raw milk literature said that "certified" meant the milk was safe, pure, and nutritious because the cows were free from disease and were kept in a clean en- vironment. My wife Patricia began using certified raw milk products prior to our marriage and we continued using them until 1983. In the summer of 1982 Patricia became pregnant. In the course of prenatal care we found that Patricia was carrying twins. Patricia's health was good and her preg- nancy was uneventful for the most part. Patricia became physically ill in late March of 1983. Patricia's symptoms included severe abdominal, chest, and back pains, diff i- culty in breathing, nausea, diarrhea, vomiting, loss of appetite, and difficulty sleeping because of pain and general discomfort. Patricia's illness continued until PAGENO="0013" 7 April 15, 1983 when Patricia became concerned at the lack of fetal movements. An ultrasound test revealed fetal demise of the twins. Two and one-half weeks later, on May 4, Patricia delivered stillborn twins at UCLA Medical Center. During labor Patricia experienced a high fever. Blood tests revealed she had a Salmonella infection in her bloodstream. We were told this infection was "life threatening." Antibiotics were given until the infection subsided. Autopsies of the twins revealed the cause of death to be Salmonella Dublin infection which was trans- mitted from Patricia to the twins. A recall of certain certified raw milk products was ordered by the California Department of Health Services during the above-mentioned timeframe. The recalled products' lot num- bers matched those of milk in our refrigerator. Testing of our milk by the Pasadena Health Department and Califor-' nia Department of Health Services in Berkeley revealed the milk to be contaminated with Salmonella Dublin--the sane bacteria which killed the twins. It is impossible to adequately express the emotional pain, trauma, and distress which these events placed upon us! The dairy where we purchased our certified raw milk pro- ducts is the leading producer/distributor of raw milk in the USA. This dairy denies that its milk is ever con- taminated with Salmonella bacteria. Furthermore, they deny that Salmonella is a harmful bacteria, nor has ever caused human illness or death. These claims are made de- spite the fact that over 22 state-ordered recalls of con- taminated, disease-ridden milk have occured since 1978. The dairy's claim is that the recalls are the result of governnent harassment of the raw milk industry. Numerous lawsuits against this dairy have been filed. The dairy's unfortunate, calloused attitude gives the raw milk consumer the impression that certified raw milk products are safe for human consumption, and are the target of harassment. It is our concern that other people will drink contamin- ated raw milk products, become ill, and die. Untold suffering can be prevented! Warning labels, such as appear on cigarette packages, are the minimum which should be done to alert raw milk consumers -to the. potential hazards of raw milk. However, it is not unreasonable to discontinue the sale of raw milk for purposes of human consumption. A wealth of medical and scientific evidence is available to show the hazards of raw milk products, whether certified or not. Salmonella Dublin, in particular, is almost ex- clusively contracted from drinking raw milk. Other vir- ulent bacteria thrives in raw milk as well. PAGENO="0014" 8 Another measure should be taken on the federal level. The FDA annually subsidizes dairies for the nonproduction of milk so that milk prices can remain stable. The California dairy mentioned in this statement was the recipient of three million dollars in 1983 for nonproduction of milk which the dairy then sold as raw milk. The FDA should establish regulations forbidding that subsidized milk can be sold as raw milk products. The government has an obligation to introduce and pass legislation forbidding the sale of raw milk products. Medical authorities and scientists have an obligation to warn the public of the hazards of raw milk. Those whose lives have been affected by contaminated raw milk products have an obligation to speak out as able. Dairies, especially raw milk dairies, have the greatest responsibility! They must accept responsibility for their products. They must recognize the hazards of raw milk and adequately warn the public of the risks as well as the purported benefits of raw milk. Sincerely, William Hesser and Patricia Hesser , Californi4 PAGENO="0015" 9 Mr. WAXMAN. Thank you very much, Mr. and Mrs. Hesser. Mr. Telford. STATEMENT OF PAUL TELFORD Mr. TELFORD. Thank you, Mr. Chairman. My father died July 26, 1982, in the Glendale Adventist Hospital. He had been admitted July 21 suffering from diarrhea and weak- ness and fever. Blood cultures revealed the presence of salmonella dublin and Listeria monocytogenes. The cause of death as listed by the coroner's death certifIcate, was purulent meningitis as a result of the Listeria. A brain swab showed Listeria monocytogenes type 4. My father was extremely healthy all his life and was working just shortly before the time of this and at that time he had, in June, been admitted to Glendale Adventist Hospital for detection of cancer in the upper lung, the right lung area. He was discharged on June 14 after about a week in the hospital, and continued out- patient radiation and chemotherapy. He was able to drive himself back and forth for these treatments and was progressing very well. We had good reason to have high hopes for his recovery from the cancer. Due to the radiation therapy, he began to develop soreness in his throat and it made it very difficult for him to eat anything of a solid nature and so he went to a liquid diet. Part of the products that he partook of were WaEe-On, Meritene, and Ensure, which are commercially prepared products. They are dietary products commercially available. He also took these with milk. He was concerned that he had enough calorie nutritional intake to keep up his strength, so he decided to purchase certified raw milk. It was readily available to him. Alta-Dena's outlet was just a few blocks from my parents' home so he would stop and purchase it on the way home from treatment. On the last period, the last time that raw milk was purchased at Alta-Dena's outlet, was July 16. On Monday, July 19, he had diar- rhea and was very weak. On Tuesday, we thought that it was prob- ably due to his inability to eat and we decided to admit him to the hospital on Wednesday, and I was to pick him up, but at 5 a.m. in the morning, he was feeling so poorly that my mother called an ambulance and he was admitted to Glendale Adventist with fever and extreme chills. My father's demise was very quick. He was in the hospital until July 26. He was not able to communicate with us after about 3 days in the hospital. He had fevers at times exceeding 104 degrees. After my father's deaths there was a great deal of media atten- tion to producers and distributors of raw milk, particularly the Alta-Dena Dairy as a result of Alta-Dena's lawsuit against the State of California, which, to my understanding, Alta-Dena later dropped. These producers and distributors of raw milk in the State have made tremendous gains in their continuing effort to be relieved of government testing of their product. They have been able to do this PAGENO="0016" 10 essentially because of their ability to hire lobbyists and to contrib- ute to campaign funds of legislators. Their latest effort was SB565 which would appoint a commission, the majority of which would come from the producers themselves, who would be entrusted with protecting the public health from the harmful bacteria this product can contain. Although this bill passed the legislature, Governor Deukmejian did not sign it. How can anyone expect an industry to police itself whose largest producer, Harold Stueve, owner of Alta-Dena, is quoted as saying, "The Lord gives us everything in its wholeness, and that's the way He meant us to keep it"; a man whose single great passion is said to be "the production and sale of raw milk"; who vehemently denies that any harm could come to anyone drinking his milk? I think Louis Pasteur would roll over in his grave as pasteuriza- tion has generally been regarded as one of the most important public health measures ever undertaken. Mr. Stueve and his industry have been able to continue this de- ception on the American public because of the elusive nature of the bacteria and its being found in other foods. However, in my fa- ther's case, there is no other food intake to which they can shift the blame. This fact and the occurrence of the two bacteria togeth- er, salmonella dublin and Listeria monocytogenes, which occur almost exclusively in barn yard situations, make it difficult to be- lieve in the innocence of raw milk and its producers and distribu- tors. How long can you, our elected representatives, listen to the clever deception of this industry? How long can you turn a deaf ear to those public agencies whose duty it is to protect us? Can you, in all honesty, let an industry who tries so hard to remove itself from liability, when people become ill and die, police itself? Please provide for more Government supervision and testing. At least require a warning label to be placed on this product which describes its potential lethal consequences to those whose resist- ance has been lowered in any way. Allow the American public the opportunity to at least make an informed choice. I thank you for this opportunity to share my family's experience with you. I wish that my father and countless thousands who have been or will be affected by the consumption of raw milk could do the same. [The statement of Mr. Telford follows:] PAGENO="0017" 11 STATEMENT OF PAUL A. TELFORD My father, Paul B. Telford, died July 26, 1982 in Glendale, California. He had been admitted to Glendale Adventist Hospital on July 21, 1982 suffering from diarrhea, weakness and fever. Blood cultures revealed the presence of Salmonella dublin and Listeria monocytoqemes. The cause of death as listed by the Coroner's death certificate was purulent neningitis. A brain swab taken by the coroner showed Listeria monocytogenes type 4. My father was 66 years old and had been extremely strong and healthy all his life with no significant illnesses or accidents and was never hospitalized. He met a demanding work schedule as building engineer for Yamaha International in Buena Park, California. He lived with my mother in the Brookside Mobile Home Park in El Monte, California. He was admitted to Glendale Adventist Hospital on June 6, 1982 after chest x-rays revealed some abnormalities. A biopsy resulted in a diagnosis of small cell carcinoma of the upper right bronchial area. He was discharged June 14, 1982 and returned five days a week for radiation therapy. He also was undergoing chemotherapy. He was however, able to drive him- self from his home to the hospital and back, thirty miles round trip, and was progressing very well. He began developing a soreness in his throat in July which progressively worsened to the point that swallowing was so painfull that he went to a liquid diet of the commercially prepared products Wate-on, Meritene and Ensure. He mixed some of these with milk. He was concerened that he would have enough calorie and nutritional intake to keep up his stength. This led him to purchase Alta-Dena Certified Raw Milk thinking it to be higher in calories and nutrients and being unaware of any potential health risks. It was also convenient since Alta-Dena had a drive thru location a few blocks from my parents home. He purchased three one-half gallon containers over a week to ten day period, the last being July 16, 1982. On Monday, July 19, 1982 he had diarrhea and was quite weak. Tuesday, July 20, 1982 thinking that his condition was due to his being unable to eat properly we decided to admit him to the hospital on Wednesday, July 21, 1982. I was to pick him up but his discomfort was so great early Wednesday morning that my mother called an ambulance at 5:00 am. He was admitted to Glendale Adventist Hospital experiencing periods of fever and extreme chills. Thursday afternoon, July 22, 1982 his temperature continued to increase despite efforts to keep it down medication, sponge baths and ice packs ). (1) PAGENO="0018" 12 Friday, July 23, 1982 he was no longer able to speak to us in the afternoon, his temperature ranged as high as 104 degrees. Saturday, July 24, 1982 with fever raging and his temperature exceeding 104 degrees he was unable to respond to us in any way. He went through periods when he did not breathe causing my mother and those of us present a great deal of anxiety. We now had real fears that he would not survive. Sunday, July 25, 1982 his condition was unchanged. Monday, July 26, 1982 at approximately 5:00 am my father died. My mother has not been the same since and has been hospitalized twice the last time for a stroke which has left her with some paralisis. Over the next several weeks there was a great deal of "media" attention to producers and distributors of raw milk especially Alta-Dena Dairy. Part of this due to Alta-Dena's law suit against the State of California because of various agencies efforts to protect- the public. Alta-Dena later dropped the suit. These producers and distributors in the past few years have made tremendous gains in California in their continuing effort to be relieved of government testing. This they have been able to do because of their ability to hire lobbiests Alta-Dena Dairy has gross revenues exceeding $100 million and contribute large sums to legislators. Their latest effort was SB565 which would appoint a commission, the majority of which would come from the producers themselves, who would be entrusted with protecting the public from the harmfull bacteria this product can contain. Although this bill passed through the legislature, thankfully, Governor Deukmejian did not sign it. How can anyone expect an industry to police itself whose largest producer Harold Stueve, owner of Alta-Dena, is quoted as saying, " The Lord gives us everything in its wholeness, and that's the way He meant us to keep it". A man whose single great passion is said to be " the production and sale of raw milk ". Who vehemently denies that any harm could come to anyone drinking his milk. Louis Pasteur would roll over in his grave. Pasteurization is generally regarded as one of the most important public healthmeasures ever undertaken. Mr. Stueve and his industry have been able to continue this deception of the American public because of the elusive nature -of the bacteria and its also being found in other foods. However, in my fathers case, there is no other food intake to which they can shift the blame. This fact and the occurrence of the two bacteria together, Salmonella dublin and Listeria monocytogenes, which occurs almost exclusively in barn yard situations make it difficult to believe in the innocence of raw milk and its producers and distributors. How long can you, our elected representatives, listen to the clever deception of this industry. How long can you turn a deaf ear to those public agencies whose duty it is to protect us. Can you, in all honesty, let an industry who tries so hard to remove itself from liability when people become ill and die police itself. Please provide for more government supervision and testing. Require a warning label to be placed on this product which discribes its potential lethal consequences to those whose resistance has been lowered in any way. Allow the American public the opportunity to at least make an informed choice. I thank you for this opportunity to share my families experience with you. How I wish that my father and the countless thousands who have been or will be affected by the consumption of raw milk could do the same. PAGENO="0019" 13 Mr. WAxIsi*i.~. Thank you very much, Mr. Telford. We thank you all for sharing your personal and tragic experi- ences with us. In each case, you attribute the raw milk that you or your family member consumed to be the source for the medical problems. Mr. and Mrs. Hesser, as I understand your testimony, the autop- sy of the twins showed that there was salmonella? Mrs. HESSER. Yes, it did. Mr. WAxMAN. And when the milk in your refrigerator was tested, there was an indication that that had also been infected? Mrs. HESSER. Yes. Mr. WAXMAN. I think you mentioned you had consumed other products; you had been consuming this product for years before, and that you had other natural products that you had or still may consume. Was there any particular reason why you decided to drink raw milk? Mrs. HESSER. The general health benefit that it proposed to have. It obviously didn't have as much as I thought. Mr. WAxMAN. You thought it would be better for your health to drink raw milk and have natural foods? Mrs. HESSER. Yes. Mr. WA.xr N. Did you ever hear of any problems or potential risks from raw milk? Mrs. HESSER. I had heard of the occasional recalls that had been made and I also believed the papers which stated both sides very clearly, and Alta-Dena's side was "We are being ha~rassed." Mr. WAx1 N. The milk you were drinking was labeled "certified raw milk", I believe? Mrs. HESSER. Yes. Mr. WAxi~N. What did you think "certified" meant? Mrs. HESSER. Personally, I thought it meant it was checked, and it was safe for consumption and there would be no problem. Fur- thermore, with the recalls themselves, I felt when it was recalled, it meant they were not having a bad product on the shelf~ I felt that it was obviously taken off and that people did not have the opportunity to buy it. Mr. WAx N. I see, and did you know that there was a recall before you drank the milk or was this something you discovered afterwards? Mrs. HE8SER. It was always afterwards. Mr. WAXMAN. Would you have been drinking raw milk if you be- lieved there to be a potential health risk? Mrs. HESSER. No. Mr. WAx1~~t~. If there had been a warning label on the milk, do you think that would have influenced you? Mrs. HESSER. I don't really know. Mr. WAx~. All right. Did you have any other problems that were associated with drinking raw milk? Mrs. HE5SER. Like I said, from the past-when I came to Califor- nia and started drinking the raw milk because it was available, I did have occasional diarrhea and nausea and things like that that I assumed were my stomach upset, never connecting the two. PAGENO="0020" 14 Mr. WAXMAN. So after you learned more about the problems with raw milk, you thought back to those other occasions and thought there might have been a connection? Mrs. HESSER. Yes, and since I stopped drinking it, I don't have that problem on occasion. Mr. WAXMAN. Now Mr. Telford, your father was going through chemotherapy and radiation therapy? Mr. TELFORD. Yes. Mr. WAXMAN. Did the doctors explain to you afterward that be- cause he was going through chemotherapy and radiation, that he was more vulnerable to infection than otherwise would be ~he case? Mr. TELFORD. That is correct. Mr. WAXMAN. Did he consume raw milk over a long period of time? Was this a regular habit of his? Mr. TELFORD. No. He had just started consuming it again. My father grew up on a farm as many people his age would have done, he was 66 years old, and so as a youth, he consumed raw milk probably almost exclusively from the dairy cattle on their own farm. So my father's experience with raw milk as a youth was prob- ably excellent and he just felt that it would be a good source of nu- trients and calories that he needed. Mr. WAXMAN. I am wondering if he thought that because he had been ill that raw milk would be especially healthful for him to take at that time and what might have happened was because his body was more vulnerable to an infection, that might not otherwise have infected him at all, became much more serious? Mr. TELFORD. Certainly the family would have been a great deal more concerned had there been some type of a warning. Then we could have at least had asked his doctors whether they thought it was a good idea that he be ingesting raw milk. They were aware of the fact that he wasn't eating and they had suggested the commer- cially prepared products for him to try and use, but I can't say for sure if my father alone would have been discouraged from taking the milk if a warning label were there, but certainly my mother and others of us in the family would have at least looked into it. You don't see a warning label and then disregard it particularly when someone's health is in jeopardy. Mr. WAXMAN. Your father took the raw milk voluntarily and Mrs. Hesser took it voluntarily with the expectations that the kind of thing that happened wouldn't have happened, but, Mr. Oka- mura, your daughter was how old? Mr. OKAMURA. Five or six. Her birthday is in May. Mr. WAXMAN. So one doesn't think of children at five or six making informed, voluntary decisions-even though it may be vol- untary-to eat something that will affect her health. Did you know she was going to be taking this? Mr. OKAMURA. We were not told there would be any food prod- ucts served, but we knew about the trip. Mr. WAXMAN. You didn't imagine there would be any problem with the food products, did you? Mr. OKAMURA. No, I never did. PAGENO="0021" 15 Mr. WAx1~i,~. If they had said she was going on the tour and, "We will give her raw milk," would you have said, "No"? Mr. OKAMURA. I believe so, because we don't use raw milk in our household. We never have. Mr. WAxi~&r~. She went with a class? Mr. OKAMURA. With her class. Mr. WAXMAN. Did other children become ill? Mr. OKAMURA. Yes. Nine others in her class of thirty were out that same Monday that she came down with it. Mr. WAx~&N. Thirty kids went on the trip, and nine became ill? Mr. OKAMURA. Right. Nine were not in school. I am assuming there were others in her class that were sick, plus the parents of the children that went on the field trip came down with some posi- tive reaction, also. Mr. WAxi~w~. Did they eat any other foods that might have caused the problem? How do you know for sure it was raw milk? Mr. OKAMURA. It was just her class that came down with any kind of illness in the whole of the school, because Public Health came in and took a random stool sample from all the children in school. I don't know what was the number, but in her class, they took a stool sample from everyone and there were close to half the class was a positive reaction of the campylobacter. The only other thing they ate that was different from their normal diet-on that Friday was what they call McDonald's day and whatever part of the school that wants, they can have McDon- ald's hamburgers. Like I say, the balance of the school had no signs of the campylobacter. It was just her class. Mr. WAXMAN. Everybody had hamburgers, but not everybody had the milk, is that what you are saying? Mr. OKAMURA. Right. Only her class of 30 went on the field trip. Mr. WAXMAN. But everybody had hamburgers at school? Mr. OKAMURA. Right. Mr. WAx1~N. Only the kids in her class became ill, then? Mr. OKAMURA. Right. Mr. WAx~&N. Thank you very much. Mr. Dannemeyer. Mr. DANNEMEYER. Thank you, Mr. Chairman. Mr. Okamura, the field trip was on a Friday? Mr. OKAMURA. No. The field trip was on a Thursday. Mr. DANNEMEYER. And was your daughter's class the only one that went on the field trip? Mr. OKAMURA. Yes, it was. Mr. DANNEMEYER. And did all the children in the class drink milk at the Alta-Dena Dairy? Mr. OKAMU1ti~,. They were all given-whether they consumed it or not, I have no idea. Mr. DANNEMEYER. When did your daughter first evidence signs of illness that you describe? On Sunday, did you say? Mr. OIWvIUKA. Sunday evening. Mr. DANNEMEYER. Sunday evening? Mr. OKAMURA. She just looked a little strange Sunday evening. It is one of those things that a parent sees in their child, you know. She just didn't act like herself. PAGENO="0022" 16 Mr. DANNEMEYER. How about the other children? Did you find out when they began to manifest these signs of illness? Mr. OKAMURA. The other children in her class? Mr. DANNEMEYER. Yes. Mr. OKAMURA. We didn't know about the others until Public Health informed us. Mr. DANNEMEYER. How about any of those other children that had hamburgers on Friday? Did any of them complain of any ill- ness at all that you are aware of? Mr. OKAMURA. No. Like I said, the balance of the school was of- fered the opportunity to get McDonald's hamburgers of which I am assuming at least 65 percent buy the hamburgers, and it was only her class that came down with the positive reaction. Mr. DANNEMEYER. Thank you. Mr. Hesser and Mrs. Hesser, during the pregnancy that you de- scribed, were you taking insulin at the time? Mrs. HESSER. No, I wasn't. Mr. DANNEMEYER. Did the doctor prescribe insulin for you? Did he suggest you should take it? Mrs. HESSER. One did. Mr. DANNEMEYER. You declined to take it; is that right? Mrs. HESSER. Yes, that is true. Mr. DANNEMEYER. How long had you been using Alta-Dena's cer- tified raw milk products? Since .1974? Mr. HESSER. 1974, yes. Mr. DANNEMEYER. How often did you consume them? Mrs. HESSER. Every day. Mr. DANNEMEYER. Both you and your husband? Mrs. HESSER. Oh, yes, absolutely. Mr. DANNEMEYER. And did you, Mr. Hesser, experience any of the symptoms similar to your wife? Mr. HESSER. I did not become ill. For 2 months during the time my wife was pregnant, I was experiencing slight stomach upset and diarrhea. A stool culture showed I did not have salmonella at the time my wife did. At that time, I was working two jobs though, my full-time job during the day, and I had a part-time job in the evening. I would eat most of my meals out. I would catch dinner on the way to my second job and by the time I got home, it would be 11 o'clock and I would probably not eat at that time. So I was not eating at home normally as I would have been. Mr. DANNEMEYER. In any event, your wife said she consumed Alta-Dena's certified raw milk from 1974 onward. I would assume you would be consuming it in the home as well; is that right? Mr. HESSER. Yes, throughout the seventies and into the eighties. Mr. DANNEMEYER. I take it in that large part of that interval, you were not manifesting symptoms of illness yourself is that right? Mr. HESSER. Not that I felt I needed to be treated for, no. Mr. DANNEMEYER. Thank you. Mr. Telford, how long had your father been suffering this menin- gitis, I think, you described, or the cancer that you described? How long had he been-- PAGENO="0023" 17 Mr. TELFORD. The meningitis is a result of the Listeria monocyto- genes, and that manifested itself in the last week of his life. He had been diagnosed on June 6, 1982, as having cancer. Mr. DANNEMEYER. June 6, 1982? Mr. TELFORD. That is correct. Mr. DANNEMEYER. And prior to that time, was he in good health? Mr. TELFORD. Yes. Mr. DANNEMEYER. And I take it he began what? What type of treatment did he begin after the diagnosis in June 1982? Mr. TELFORD. Well, he went into the hospital. A biopsy was per- formed on the seventh, I believe, to determine what he had. The result was that they diagnosed a small cell carcinoma. He then began radiation treatment and one chemotherapy treatment in the hospital. He was released on June 14 and then returned 5 days a week to the hospital from the 14th until he returned to the hospi- tal in July, 1 day a week-sorry; 5 days a week for his radiation treatment, and I think a weekly chemotherapy treatment. Mr. DANNEMEYER. And did I understand correctly that you first purchased-when did he first purchase Alta-Dena's certified milk? Mr. TELFORD. It would be hard for me to tell you exactly, but I would say it was the first part of July, probably, as he developed the throat soreness. That was the first time that he purchased Alta-Dena's raw milk. Mr. DANNEMEYER. Where was the cancer in his body, in his throat? Mr. TELFORD. Upper right lung. Mr. DANNEMEYER. And do you know how many times your father purchased the milk before he passed away? Mr. TELFORD. At least three. There were three containers in the house. Mr. DANNEMEYER. Were these containers tested for what they may contain after his death or at any time? Mr. TELFORD. Two were empty and one was partially consumed and one of them tested positive. Mr. DANNEMEYER. For what? Mr. TELFORD. For salmonella dublin. Mr. DANNEMEYER. I see. Mr. TELFORD. That doesn't necessarily mean anything as far as I understand, however. Mr. DANNEMEYER. Well, we will let the scientists worry about that, I guess. Mr. TELFORD. Right. Mr. DANNEMEYER. Thank you, Mr. Chairman. Mr. WAxM~. I want to thank each of you for being with us today and helping us look at this issue from your own personal ex- periences. Our next witnesses represent physicians with personal experi- ences in assessing the risks of illness associated with raw milk. John Bolton is a pediatrician representing the American Acade- my of Pediatrics. Joshua Fierer is a physician and expert in the transmission of infectious diseases. Paul M. Fleiss is a physician in Los Angeles and secretary-treasurer of the American Association of Medical Milk Commissions. I would like to ask you gentlemen to please come forward. PAGENO="0024" 18 Mr. WAXMAN. We would like to welcome the three of you to this hearing. We know that you have prepared statements and, without objection, we will put the prepared statements in the record just as you have presented them to us. We would like to ask you, if you would, to summarize those state- ments so we can have time for questions and answers. Dr. Bolton, would you start. STATEMENTS OF JOHN BOLTON, M.D., ON BEHALF OF AMERICAN ACADEMY OF PEDIATRICS; JOSHUA FIERER, M.D., PROFESSOR OF MEDICINE AND PATHOLOGY, UNIVERSITY OF CALIFORNIA, SAN DIEGO SCHOOL OF MEDICINE, AND DIRECTOR OF MICRO- BIOLOGY AT THE VA MEDICAL CENTER IN SAN DIEGO; AND PAUL M. FLEISS, M.D., SECRETARY-TREASURER, AMERICAN AS- SOCIATION OF MEDICAL MILK COMMISSIONS Dr. BOLTON. Thank you, sir. The first comment I would like to make is that my prepared statement on the table over here is the one submitted in Septem- ber. I have submitted an updated statement which apparently is still in Mr. Waxman's office and didn't get brought over, so that will be supplied to the committee later. Dr. BOLTON. I am John Bolton, a board-certified pediatrician practicing in San Francisco, and I am designated as the representa- tive of the American Academy of Pediatrics on the topic of raw milk. My background includes 2 years as a medical epidemiologist with the Centers for Disease Control in Atlanta, GA, and I am currently on the faculty of the University of California in San Francisco as an assistant clinical professor of pediatrics. The data from the CDC have shown numerous instances around the country where salmonella and campylobacter have been linked to raw milk usage. For example, since 1977, more than 192 isolates have occurred in certified raw milk in California. This milk is transported across State lines by distributors. There are many organisms linked to raw milk use, but the two most seri- ous are salmonella and campylobacter. Campylobacter causes high fever and bloody diarrhea, similar to the usual salmonella infec- tion. Salmonella dublin, on the other hand, is not one of the usual salmonellae. This is a relatively new strain in this country having come in in the late sixties or so when it started to infect the herds. This is a very, very lethal bacterium. Seventy-five percent or more of the isolates of this germ come from outside the human gastrointestinal tract-this would be from brain, joint fluid or spinal fluid. Less than 5 percent of the usual Salmonellae are found outside the intestinal tract. For your run-of- the-mill salmonella, we are talking about a 5-percent hospitaliza- tion rate. For salmonella dublin, we see an 80-percent hospitaliza- tion rate. With salmonella, again the run-of-the-mill type, there is a death rate of 1 percent or less; salmonella dublin, 24 to 26 percent. It is an extremely virulent organism. It picks on the very young and the very old and weak. This has been pointed out here today in PAGENO="0025" 19 the testimony by the Hessers, by people like Megan Day, a little girl up in the East Bay now living in southern California. Her mother thought it was right to give her infant raw milk; gave her raw milk, shortly after which Megan developed a brain abscess with salmonella dublin. Her brain was operated on two dif- ferent times to drain this abscess. This child today has cerebral palsy, mental retardation, has a seizure disorder, epilepsy-all of this courtesy of salmonella dublin. Again, this is not the run-of-the-mill salmonella. Salmonella, some people say, is ubiquitous-everywhere. But it is not every- where. Salmonella is everywhere you find faecal matter. It is asso- ciated with the gastrointestinal tract of animals. Any place you find salmonella, you know there has been faecal contamination. As Mr. Dannemeyer pointed out, there have been outbreaks all over the country with various foodstuffs but the assumption in all these, if you check the CDC documents and look, is that most likely there was faecal contamination. There is one exception to this, one exception only that I know of, where salmonella does not have its origin or hometown in the GI tract of some insect or turtle or animal or whatever. That is in raw milk and in cattle. Salmonella dublin is a host-adapted organism. This means it doesn't live in you, doesn't live in us and colonize us, doesn't like to live in pigs, goats, and sheep and other animals. It is host-adapted to cattle and it is very sneaky in one special respect; that is, it can be carried in a nonsick animal and carried outside the intestinal tract where, instead of being shed in the stool, in the faeces as most salmonella are, it is shed intermittently in the milk. This is why the raw milk problem is so great, that no matter how much you clean the cattle, no matter how you scrub them or anything, if you have a shedder cow in a herd that is intermittently dropping these organisms in the milk, you have a great chance that people are going to get this milk and be contaminated or infected with it. No, there is a similar thing. You may have heard in your public health classes in high school and things like this, about typhoid, but what do we have, a bunch of four-legged typhoid Mary's? I don't know. Something happens to these cattle. It is like the ty- phoid Mary story, a woman who carried the typhoid germ in her gallbladder. By the way, typhoid is another salmonella, not as bad as salmonella dublin. Mary would go around and cook for people and she was loved by all, they loved her, but a large percentage of the people she cooked for died of salmonella. But here we have a cow with no malice to anyone, who doesn't have a fever or any- thing, and intermittently drops this organism in the milk. It would be great if there were some way that we could say that you could assure that raw milk on the marketplace was safe for consumption, but because of this simple fact, the fact of milk-shedding cattle, no matter how clean the dairy is, no matter how much you scrub the cattle, you have the risk of this bug coming through. You say, does it come through? This has been found in certified raw milk by 14 or 15 different agencies, including the State of Ari- zona, the State of Nevada, the State of California, 8 or 10 different counties in California, and the U.S. Food and Drug Administration. PAGENO="0026" 20 As a matter of fact, on two different occasions, the FDA picked up certified raw milk samples transported to Nevada, took 20 or 30 samples, cultured them to see if the salmonella was in there, and they found each time a range of between 10- and 20-percent con- tamination, meaning a consumer might be able to drink the raw milk and get away with it, but then again, you may have a chance that the organism is there in the milk. This is a product advertised as perfect food for infants. It is ad- vertised as a food for invalids. Every reputable health organization that I know of has come out and said this is not safe for infants. It is not safe for the elderly or people with any kind of debilatating diseases. Even the proponents' witnesses that have come forward to give testimony regarding this, the raw milk proponents-Dr. John Douglas from here in Los Angeles-was a witness at the FDA hear- ings back in November in Washington and reading from his tran- script: "The disadvantage of certified raw milk is there is occasion- al contamination with pathogenic bacteria." David Snydman, hospital epidemiologist, New England Medical Center at Tufts, brought out by the proponents to testify before the California Legislature, from a statement in his letter, if you read his letter: "It is my impression that there may be an increased risk of salmonella infection from ingesting raw milk." I could go on with this, further statements from Dr. Joseph Fleiss where he makes similar statements that there is a causal re- lationship there. So, to sum it up, I wish there were some way to make it safe. I don't think there is. Thank you. I would show your committee one thing I have just recently ob- tained. It is a copy of the warning sign being posted in San Francis- co now by ordinance that says you cannot sell raw milk in San Francisco without posting a warning sign to let people know that it should not be fed to the very old, very young, people with malig- nancy or immune deficiencies, and it is not pasteurized and may contain organisms that cause human disease. I don't know whether it will do any good, but it is a step. [The prepared statement of Dr. Bolton referred to follows:] PAGENO="0027" 21 STATEMENT OF JOHN BOLTON, M.D. My name is John Bolton. I am a Board Certified Pediatrician practicing in San Francisco, California. I am the designated representative of the American Academy of Pediatrics on the topic of raw milk. My background includes two years as a medical epidemiologist with the Centers for Disease Control in Atlanta, Georgia, and I am currently on the faculty of the University of California Medical Center in San Francisco as an assistant clinical professor in pediatrics.* The major goals of the American Academy of Pediatrics have always been the goals that would lead to the betterment of child health practices throughout the world. Our committees are actively working on guidelines for immunization, nutritional practices, child safety practices, and in many other fields which ---`impact- on children. One of our recent concerns has been the growing popularity of raw milk as a sup- -, posed 11health food." Our organization has reviewed both the nutritional proper- ties and the safety records of raw milk and has found that the risks outweigh the benefits. That is to say, there are no benefits of raw milk that would out- weigh the extreme risk of infection that sometimes follows feeding raw milk pro- ducts to Infants, children with malignancies, and children with problems Involving the immune system. Data from the Centers for Disease Control have shown numerous incidents around the country where infections with Salmonella and Campylobacter have been linked to raw milk usage. Since 1977, 192 isolates of Salmonella have been made in certified raw milk marketed in California. This milk is also transported across state lines by distributors. The most recent finding on September 28th of this year involved 4,000 gallons of certified raw milk which was distributed to con- sumers and retail outlets. It is obvious that many other instances of con- tamination may have gone undetected. There are many organisms that have been linked to raw milk usage, but the two most commonly noted at this time are Campylobacter and Salmonella dublin. Campylobacter causes high fever and bloody diarrhea, a disease indistinguishable from the usual Salmonella infection. Unfortunately, Salmonella dublin is not one of the usual Salmonellae. More that 75 percent of the human isolates of this organism have come from sites outside the gastro intestinal tract including * blood, brain and cerebro-spinal- fluid. This is a "host adapted" organism which is found almost exclusively in cattle, except for the times when it infects man with devastating results. When we consider that "usual" Salmonella infection, statistics from the United States and elsewhere reveal a 5 percent hospitalization rate and a death rate of less than 1 percent. Contrast these figures with S. dublin infections where more than 80 percent require hospitalization and approximately 25 percent die. The 1983 line listing of Salmonella dublin victims in California also indicates those who were raw milk drinkers. Significantly, out PAGENO="0028" 22 of 123 cases, 51 drank raw milk, and 1414 were customers of the same dairy. If you examine the comment column on the right you will note that the list of pre- existing diseases reads like the index to a pathology textbook: cancer, leuke- mia, lymphoma, cirrhosis, lupus, AIDS, etc. This points out one of the most tragic aspects of this problem. Seriously ill patients purchase a so-called "health food" only to be exposed to S. dublin. This product Is even advertised as a "basic food for invalids." (~xh4b1+-2) The proponents of raw milk sometimes bring up the fact that prison volunteers had to ingest up to 100,000 organisms in order to be infected with Salmonella. Since that study was done, it has been shown that some strains of Salmonella are so potent that it takes only a few organisms to produce illness. It is unlikely that there will be human experiments with Salmonella dublin, given its high case fatality rate. What about the milk itself, this milk that has been shown to be contaminated many times? Is there some property of milk that makes it a better rehicle for production of salmonellosis when it is contaminated? This is well exolained in a letter from Dr. William Foege, formerly Director of the Centers for Disease Control: "Milk contaminated with Salmonellae is particularly hazardous because the high fat content of milk pro- tects the pathogens from gastric acid, and its fluid nature shortens the gastric transit time ... We can conceive of no practical way raw milk can assuredly be safely marketed ... Unpasteurized (raw) milk is inherently unsafe. The Center for Disease Control supports pasteurization of milk and other dairy products." This is a product that is advertised as a "perfect food for infants." Could anything be further from the truth? While we are on the sub- ject of advertising, certified raw milk Is advertised in national magazines as "always pure ... wholesome ... healthful." The advocates have claimed that con- sumers know the risk they take in drinking raw milk. Our experience is other- wise. The parents of sick children ask us, "Why was there no warning that this might kill my child?". Although some people clearly ignore warning labels, shouldn't the consumer at least have a fighting chanqe, a chance to know that he is about to consume a product repeatedly contaminated with potentially lethal bacteria? As far a~ the claim by producers that certified raw milk is made safe by the practice of spraying the udders of the cattle with an antiseptic solution and then using two clean towels to wipe off, I would ask you the following question: Would you allow a surgeon to operate on you who said he did not need sterile rubber gloves since his hands would be sprayed with an antiseptic solution and then wiped off with two clean towels? This analogy is Important even though it may sound strained. It is not possible to prevent contamination of raw milk since potentially harmful bacteria still PAGENO="0029" 23 reside on the udders and inside some of the cattle as well. Cattle referred to as mammary shedders have been identified by the California State Department of Food and Agriculture. The industry attitude toward this problem has been to refuse to surrender such cattle for study even though requested by the - Department of Food and Agriculture. Another ploy of the industry is to point to other foods such as poultry which are frequently contaminated with Salmonellae, but not cultured as a routine ~praotice. What they fail to, point out is that these foods are intended to be cooked before consumption. Heat destroys Salmonellae. Pasturization, heat treatment of milk, is the only way to assure safe milk supplies. I would leave you with the following facts: 1. Certified raw milk has been found contaminated by more than 111 separate county, state and federal agencies. 2. Salmonella dublin, a host adapted organism for cattle, has been the most * frequent contaminants. 3. The antibiotogram "fingerprints" of the bacterium have shown a match between one certified raw milk dairy and the organisms found in the cases who drank that milk. - 11. Approximately 50 percent of the 19811 California Salmonella dublin cases were customers of the same dairy. * 5. The CDC has reported numerous instances around the country where Campylobacter and ~almonella infections, both sporadic cases and outbreaks, have been linked to raw milk usage. 6. The 1982 FDA investigation of' one major producer of certified raw milk showed numerous errors in lab techniques and Salmonellae on plates read as * "negative" by the dairy's lab. * 7. Culture of this milk on two other occasions by the FDA revealed 10-20 per- cent of the samples contained Salmonellae. Thank you for your time and attention. I am available to answer any questions, PAGENO="0030" 24 Mr. WAXMAN. Thank you very much. Dr. Fierer. STATEMENT OF JOSHUA FIERER, M.D. Dr. FIERER. Thank you for having me at this hearing. I am a physician who specializes in infectious diseases and professor of medicine and pathology at the University of California's San Diego School of Medicine, and Director of Microbiology at the VA Medi- cal Center in San Diego. I have written over 30 scientific articles about medical microbi- ology and infectious diseases and am associate editor of one of the two leading textbooks on infectious diseases published in the United States. I am here to tell you about my own personal experiences treating a dozen patients with salmonella dublin infections in the past 3½ years. I realize that salmonella dublin is not the only organism associ- ated with raw milk. However, it is more closely associated with raw milk than other salmonellas and even campylobacters, prob- ably because, as Dr. Bolton said, this is host adapted to bovine and is not found generally throughout the food chain. The other reason I want to concentrate on salmonella dublin is because it causes very serious infections in people, as you have heard from some of the previous testimony. Most salmonella infections are self-limited; they are illnesses characterized by fever and diarrhea that usually last 3 or 4 days and usually there is no serious morbidity. Most of the infections, in fact, go undiagnosed. Salmonella dublin infections are different and I will use my own clinical experience to illustrate this difference. First, in the United States at least, salmonella dublin affects pri- marily people at the extremes of life, infants and the elderly, and patients who have serious underlying diseases which compromise their immune responses. Second, when the infection occurs, it usually is a systemic infec- tion, not a gastrointestinal illness, but one characterized by blood- stream invasion and metastolic infections, abscesses, outside of the GI tract. We recently had a patient at University Hospital in San Diego that illustrates these properties of this organism very vividly. She is a woman in her midtwenties who had kidney failure and who required hemodialysis. She and her roommate drank certified raw milk for months and had no symptoms of infection, no ill-effects at all that either of them noticed. She was admitted to the hospital for her kidney transplantation and within 3 days of having the transplant-and immunosuppression while still in the hospital- she developed a high fever, 103 degrees, shaking chills. Blood cul- tures were done and salmonella dublin grew out. She ended up with an abscess of her cervical vertebrae and had about a 4-week hospitalization for treatment of that. This case illustrates the important points that I want to make about salmonella dublin: that is, a relatively healthy person, even somebody with chronic renal failure, can be exposed to salmonella PAGENO="0031" 25 dublin and not become ill. However, in the face of immunosuppres- sion asymptomatic infection turns into a potentially lethal one and this can happen very quickly. When salmonella dublin causes illness in an adult, it doesn't present as gastroenteritis-this woman had no diarrhea-but it presents itself as asepticemia. As a result of the invasion of the bloodstream, patients can die or suffer serious infections of their heart, blood vessels, brains, lungs, or bones. These infections are difficult to treat, partly because many salmonella dublin are resist- ant to the antibiotics we ordinarily use to treat salmonella infec- tions. Three of my 12 patients have died, 2 directly as a result of the salmonella dublin infection. The ability of salmonella dublin to invade the bloodstream distin- guishes it from most other salmonella. Since 1980, in my hospital, we have had 10 cases of salmonella septicemia-bacteria that iso- lated from blood cultures-and 7 of these were due to salmonella dublin. That is 70 percent of all the salmonella bacteriemias were due to dublin. That was true even though salmonella dublin represented less than 10 percent of all salmonella infections diagnosed in San Diego during that time period. That, I think, is illustrative of the particu- lar virulence of this organism. As I interpret information from the U.S. Department of Agricul- ture, salmonella dublin infections are now epidemic in the cattle herds of America, having spread through the West and Midwest. This bovine epidemic is now being reflected in humans with in- creasing numbers of salmonella dublin infections reported in the United States in each of the last 4 years. Raw milk is not the only source of these infections, but it is the single most common source and it is the source that can be effec- tively controlled with known technology-that is, pasteurization. Therefore, I would urge both State and Federal Governments to protect the public, protect the public health, and to require pas- teurization. Thank you. [Dr. Fierer's prepared statement follows:] PAGENO="0032" 26 Testimony of Joshua Fierer, M.D. Concerning Infection Hazard of Raw Milk U.S. House of Representatives Subcommittee on Health and Environment Introduction My testimony will be concerned with the clinical manifestions of Salmonella dublin infections in adults. Although S. dublin is not the only serotype of Salmonella that has been transmitted by raw milk, it is preeminently important in the context of this hearing for two reasons: 1) S. dublin is host adapted to bovines and is rarely found anywhere else in. the~fôod chain. Therefore, nearly all human infections with S. dublin are acquired either by direct contact with bovines (veterinarians and farmers), from eating raw beef, or from drinking raw milk. Consequently S. dublin infections can serve as a indicator of milk-borne salmonellosis. In contrast, other types of Salmonella are widely distributed in the food chain, so that even if a patient with salmonellosis drinks raw milk, it is difficult to incriminate that vehicle as the source of the infection in the absence of an epidemic; 2) 5. dublin infections in people are unusually severe. There has been an attemptb~ raw milk advocates to minimize the seriousness of salmonellosis. This review of S. dublin infection will provide evidence that S. dublin is capable of cau~Ti~j1ife threatening infections and must be considered a serious risk to raw milk drinkers who have predisposing illnesses. Backg round: Salmonella is a genus of bacteria that was discovered 100 years ago. From the very beginning this genus was recognized to be pathogenic for humans and animals. That is, Salmonella are capable of producing illness in otherwise healthy individuals under natural conditions of infection. Salmonella dublin (S. dublin) is one of nearly 1000 serotypes of salmonella.i~iff~rs from other serotypes of Salmonella in several ways: 1. 5. dublin is host adapted. The vast majority of SalmoneIIä~ serotypes can infect all animals. A few sero- types are host adapted which means they are found naturally in only a single animal species; Salmonella ~ the cause of typhoid fever, is host adapted to humans and S. dublin, in an analogous way, is host adapted to bovines. Serotypes such as S. enteritidis, which are not host adapted, are frequently ~ dUnt.ii~e in our diet so, they are the most common causes of Salmonella gastroenteritiS. One reason that S. dublin infections are uncommon in people is that our exposure is so limited. 2. S. dublin is metabolically different from other Sa1m~neIIh serotypes. For instance, S. dublin requires the vitamin nicotinic acid (niacin) for growth. This vitamin is abundant in cows. 3. The human disease caused by S. dublin is not primarily gastroenteritis, which is~i~rincipa1 illness caused by non-host adapted Salmonella. Instead, this organism invades the body through the intestine, producing very serious illness (see below). PAGENO="0033" 27 The Clinical Manifestations of S. dublin Infection: This discussion is based on my own experience with 12 S. dublin cases, and an unpublished series of cases from 1983 that was collected by the California Department of Health Services. All the cases were diagnosed in California and represent sporadic (non-epidemic) cases. The findings are summarized on tables 1 and 2. In general, the adult patients who were infected with S. dublin were "susceptible hosts." That is, they had some illness or physiological impairment that lowered their resistance. About one-third of the cases occurred in people over 60 years old, many of whom (15/55) were 70 or over., Some of these elderly people had no other known risk factors for infection, other than age. Treatments that decreased or eliminated gastric acid also predisposed to infection. This included people who had gastrectomies for ulcers and people who were taking antacids. Gastric acid is an important natural defense against all ingested pathogens. Pregnant women were also susceptible to infection. It is known that late in pregnancy the immune system is supp~essed, possibly due to hormonal changes, and pregnant women are more susceptible to other infections, such as tuberculosis. Most of the other patients had other illnesses or treatments known to suppress the immune response, such as leukemia, cancer, AIDS, organ transplants, and corticosteroid use. Only 21% of the patients had no known underlying illness and they tended to have mild disease, often only diarrhea. Table 1 Characteristics of Patients Who Developed S. dublin Infections Series V.A.M.C. California San Diego 1979-1984 1983 (% Positive) (% Positive) i~ge >60 58 30 Underlying Illness* 90 75 Cancer or leukemia 25 19 Liver disease o 5 Transplant o 5 Acquired Immuno- 17 5 deficiency (AIDS) Stomach disorders 33 5 Corticosteroids 25 14 Pregnant o 7 None s 23 :c~mbers of Patients** 12 43 5Patients may have had more than one underlying illness~ *~These 43 cases were abstracted from 123 that were reported in 1983. They are all the adults who had consumed raw milk or other raw dairy products. 52-266 0-85-2 PAGENO="0034" 28 Table 2 Clinical Manifestations S. dublin Infection V.A.M.C. California San Diego 1983 (% positive) (% positive) Hospitalized 90 84 Death 25 19 Bacteremia 90 58 (Positive blood culture) Extra-intestinal 42 26 infection Diarrhea 17 33 The manifestations of S. dublin infection in these patients were dramatically different frommost salmonellae infections. Nearly 90% of the patients were sick enough to require hospitalization. In two thirds of the cases, S. dublin invaded the blood stream usually causing a serious infection outside of the intestine. Examples of those extra-intestinal infections included: meningitis, endocarditis (infected heart valve), abscesses, and aortitis (infected aorta). About 20% of the patients died, directly or indirectly as a result of the infection. These findings distinguish S. dublin infection from nearly all other forms of salmonellosis. The usual illness caused by other Salmonella consists of diarrhea and fever that last about 72 hours. Rarely do adult patients require hospitalization, and only young infants have a high mortality rate. Only 10% of salmonellosis cases have associated bacteremia. What accounts for the dramatic difference between S. dublin and other organisms? There are two possible explanations that are not mutually exclusive. One is that S. dublin is more virulent for people than are other strains. There is precedent for this in that S. choleraesuis, a Salmonella that is host adapted to pigs, is exceptionally virulent and invasive in people. The second explanation is that the people who got infected are so impaired that they cannot defend themselves against this or any other Salmonella. There is indirect evidence to support this. In Scotland there was a large epidemic of S. dublin due to drinking contaminated raw milk. In this rural setting, nearly all the illness occurred in previously healthy people andthere were no deaths and no complications. This suggests that if healthy people are infected by S. dublin, they can limit their illness to gastroenteritis. However, I do not think the vulnerability of the host is the entire explanation for the behavior of S. dublin in California. Since 1980 there have been 10 cases of Salmoi~ella bacteremia at the V.A.M.C., in San Diego and 7 were due to S. dublin. Thus, S. dublin was represented far out of proportion. to the overall incidei~ce of S. dublin infection in San Diego County. PAGENO="0035" 29 Conclus ions In California, S. dublin infections have been very serious. They occurred in susceptible people who usually become very ill and some- times died as a result of the infection. The irony is that many of these people began drinking raw milk because they had some chronic illness and thought the raw milk was a "health food" that would benefit them. They had no warning, no way of knowing that the milk might be contaminated with potentially lethal bacteria. I think these people should be protected from this hazard. At the very least, they should be warned of the potential hazard so that they can make an informed choice as to what kind of milk they drink. At best, raw milk will be removed from sale. PAGENO="0036" 30 INFANTS AS A SOURCE OF In 12 of the 48 households where animals were kept, Sal- SALMONELLA the "baby type". Only once was the infant milk formula found to be positive and in 9 cases the animal feed. CONTA1~4I1~4ATION In ~% of the households Salmonella could be isolated from various surfaces. In 92% of these cases the type was M. VAN SCHOTHORST the same as that of the baby. These surfaces included those of the baby's bath, the bottle and nipple, playpen, dish cloth, rubbish bin, etc. The kitchen sink was found to be contaminated in 42% of the households, in 97% of these In the Netherlands, about 10,000 Salmonella strains are cases the "baby type" was isolated. isolated yearly from humans. Circa 9% of these originate The number of samples examined and the number of from infants, It is assumed that in most cases sainsonellosis samples found positive are presented in Table 2 as well as of older children and adults is caused by consumption of the number of samples from which the "baby type" was iso- contaminated foods. It is not likely that food is the cause of lated. the infection as long as the baby is being breast or bottle When the columns indicating the total number of posi. fed. Also after weaning the infant is mostly fed with Salmo- tives and the number of samples with the "baby types" are nella free food, suth as canned food, biscuits and freshly compared, it is evident that in most cases the Salmonella prepared, adequately heated meals. isolated from the various samples was of the same type as Since little is known about how a baby catches salmonel- that found in the faeces of the baby. It is possible to think losis, an attempt was made to try and obtain information of various sources of these household contaminations. on the methods of food preparation and hygiene habits in a Animals are frequently regarded as an important res- household with a case of infant salmondllosis. Such ervoir of Salmonella but it is highly improbable that ani- households were visited and farces of the baby and also of mals or animal feed have contaminated the kitchen sink other inhabitants, pet animals, relevant foods, swabs from and other surfaces. Also in those households where no pets kitchen sink etc. were examined for the presence of were present, a high percentage of the kitchen sinks were salmonellae. Furthermore, by talking to the family, an idea found to be contamined with the "baby type". of the hygiene awareness of the family was obtained. Human carriers could be the source of the "baby type" During the course of these studies, although it became but only in 36% of the homes such carriers were actually * apparent that the causes of infant salmonellosis were diffi- found. Although animal and human excreters cannot be cult to identiI~', a new source of contamination of a house- excluded as the origin of the infection of the baby, it is hold was discovered. This paper deals mainly with the 1st- much more likely that the babies were the source of the ter aspect. household contamination. The studies were carried out in the Netherlands in the This assumption is substantiated by the results of the National Institute of Public Health (Bilthoven) and the quantitative examination of faeces of some of the babies. mtdical center in Rotterdam. These results revealed that during various periods of time, During a period of one year 74 households were visited high numbers of Salmonella may be present in the faecal by public health nurses, one or more weeks after a case of material. It should be mentioned here that often the babies infant sa.lmonellosis was diagnosed and confirmed. were fully recovered after only a few days of illness and The samples of faeces, foods and swabs were examined their farces looked completely normal. according to the EEC standard method using buffered pep- When a mother is attending to baby's toilet, it is clear tone water for pre-enrichment during 16 to 20 hours at that a hundredth of a gram of faecal material may easily 37"C, tetrathionate brilliant green bile broth for enrichment adhere to the fingers. When this baby is excreting a million at 43uC for 48 hours, and brilliant green agar as selective salmonellae per gram, a thousand can thus remain on the agar. hands of the mother. Via the mother's hands other mem- A surprisingly great variety of different Salmonella scm bers of the family, animals, foods and surfaces may become and phage types were found, namely 15 serotypes, 4 phage contaminated and the infant may even become reinfected. types of Salmonella panama and 16 phage types of Salnso- This assumption is strongly supported by the finding nella typhimurium. in 74% of the households, however, the that only 0.6% of the family members were infected with Salmonella type isolated from the other people, surfaces, another Salmonella type (a percentage that is more or less etc. was the same as excreted by the baby (the "baby type"). normal for carriership) while 17% were infected with the The most important Salmonella findings in the various "baby type". households are presented in Table 1. In 31 of the 74 house- This risk of contamination may occur over long periods holds where farces of the family was collected, at least one of time as can be learned from Figure 1 and Table 3. In the of the family members was excreting Salmonella, and in 27 figure two excretion patterns are illustrated, both indicating of the households (36%) they were excreting the "baby that several months after illness, quite a high number of sal- type". monellae may still be present in the faeces. In Table 3, the TABLE t Salmonella isolations in 75 households. TABLE 2 Salmonella in household-samples. Number of households Number of samples With With Examined Positive "balpy~ype~ Examined Positive "baby type~ Human faeces 74 31 27 Human faeces 232 44 39 Animal faeces 48 12 11 Animal faeces 84 15 14 Baby food 49 1 1 Baby fisod 65 1 1 Animal feed 31 9 5 Animal feed 63 9 5 Kitchen sink 73 31 30 Kitchen sink 140 39 -- 36 PAGENO="0037" 31 TABLE 3 Time of salmonella excretion. -~ >9 months 4 babies >7 months 8 babies > 5 months 14 babies >3 months 22 babies Eeamiaed: 25 babies lag N ~5moxths FIGURE 1 Salmonella exaction pattern of two babies. periods during which 25 non-selected babies were excreting Salmonella is presented. It is disquieting to fond that almost 90% of these babies were excreting Salmonella for more than 3 months. In conclusion it is clear that babies who had at one time Salmonellosis may continue to be an important source of salmonellae in a household. However, many cases of Sal- monellosis go undetected, therefore it can be stated that to limit the spread of salrnonellae in households, on any occasion, mothers should wash their hands very carefully after attending to the baby's toilet and adhere more closely than normal to the basic rules of food hygiene. REFERENCE I. VAN SCHOTHORSTM., Htt/SMANJ. axdVANOtM.,N,tT.G,e,xk 197n, 822, 1121-1125. Ae&*catdgeretThuarnrtrJ5,aappea,elie Pexxd~egi#f:beXx:h txeea,ie~.,t H)ge*eS)ep,~~en - ~ 31-32, 1981'. a,,Ireu,egarf~O8. Tb. G.!d- Q 6mnuth, BOVINE MILK ANTIBODIES IN THE TREATMENT OF ENTERIC INFECTIONS AND THEIR ABILITY TO ELIMINATE VIRULENCE FACTORS FROM PATHOGENIC E. COLI J.-J. PAHUD, H. HILPERT, K. SCHWARZ, H. AMSTER AND M. SMILEY Diarrhoeal diseases as a group, are known to be the major single killer in several areas of the world. Infectious diarrhoea itself remains an essential problem in pediatrics, as dehydration and electrolyte losses in premature and new- born infants, frequently have a fatal outcome. The gut asso- dated lymphoid organs are not yet fully developed in the newborn child, who is particularly vulnerable to enteropa- r.hogenic microorganisms. Maternal antibodies transmitted to the human foetus in utero consist mostly of 7S IgG, but do not include any IgA [1-2]. These antibodies remainpri- manly in the child's blood, and the limited amounts of lgG transferred to the intestinal mucosa are unstable in the secretions and demonstrate only weak activity against the enreropathogens. Mother's milk plays an essential role in compensating this deficiency by transmitting protective fac- tors to the infant's digestive tract, induding immunoglobu- lins (mostly secretory IgA), lactoferrin, lysozyme, lympho- cytes and macrophages. It is now well established that breast-fed infants show a significantly higher resistance against bacterial and viral infections, compared to infants fed with adapted cow's milk [3-5). In the formulation of artificial infant milk, priority is usually given to the nutritional value and safety of the pre- paration, but little attention is paid to the sheer absence of immunobiological factors. Passive oral immunization using milk immunoglobulins from specifically vaccinated cows was first proposed by Petersen and Campbell [6). These authors dalmed that the intestinal resorption of milk anti- bodies was sufficient to induce general humoral immunity. Current evidence tends to disprove the transmissiunper Os of significant immunity to the circulation of the newborn infant [2]. However, as an alternative to mother's milk, oral administration of bovine milk antibodies may contribute to the local immunity of the infant's gut against human ente- ropathogens. Several aspects of this concept previously under discussion will be briefly reviewed, namely the speci- ficity of bovine milk antibodies, their stability during tech- nological processing, antibacterial activity, resistance against difestion efficiency in clinical trials and absence of toxicity The antibody specificity of cow's milk was actively induced with a polyvalent vaccine incorporating the entero- pathogenic E. coli (EPEC) serotypes most frequently encountered in infantile gastroenteritis. After skimmin colostral milk and precipitating casein, the imniunoglo u- lins were concentrated from lactoserum by ultrafiltration. Diafiltration was applied to remove lactose and mineral salts. Sterilization was performed by filtration and drying by lyophilisation, in order to avoid denaturation by heat treatment. The antibody activity was fully retained through- out the entire industrial processing. The immunobiological activity of the antibody prepara- tions was demonstrated on v:oni by passive hemagglntina- ton, bacterial agglutination and bacterial growth inhibition. 0 PAGENO="0038" 32 Mr. WAXMAN. Thank you very much, Dr. Fierer. STATEMENT OF PAUL M. FLEISS, M.D., M.P.H. Dr. FLEISS. Thank you. I am Dr. Paul M. Fleiss. I am a board cer- tified pediatrician in the private practice of pediatrics in Holly- wood. I am assistant clinical professor at the University of South- ern California School of Medicine. I am a lecturer at the UCLA School of Public Health. I am on the staff of Children's Hospital, Los Angeles, Cedars-Sinai Medical Center, and several other hospi- tals in the Los Angeles area. I am also on the professional advisory board of La Leche League International. That is an organization that you might be familiar with. It is involved with support of mothers breast feeding their infants. I am also the chairman of the Los Angeles County Milk Commis- sion. The Los Angeles County Milk Commission is composed of four physicians, one veterinarian, and one public member. But it is our job to ensure that raw milk meets the standards. Our job is to certify, and our standards are set by our commission and the American Association of Medical Milk Commissions. We check milk, raw milk daily for the total number of bacteria, and number of coliform bacteria. We check for salmonella on a once-a-week basis from raw milk that is sold. It is my belief that this raw certified milk is a healthy, safe prod- uct to consume. I would like to-I would say that I would like to comment on my colleagues' statements but I am not going to do that. Also the people that had the very unfortunate experiences, I would like to comment on those but I will not do that at this time. I would like to review what exactly pasteurization is. It is the heat treatment of milk. It in no way guarantees the safety of milk. Pasteurization will kill approximately 90 percent of the bacteria that are found in milk. There have been many milk-borne epidemics that have been caused by pasteurized milk. So I would like to make that clear. Pasteurization was not a process invented for milk. It was begun for wine and beer more than 100 years ago. It was used on milk because there was a time in the beginning of the century when there were milk-borne epide- mics which were quite common. There was TB and brucellosis, spread by milk. And it was a very important public health measure at that time. Milk-borne epidemics had to be stopped, and pasteuri- zation was effective in putting an end to milk-borne epidemics of TB and brucellosis. But this is not the turn of the century. This is 1985 that we have now a great deal of change that has taken place in dairy technolo- gy. We might say it is not the same to practice medicine in 1900 as it is in 1985. Modern dairy technology has allowed us to produce milk that is free from contamination. You~an take healthy cows, check the cows. You have very sterile equipment. You have milkers that are checked for disease, trained especially in sanitation methods. You can have the whole process being overlooked by a sanitarian, regis- PAGENO="0039" 33 tered sanitarian. And you can have a process where the milk is checked for bacteria. You have a process that can allow raw milk to be sold that is safe from contamination, whereas, pasteurization alone is not enough to guarantee that milk is going to be safe. In a lot of cases we have dairies that can use sloppy milking techniques and techniques that are outdated and pasteurize their milk; and the pasteurization is rather an excuse for good sanita- tion, and this should never be. I have visited dairies all over the world. I can tell you that in some places they, like in England and I visited dairies in Scotland, those using equipment that has been essentially outdated in the United States for the last 40 years. I saw milk being delivered in horse-drawn carts, unrefrigerated carts. We don't have those condi- tions here in the United States. It is possible to produce milk that is free from contamination. One point I would like to make, some dairies do not only pasteur- ize milk, they are sterilizing the milk. There are standards that are set for the minimum pasteurization but in a study we did that was done by Dr. Anderson at Cal State, Los Angeles, it was found that a study of bacteria contents of pasteurized milk, there were patho- gens in pasteurized milk such as proteus and other known causes of human disease in samples of pasteurized milk. But we found some samples of milk where there were no bacteria, which means that the dairies were not only pasteurizing their milk, they were sterilizing it, submitting it to temperatures that were well beyond the standards for pasteurization. Some people might say this is, might be a good thing to do be- cause you have sterilized the milk but actually what you have done is changed a good deal of the nutrients. We not only have a prob- lem in the United States with infectious disease, but we have a problem of nutrition. And we have a problem where milk is one of the major sources of human nutrition. It has been estimated that milk and milk products make up 25 percent of the diet of Ameri- cans. Now if we are going to substantially decrease the nutrients of one of the major products of our diets, we will have more people that are susceptible to infectious diseases. Of course, the average consumption in the United States is about 6 ounces of milk per capita. There are quite a few people who don't drink milk at all, and some drink a great deal. Where there have been epidemics of salmonella dublin in other parts of the world and indeed the person with the most experience with salmonella dublin is Dr. Sharp, who reported on his findings in the British Medical Journal, and he did not have the experience that has been found in the United States that it was a particular virulent organism. His statement was that illness from salmonella dublin more likely results from the impairment of the host than from invasiveness of the organism. The heat treatment of milk does a lot of things to it. Now, you don't have to be a biochemist and measure what the heat treat- ment does to milk. You can just go and look at the pasteurization tanks and after milk has been pasteurized there is a residue that has to be scaped from the sides of the tanks as this represents cal- cium and casein deposited on the sides of the tank in pasteuriza- PAGENO="0040" 34 tion. So, we don't have to ask for studies to tell us that milk that is heat treated has less protein in it. It has less available calcium. And heat treatment of milk destroys some of the immunoglobulins found in milk. Some of these immunoglobulins have been found to be effective in human disease. Heat treatment of milk does destroy the enzymes present in milk. There are enzymes in milk such as lactase, which splits lac- tose. This is a concern for people that have lactose intolerance, and a good deal of the adult population has lactose intolerance. There are many reports of-from consumers saying they can tolerate raw milk, and they cannot tolerate pasteurized milk. This has been stated to me many, many times. Of course, this might be due to the presence of the lactase enzyme that is present in raw milk. There is also lipase in raw milk. This is why some- times raw milk in storage can deteriorate because of the liberation of free fatty acids. This has an advantage for people possibly with fat absorption problems. There are also vitamins and minerals. You might say 25 percent of the vitamin contents on average are changed or altered by the heat treatment of milk. Many consumers of raw milk have stated to me that they were very sickly before they began consumption of raw milk, and they have-that they owe their good health to avail- ability of raw milk in Los Angeles County. I would like to say my experience, I came about my opinions mostly from my experience of dealing with patients. When I first started in private practice of pediatrics I would advise people not to drink raw milk or raw certified milk. But it wasn't long before I was in practice. Since I was in Hollywood, I have a very large number of patients who depend on raw certified milk. They would come, they came to me and said they were drinking the milk. I can remember advising people they should never do this. But enough people came in with nice robust healthy babies that I began to ask them more about that. They told me where they were buying the milk. I called up the dairy. I talked to the veterinarians. Then, of course, I visited the dairy and I saw the process for myself. I became more and more convinced that what I had been taught in my public health courses in medical school had been outdated by modern dairy technology. I would like to say that there are a lot of critics of raw milk who have never visited the dairy and don't have any experience with the way it is produced. I would say that it was patients and consumers-and there are many of these, and at times the dairy produces 18,000 gallons of milk a day. If you think the average person drinks approximately 6 ounces of milk a day, you don't have to be a biostatistician or epi- demiologist to know there are a lot of milk drinkers out there, per- haps 100,000 to 200,000 people per day. Then if you end up with-I don't have the figures in front of me. But a few scattered cases of salmonella you see the incident relatively low. Of course, as far as I know, there has never been a cluster, what epidemiologists term a cluster of disease attributed to the consump- tion of raw certified milk. [Dr. Fleiss' prepared statement follows:] PAGENO="0041" 35. STATEMENT OF PAUL M. FLEISS, M.D., M.P.H. PEDIATRICS, PEDIATRIC NUTRITION Dairy technology has advanced a great deal since the early 1900's. While pasteurization was once the only way to prevent the spread of milk-borne diseases such as tuberculosis and brucellosis, their procedure is not now enough to guarantee the safety of dairy products. Milk must be produced under the most stringent of standards and under constant supervision to ensure its sanitation. Once milk is produced with modern advances in technology and strict regulations such as those of the A.A.M.M.C., pasteurization is not necessary and obsolete. Raw milk should be available to the consumer for the following reasons: 1. Fre~edom of choice. Many people prefer to eat their food unheated. This should be obvious by observing the popularity of Japanese sushi bars in the U.S. Also many people ingest raw oysters, beef liver and steak on a regular basis. Food intake histories on a random basis have revealed that people eat a wide variety of food products, heated and unheated. 2. ~1~aste. Unheated milk does not taste the same as pasteurized milk. One does not have to be a physician or scientist to make this observation. 3. Nutritional benefits. Major nutrients are decreased 10-50% by the heat treatment of food(l). This would not be significant except that milk products comprise 25% of the American diet and for some few individuals this could mean the PAGENO="0042" 36 difference between health and a deficiency state. 4. ~ This begins prior to the milk reaching the stomach. The lipase found in milk splits off free fatty acids and is responsible for the rancid flavor of unheated milk as it ages. The presence of enzymes (lipases) is the reason *why ice cream made from raw milk cannot be stored. The lactase present ,in milk breaks up some lactose into glucose and galactose. Both glucose and galactose are sweeter than lactose. This is why raw milk often tests sweeter than pasteurized milk and why many people with lactose intolerance report that they are able to tolerate raw milk and not pasteurized milk. 5. Antibo~lies. These have been found in raw milk and they have been effective against enteric infections. 6. Processing. Many dairies are not pasteurizing their milk but are sterilizing the product. Milk is now being subjected to very high temperatures in order to reduce the bacteria found because of poor dairy practices causing obvious contamination. Many new substances, especially altered antigens, formed from heat treatment, and the health effects of such treatment are unknown but to some people present additional health hazards(2). 7. Safety. Milk produced under the standards of the American Association of MedicalMilk Commissions has not been associated with any clustered outbreak of disease. On the other hand, outbreaks of disease have been traced to pasteurized milk. Milk, raw or heated, may be a source of vital nutrients and of disease as well. There is a need for unbiased scientific investigation into the ramifications of changing this food. After all, the raw unheated product is the oldest known food of baby mammals and mankind. Since the studies of raw versus pasteurized milk are all suspect, what is needed is for an unbiased group to scientifically design a study of weanling laboratory animals raised exclusively on pasteurized or unpasteurized milk. Only then will we have the data necessary to weigh risk versus benefit in this matter. PAGENO="0043" 37 CERTIFIED RAW MILK: IS IT WORTH SAVING? Milk of animals has been used as human food since before--the beginning of recorded history.' In the United States the unqualified term, milk, is usually considered to refer to cow's milk, since virtually all milk destined for human consumption is from the cow. Although similar constituents are pres~nt in the milk of all mammals, the proportions of constituents vary greatly among each individual mammal. The milk of each species is unique and is a complete food for its young for a definable period of time after birth.2 Human milk, raw and direct from mother's breast, is without question the food of choice for humans for the first six months of life. There have been many reports of antiviral and antthacterial properties of human milk being destroyed 3,4,5,6,7 by heat treatment, and calcium and fat absorption are decreased by heating human milk.8 Raw human milk has mitogenic activity which heated formula does not.9 Further, animal experiments have repeatedly demonstrated that newborn animals survive best with raw colostrum milk.2 On the other hand, pasteurization of milk has been one of the significant public health events of the last 80 years. It virtually stopped milk-borne epidemics - and partially solved the problem of milk spoilage. It has been responsible for the milk industry growing from virtual obscurity to a giant of t~e food industry. (The pediatrician, Henry Koplik, M.D. [of Koplik spots fame) was one o the early advocates and promoters of the heat treating of milk for infants.7) The growth of large cities at the turn of the century made pasteurization a necessity as milk was produced under unsanitary conthtions, handled without medical supervision of workers and transported without refrigeration before being consumed. Pasteurization is not -sterilization, but it can destroy 90% of the bacteria present in milk. Still, bacterial opores and thermoduric bacteria may survive pasteurization, and although thene organi ems usually PAGENO="0044" U do not cause disease, they may produce intestinal gas under anerobic conditions in the colon. Raw milk, by comparison, is milk that has not been heated. Thirty-one states in the United States allow raw milk to be sold. There is no medical super- vision of the producer or the bottler (if it is bottled). Raw milk is usually marketed directly from the farm to the consumer and has been assc*iated with disease outbreaks in humans.1° Certified Raw Milk (CR11), not to be confused with Raw Milk or pasteurized Milk, is produced by dairies operated in accordance with the Methods and Standards adopted by the American Association of Medical Milk Commissions ~`\AMMC) and under the direct supervision of a local Milk Commission. `Certified Raw Milk is a basic product and must be pure, clean, fresh, nutritious milk in its natural state, not having been heated and without the addition of coloring agents or preservatives" is the definition of Methods and Standards of the A.A.M.M.C.11 CR11 bears the certification of a county milk commission. In Los Angeles County, the los Angeles County Milk Commission consists of six members residing in the county, presently comprising four physicians, one veterinarian and one public member11 appointed by the Board of Supervisors for a term of four years. Standards for CR11 state that the milk must be tested daily by an inde- pendent bacterialogical laboratory. Allowed total bacterial count is less then 10,000 per ml and total coliforms less than 10 per ~i.l2 Cows in the dairy herd are checked regularly for tuberculosis, ~rucella and Salmonella. All employees areTgiven regular physical examinations, and all equipment used in producing CR14 is checked by a sanitationist employed by the milk commission. Alta Dena Dairy, the only producer of CRM in the State of California at the present time, has 8,300 cows in their Certified herd that produce 20,000 gallons of CRM each day. This means that approximately 160,000 Cal1fOrnIu"~ drink CR11 every day, and there are probably une mill ion users of CkM, represent jog PAGENO="0045" 39 about 5% of the State's population. Alta Dena Dairy also produces Pasteurized Milk. (CRM represents about 20% of their total milk sales.) The dairy has a reputation for being a model for the industry. Consumers, dairymen and interested physicians may tour the dairy on any day. Cows producing CRM are washed carefully before each milking and then milked by electric vacuum milkers, taking milk to coolers without touching air or human hands. All equipment is kept clean, and surfaces coming in contact with the milk are sterilized before and after each run of milk. Consumers of CRM obviously believe strongly in the product as the demand has continually grown in recent years despite recommendations of some medical authorities. Some of the reasons consumers give for demanding CRM are: (1) Pasteurization, although it eliminates harmful bacteria from milk, does not eliminate dirt, and pasteurization promotes carelessness in milk production sanitation. (2) CRM has a superior taste and tends to stay fresh longer. (3) Vitamins are destroyed by heat: pasteurization reduces vitamin content of milk by 10 to 40%. (4) Minerals are not as available for absorption after pasteorizat ion. (5) Fat absorption decreases after pasteurization. (6) Pasteurization destroys enzymes present in silk. (7) Protein is partially denatured by pasteurization. (8) Homogenization is a factor in heart disease as Bovine Xanthine Oxidase then can be absorbed in a form which damages arteries. (9) Pasteurized Milk Protein is more likely to be allergenic than unheated milk. (10) Experimental animals fed unheated milk were much healthier thaii those fed pasteurized milk. PAGENO="0046" 40 Discussion Milk, an important source of nutrients in the lanerican diet, his been recognized as a vehicle of infection for over one hundred years. infection `miy occur in two ways. One is from direct infection from the cow; the other is by infection of the milk during its passage from cow to consumer. Even though the consumer should feel secure that milk is nutritious and free from diseise carrying organisms, neither pasteurization nor certification can absolutely guarantee the absence of pathogens in milk when it is consumed. Uncertified, however, is far more likely to contain disease carrying organisms. There are many reasons why consumers may desire to ingest unheated milk; some may be valid, but some are not, as milk is only one source of nutrients in the diet. These consumers are willing to accept the small risk of infection associated with drinking CRM. Indeed, CRM buyers have expressed rage that some medical people attack CEM while tacitly condoning vastly more dangerous substances, i.e., tobacco, marijuana and alcohol. And although no proof exists that adult humans and their offspring should drink cow's milk, many consumers will find raw milk to drink if CRM is not avinlablc: this could become a severe Public Health problem. We therefore ;uspect phynic)ins, consumers and Public Health officials should support the market~';y of CRM since there is such a large public demand for this reasonably safe and nutritious product. PAGENO="0047" 41 REFERFNCES 1. Whittier, E.O.: Encyclopedia Britannica, 1968, Vol. 15, pp 446 2. Jelliffe, D.B.; Jelliffe, E.F.P.: Human Milk in the Modern World, Oxford University Press, 1978 3. Bjerksten, Bengt; Berman, L.G.; Dc Chateau, P.: Collecting and Banking Human Milk: To Heat or Not to Heat, British Medical Journal, 2d1:765, 1980 4. Matthews, T.H.J.; Lawrence, N.E.; Nair, C.D.G.; Tyrell, D.A.J.: Antiviral Activity in Milk of Possible Clinical Importance, Lancet, Dec. 25, 1976, 1387-1389 5. Ford, J.E.; Law, B.A.; Marshall, V.M.E.; Reiter, B.: Influence of Heat Treatment of Human Milk on Some of its Protective Constituents, The Journal of Pediatrics, Vol. 90, No. 1, pp 29-35, Jan. 1977 6. Raptopoulou-bigx, M.; Marwick, K.; McClelland, D.13.L.: Antimicrobial Proteins in Sterilized Human Milk, British Medical Journal, 1977, 1, 12-14 7. Hall, C.; Trout, C.: Milk Pasteurization, Avi Publishing Co., 1968 8. Williamson, S.; Finulane, E.; Ellis, H.; and Cansu, I.R.: Effect of Heat Treatment of Human Milk on Absorption of Nitrogen, Fat, Calcium and Phosphorus by Preterm Infants, Archives of Disease in Childhood, ]97fl, 53, 555-563 9. Klagsburn, N.; Neumann, J. and Tapper, D.: The Mitogenic Activity of human Breast Milk, Journal of Surgical Research, 26, 417-422, 1979 10. California Morbidity, April 10, 1981, No. 13 11. Food and Agricultural Code, Div. 15, Article 7, p 466 12. TJe American Association of Medical Milk Commission, Inc.: Methods and Standards for the Production of Certified Milk, Revised 1981 PAGENO="0048" 42 Mr. WAXMAN. Thank you very much, Dr. Fleiss. Dr. Fleiss, your testimony was at odds with what we just heard from Dr. Fierer and Dr. Bolton. If I understand correctly, Dr. Fleiss questions the infectious nature of salmonella, first of all, whether it is as virulent as Dr. Fierer would claim and; second, whether it is in raw certified milk and; third, he claims sometimes it is in pas- teurized milk and that pasteurization isn't a certain enough way of eliminating infection. And, fourth, that pasteurization can lead to less nutrition in milk. Dr. Fierer, Dr. Bolton, would you respond to those points, if I stated them correctly, and I think I have. Dr. FIERER. Is it a correct statement? Dr. FLEISS. Yes; that was a very good summary. The only thing I would like to add is that pasteurization is not enough to guarantee the safety of the milk. We need strict standards of sanitation. Then what you have is strict standards of sanitation and then pasteuriza- tion is no longer necessary. Mr. WAXMAN. Let me just isolate it because otherwise my ques- tion is so broad we will get the testimony repeated. Let's take some of these more narrowly. Dr. Fierer, do you be- lieve pasteurization is a sufficient process to prevent any infection and, two, do you believe that the way the raw milk is handled without pasteurization is a way to ensure that there is not going to be infection communicated to people? Dr. FIERER. I am not-I am a physician, not an expert in milk handling. But obviously pasteurization is not sterilization. It is not an attempt to kill all microorganisms in the milk. If you contami- nate the milk heavily enough with whatever organisms, then pas- teurization will not completely eliminate the hazard from the milk. One hopes that the dairy industry doesn't do that. On the other hand, what we are hearing is an attempt to substitute sanitation for pasteurization. The issue is will that ever be completely effec- tive. From talking with veterinarians who specialize in bovine in- fections, I can tell you that this infection, salmonella dublin infec- tion, can remain latent in the cattle. The cattle, when stressed, re- activate the infection-calving is such stress-and in these circum- stances the organism circulates in the blood, and appears in the milk excreted directly. There is no way that amount of sanitation can prevent that. Mr. WAXMAN. In other words, if I went to Alta-Dena Dairy and found them to be very sanitary in how they handled the cows and the milk and then went through the procedures in how they try to take special precautions to be sanitary, I-- Dr. FIERER. Terrific, but it doesn't eliminate the problem. Mr. WAXMAN. Why doesn't it eliminate the problem? Dr. FIERER. Because of the direct shedding into the milk. If Alta- Dena wasn't as careful as they are-and I believe that, that they are extraordinarily careful in the way they produce their milk-we would have epidemics as they have had in Scotland over the years. There, when the milk is heavily contaminated through gross fecal contamination then everybody gets ill who drinks it. Mr. WAXMAN. If they used sanitary methods they probably elimi- nated a lot of potential. Dr. FIERER. Absolutely. PAGENO="0049" 43 Mr. WAXMAN. But as careful as they might possibly be, it is your opinion that because of the fecal discharge by the cow there is still going to be some transmission of infection? Dr. FIERER. Because of the milk discharge. Mr. WAXMAN. The milk discharge. Dr. FIERER. Milk discharge, that is right. Mr. WAXMAN. Dr. Fleiss, what do you say to that? Dr. FLEI5s. I think that this question of shedding is not a uni- formly accepted process. Theoretically it is possible but also theo- retically this means that the bacteria cross from the blood to the milk. This is not a usual kind of procedure that happens in the process of milk being formed. So, shedding is really in theory. It is not really established fact. I think again, if sanitation isn't good, well, pasteurization isn't a guarantee either. There are numerous studies that have shown that there have been disease-causing bacteria in pasteurized milk samples. Mr. WAXMAN. Do you deny there are disease-causing bacteria in raw milk? Dr. FLEIs5. Well, there may be. Mr. WAXMAN. Do you think there is never any disease-carrying bacteria in raw milk? Dr. FLEI55. No; I can't guarantee that. I think the possibility is always there. Mr. WAXMAN. Is the possibility equal if the milk is pasteurized on the one hand or raw on the other? Dr. FLEIS5. My personal belief is that it is probably greater, there is more chance of disease-causing bacteria being present in pasteur- ized milk because I do not believe that the majority of the dairy industry sticks to the strict sanitary conditions that the producer of raw certified milk does. Mr. WAXMAN. Dr. Fleiss, your views are so at variance with the other two witnesses, but also with the American Academy of Pedi- atrics, A.M.A., American Public Health Association, all those groups are on record opposed to the use of raw milk because they believe it is a risk to the public health. Dr. FLEI55. Yes. Mr. WAXMAN. In light of their views, what special expertise or data do you have or how do you explain why they have such an overwhelming consensus of those groups saying there is a greater chance of infection from raw milk, and your contradicting them? Dr. FLEI55. I would like to say that historically they are correct, but they are perhaps 40 or 50 years behind the times. I think that we had a time when milk-borne disease was a real threat to our health, when TB and brucellosis were extremely rampant and we needed some guarantee. At that time pasteurization was a miracle. It was like the advent of penicillin or other modern major ad- vances. But now we have come further than that. I think that with time there has been a lag in the appreciation of nutritional bene- fits by all of those organizations that you have mentioned. I think the American Medical Association, American Academy of Pediatrics, American Veterinarian Association, they have all been a little-they have been lagging behind in their appreciation of what nutrition means to Americans. PAGENO="0050" 44 Mr. WAXMAN. Let me ask you this question. How do you handle the suggestion that there are some groups of people that are more vulnerable to infections, such as babies, people who are suffering from some disease, or the elderly? Do you dismiss that or do you think that that is more likely a group to be affected? Dr. FLEISS. Oh, no, as I stated, pregnancy, the very young infant, debilitated, the cancer patient, the patient that is under chemo- therapy, the patient that has had radiation therapy-these are spe- cial groups of patients. They are very vulnerable to disease-causing organisms. They should, of course, be treated as such. I think when a patient does have a debilitating disease or cancer or is being treated by immunosuppressive drugs, that they should be warned about the potential for infection, potential for infection both from food, from water, and from other persons. Certainly these people are at risk for infections from-their physicians should warn them to stay away from sick people, for instance. But that doesn't always happen. Mr. WAXMAN. If you recognize there are some groups that are at higher risk of infections, do you think we ought to look with special care when there are products such as raw milk that are targeted for those markets, the children, elderly-the very people who want to make sure that they are getting the best health care because they happen to be sick already? Dr. FLEI55. I don't think that raw certified milk is targeted for sick individuals. I think that you will find that healthy people are consuming raw certified milk-- Mr. WAXMAN. Let me interrupt you and place in the record a publication put out by Alta-Dena Certified Dairy. They say "It is the safest, purest, most wholesome milk you can buy. Its easy di- gestibility makes it the ideal formula-milk for babies . . . and for the same reason, a basic food for invalids." Aren't we talking about two high-risk groups that are more sus- ceptible to infection yet Alta-Dena is suggesting they ought to drink raw milk? [The publication referred to follows:] PAGENO="0051" 45 1'1\~. 54_ `C What is Certified Milk and Why should you buy it in preference to other milk? Certified Milk is the highest grade milk that skill and care can produce or money can buy. It is produced according to the rigid standards and con- trols of the American Association of Medical Milk Commissions. Its produc- tion is supervised by the local Milk Commissions. It is the safest, purest, most wholesome milk you can buy. Its easy digestibility makes it the ideal formula-milk for babies.. and for the same reason, a basic food for invalids. Healthy youngsters and adults, too, enjoy the fine rich flavor, of this purest of milks. IS THERE PROOF OF CERTIFIED MILK'S SUPERIORITY? The world's finest milk has the lowest Bacterial Count allowed in milk- Certified Milk must test less than 10,000 bacteria per mililiter. The State & County regulations permit 50,000 bacteria per mililiter before pasteuriza- tion, and 1 5,000 bacteria per mililiter after pasteurization. Certified Milk must have less than 10 coliform per mil-whereas milk before pasteuriza- tion may be as high as 750 coliform per mil-so it may readily be seen that Certified Milk virtually is The Perfect Milk. PAGENO="0052" 46 Is Certified Milk economical? Yes. Quoting W. E. Krauss, noted authority of the Ohio Agriculture Ex- periment Station, "In a Suitable menu designed to meet the daily needs according to the accepted nutritional yardstick, MILK CONTRIBUTED RELA- TIVELY MORE FOOD VALUE FOR LESS MONEY than did the other foods comprising the meal." The added safety and purity of Certified Milk makes it a definite factor in food value and economy. What are the rigid and exacting standards under which Certified Milk is produced? Many special elemenls enter into the careful production of Certified Milk involving (1) the selected milk producing herd . . . (2) the special employees connected with every step of production and processing . . . and (3) the unique facilities ar~d modern equipment used. How does the herd producing Certified Milk differ from others? A Certified Herd is composed of only carefully selected cows. They are chosen for the select certified herd" because they have passed with flying colors the most rigid and exacting tests. They are subjected to reg- ular examinations by a veterinarian who checks for every known cow infec- tion. Their product is checked daily by laboratory technicians and their health records must have been perfect since they were calves. Each cow is fed scientifically balanced rations to insure the consistent quality and flavor of her milk. Alta-Dena Dairy, owned and operated by Stueve Brothers, produce all their milk in order to give you the highest quality milk available. We believe in order to keep cows healthy, proper feeding is essential and since the soil is depleting in minerals we add them to our feed. It is proven that the mineral feeding to the cows shows through in the milk. We feed green alfalfa during the summer and dry alfalfa during the winter. A ration is fed to milking cows consisting of barley, oats, milo, almond hulls, bran, beet pulp, orange pulp, milo mill feed, cotton seed hulls, soy PAGENO="0053" 47 meal, copra, cotton seed meal, molasses, kelp, corn fermentation solubles, salt, yeast and trace minerals. Under what rigid sanitary conditions is Certified milk produced? All cows are washed very carefully before each milking, and then milked by Electric vacuum milkers, taking milk over to coolers, without touching air or human hands. Certified buildings are constructed to provide the best possible sanitary features; adequate light, mechanical ventilation and flooring. All equipment is kept scrupulously clean, in perfect repair, and all surfaces coming in con- tact with the milk are sterilized before and after each run of milk. The highest standards are required to provide the public with the purest, most whole- some milk possible. What are some of the Standards that must be met by employees connected with the production of Certified Milk? Physicians give regular examinations to every person employed in the dairy or in any capacity connected with the production, bottling or distribu- tion of Certified Milk. A new employee must pass a rigid examination and must present a satisfactory past health record . . . in addition to his regularly scheduled examinations. How are these standards and protections actively practiced? In addition to the above mentioned requirements, physicians visit the farms periodically for a thorough inspection of the working media and to insure you top quality Certified Milk. All persons handling Certified Milk must wear clean, white suits and caps that may be worn for no other purpose. These are only a few of the precautions taken to assure consumers that Certified Milk is the cleanest, purest, most wholesome milk possible. Alta-Dena Dairy has a complete laboratory which is controlled by a licensed bacteriologist where we are able to run tests on all of our products and maintain consistent quality control at all times. PAGENO="0054" 48 Dr. Fi~iss. I don't know anything about that particular brochure. I think that there are groups throughout our population that con- sume-- Mr. WAXMAN. I have just been told this document I just read to you has the seal of the American Association of Medical Milk Com- missions, and you are an official of that organization. Is that cor- rect? Dr. FLEISS. Yes. Mr. WAXMAN. With babies, do you think that raw milk is more easily digestible and therefore the ideal formula milk for babies? Dr. Fr~iss. No. Babies should be breast fed. I think that this is a very, very important point. I think that raw milk is inappropriate for very young babies. I also think that formula as it is now pro- duced is inappropriate for babies. I will make my point. I have heard strong opinion on that. If you want to talk about that, I have many examples of why infant formula is-- Mr. WAXMAN. I gather that is an area where the three of you would concur, Dr. Bolton, Dr. Fierer? Dr. FIERER. Yes. Dr. BOLTON. Yes. Dr. FLEISS. One thing about infant formula, there was recently found in one of the most common infant formulas, found to be high in trichloroethylene, an organic solvent. Mr. WAXMAN. I will interrupt you because-- Dr. FLEISS. I just want to say-- Mr. WAXMAN. It is a little off the subject. I agree with you, from all I have heard as well. Dr. FLEISS. OK. Mr. WAXMAN. I am sure the other two witnesses would agree. Let me ask you one last question. You are the secretary-treasur- er of the American Association of Medical Milk Commissions. The certified milk standards of the AAMMC were recently reYised. Were these changes intended to strengthen them or weaken the quality control procedures required to manufacture certified raw milk? Isn't it true the revised standards no longer require that cer- tified raw milk be free from salmonella organisms? Dr. Fu~ass. I am not aware of that. I don't know that. I think that as it is stated in the beginning of the standards for the AAMMC it says the goal is to produce the most nutritious free from disease-causing organisms milk that is possible. Mr. WAXMAN. I want to put into the record at this time both sets of the AAMMC standards which would indicate that the latest re- visions specifically delete the requirement that certified raw milk be free from salmonella organisms. And I want you to have a chance to look at that. If you want to submit a reply or explanation for this, we would be pleased to receive it and put it in the record. [The information referred to follows:] PAGENO="0055" 49 AMERICAN ASSOCIATION OF MEDICAL MILK COMMISSIONS, INC. Paul M. Fleiss, M.D., MPH., F.A.A.P. Secretary 1824 North Hillhurst Avenue Los Angeles, California 90027 (213) 6641977 February 15, 1985 Congressman Henry Waxman 2418 Rayburn House Office Bldg. Washington, D.C. 20515 Honorable Waxman: This letter is in reference to your questions regarding the test- ing of raw certified milk. Without specifying every potential bacteria, THE METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK established a criterion which far exceeds that required of pasteurized milk (even after pasteurization). Page 6, Title 5 specifies what laboratory standards must be fol- lowed in testing certified milk. Page 2, Title 2, Sec. 1, para- graph 3 states, "... these ... standards ... shall be regarded as minimal and may be augmented by the requirements of local milk commissions." Finally, the Appendix (page 20) states, "The ultimate aim of the procedures shall be to provide a product in which the original nutritive qualities, flavor and appearance have been preserved and to ensure that no harmful organisms or substances are present to adversely affect the consumer." Salmonella is not specified because to do so would require that other bacteria be listed as well. In my opinion, these standards more fully ensure the quality of the finished product. Sin72( PAUL M. FL ISS, M.D. Secretary and Treasurer PMF:cjr enclosure PAGENO="0056" 50 1~IethO(1S afl(I Standar(ls for the Production of Robert Tjqjtçnger, Jr., M.D. President Of `lifE AMERICAN ASSOCIATION OF MEDICAL MILK COMMISSIONS, INC. 1136 East (;reei~ Street Pasadena, California 91101 L. Allen MeDonough, M.D. Chairman of Council of AAMMC 1036 Lindbergh Drive, N.E. Atlanta, Georgia 30324 National Head1uarters P. 0. Box 554 Alpharetta, Georgia 3020! ~1'~H~fl 1Gl~- J. L. flopping, Jr., D.V.M. Ar~a Codt.~ 404!*t' Revised 1976 PAGENO="0057" 51 CONTENTS TITLE 1 HISTORICAL INTRODUCTION 1 TITLE 2 DEFINITION OFCERTIFIEDMILK 2 1. Definition 2 2. Certified Milk, the Basic Product 3 3. (:~-t~fkd Milk, Pasteurized 3 4. C~tj lied Cream, Certified Half and half, and Certified Fat-free (Skim) Milk :3 5. Special Certi fled Milks 4 a. Certified Milk with Vitamin D Added 4 li. Certified Milk - Homogenized 4 c. Certified Fat-free (Skim) Milk with Vitamins A and D Added 4 d. l,ow Sodium Certified Milk 5 e. ( ~t-rti lied Acidophilus Milk f. other Prod nets Made liv Culturing or (.:liiirtiitig Certified Milk or Cream . . . 5 6. I ~alwli ng special Certi lied Milk 5 7. Certified (;~at's Milk 5 TITLE 3 NUTRITIONAL VALUE AND FLAVOR OF MILK 6 TITLE 4 MEDICAL MILK COMMISSIONS 7 I. ( )rgan ization 7 2. l)u ties of \kdieal Milk Corn r1ii~ions . . . 7 a. 0 )flieers and supervisors of \lediral Milk (:o,iitiik.ioi~. 7 li. \lethods of ( :~rti heat ion 8 e_ Report () I \leilieal \ lilk ( ominissions 9 ~l. .\d~ frti~.ing 9 TITLE 5 LABORATORYSTANDARDS 9 - ~1J l~''~"''~ inil Rep()rt~ 9 2. lLLrterU)loglcal \ lethod5 and ~tandard5 - - 9 3. ll~~~d and ( :heui ieal ~ lethods and 10 ~1. ~`((liin4nt iln(1 I' l~vor lests 11 5. I )eteetion of \lver5)bial I uhi hitants ( \n I ihiotir..) II TITLE 6 BUILDINGS AND EQUIPMENT II ~iiptrVisioii and Report I I 2. (;iriiral II a. Location of Building. II li. Surroundings of Buildings II (. Lx trrmi natii m of LI ies and other lNtS 12 PAGENO="0058" 52 d. Exclusion of Rats and Vermin . t2 e. Water Supply 12 f. Drinking Fountai~or Cups 12 g. Toilets..... . 12 h. Homes, Dormitories, Boarding Houses. 13 i. Visitors 13 j. Pollution 13 3. Cow Barns .`. 13 :4. Milking Barn or Room and Equipment ~.. 13 a Construction and Condition 11 b. Cleanliness 14 5. Milk Receiving Rooms 15 6. Dairy Building 15 a.. Construction and Condition 15 b. Rooms Required 15 * c.Use 16 7. Dairy Building Equipment and Bottles. . 16 a. Necessary Equipment 16 b. Construction 1 6 * è. Condition. 1.6 d. cleaning and Sanitizing. . ... 17 TITLE 7 VETERINARY SUPERVISION . 19 1. Supervision and Reports 19 2. Herd Management 19 a. Identification of Cows 19 b. Herd Records 19 c. Milking and Calving Period 19 d. Pastures and Yards 19 e. Feeding 20 f. Bedding 20 3. Disease Control 20 a. Isolation of the Herd 20 b. Admission to the Herd 20 c. Tuberculosis 21 d. Brucellosis . 21 e. Salmonella 22 f. Withdrawals From the Milking String 22 g. Mastitis and Abnormal Milk 22 h. Notification of Veterinarian 23 i. Disposition of Dead Animals 23 TITLE 8 MILKING, PROCESSING, DISTRIBUTION.... 23 1. Supervision and Reports 23 2. General 23 a. l'~mployees Clothing 23 h. Things to lie Avoided by 1~mpIoyees 23 3. Milking 24 a. Protection from Contamination . . . . 24 b. I'reparation aml Handling of Cows. . . 24 e. Milkers' Ilands 4. Milk I landling dud Processing 25 a. Collecting aud Filtering 25 b. Cooling 25 PAGENO="0059" * .53 * I rocessing, Bottlingand Sealing .. . . . 25 d. Labeling 27 5. Iransportation and Distribution 27 a. Equipment 27 b. Temperature 27 c. Delivery Time Limit 27 d. Bottles from Quarantined Homes . .,. 28 6. Preservation of Vitamins and Good Flavor 28 TITLE9 PERSONNEL, MEDICAL SUPERVISION 28 I. supervision and Reports .28 2. Duties of the Physician 28 a. Medical Examinations 28 h. Medical Inspect ion 29 c. Special Examinations 29 3. Duties of Owner or Superintendent. . . . 30 4. Duties of Employees 30 5. Management of Communicable Infections 30 6. Records of Employees . . . 30 APPENDIX APPROVED LABORATORYMETHODS 32 1. total Bacterial Counis. . . 32 2. The I)etermi,thtion of Coliform Organisms ~ 32 3. Heat-Resistant Bacteria in Milk 32 4. Examination for I lemoly tic Streptococci 33 5. Suggested Routine Bacteriological Procedure 37 6~ Diagnosis and Control of Mastitis 37 7. Sanitizing Methods and Materials 38 8. Determination of Curd Tension of Milk (American I)airy Science Association) . . 39 9. litration of Ascorbic Acid in Milk (New Jersey Agricultural College) 41 10. Tests for Brucella Agglutinins in Milk. . . 42 a. Titration of Agglutinins in Whey . . . . 42 b. The Ring Test for Whole Milk 44 I I . I )eteetion of microbial I nhibitants (:~ntihiotics) 44 PAGENO="0060" 54 METHODS AND STANDARDS for the Production of Certified Milk TITLE 1 Historical Introduction Certified Milk had its origin in the medical profes- sion. In 1893 Dr. Henry L. Colt of Newark, N. J., formulated a plan by means of which he and his col- leagues might obtain for infant feeding a supply of clean, safe, pure, nutritious milk, the best which the knowledge of the time could produce. In accordance with this plan the Medical Society of Essex County, N. j., appointed a Med teal Milk Commission which en- tered into contract with a dairyman (Stephen Fran- CISCO of Caldwcll, N. J.) willing and able to produce this iiiilk which was to be "certified" by the Commis- sion and labeled with the copyrighted and trade- marked iiaine ``Certified Milk." 0th er medical socie- ties soon followed the example of the Essex County Medical Society and by 1909 there were 58 local Medical Milk Coininis~ions, functioning in different parts of the country ; each formulating its own metli- ods and standards but showing a remarkable similarity in fIIIl(lallletItal requirements. In 1907 most of these local COfllflhiSSiOflS were or- ganii.ed into the American Association of Medical Milk Co,ii,,iiMsions~ 1 iir .. which had br its ohject~ the adoption of iiiii form methods and standards for the production of Certified \lilk and the extension of the inuvenietit throughout the country. Four standing commi (tees were appointe(l: Medical Examination of Employees; Chemical Standards; Bacteriological Standards; and Veterinary Inspections and Protection Against Tuberculosis. The personnel of these corn- tnittees, giving their ServiCes without pay for many years for the development of methods and standards is cause for Pri(1C I)octors \V. 11. Park, M. J. Rose- nau, I). L. Edsall, L. L. Van Slyke. henry Dwight (:hapiii, Rowland C. Freeman, M. P. Ravenel, Francis 11. Slack, A. R. \Vard, Leonard Pearson and others. These eo,nnnttees submitted reports which were a- (lopted by the associations and in 1909 were published in the form of "a Manual of the Working Methods an(1 Standards for. the use of the Medical Milk torn- iii is.sion. Since that time the Methods and Standards have been revised from year to year at the annual conven- PAGENO="0061" 55 tion~ of the American Association of Medical Milk Commissions in accordance with advancing scientific knowledge. : Certified Milk has retained a position of leadership in the dairy industry which has exerted an itifluence far greater than v~Iume of its sales may indicate~'It is the object of this Association to retain this leader- ship and it is the belief of its members that regardless of what subsequent treatment may be given to milk, improvements of the product as to safety. and nutri- tional factors, can best be accomplished at the source of production. it is the belief of the Association that Certified Milk is the highest grade of milk obtainable. Recognition of the standing of the Association is to be found in the laws, of many states and municipalities which require that Certified Milk shall be produced in accordance with the Methods and Standards as `cur- rently published by the American Association of Med- ical Milk Commissions (or words to that effect) and by a similar definition which occurs in the United States Public Health Service Milk Ordinance. TITLE 2 Definition of Certified Milk Sec. 1. Certified Milk is produced by dairies operated in accordance with time Metlu)ds an (1 Standards ~1(h)1)tC(l by the American Association of Medical Milk Corn- missions, Inc., and under the direct supervision of local Medical Milk Commissions or other agencies recognized and approved by the American Association of Medical Milk Commissions, Inc. herein the terni Medical Milk Commission may be understood to apply to any such recognized and approved agency. Only milk produced in accordance with the Meth- ods and Standards and by approved dairies shall be * labelcd CERTIFIED MILK and shall bear the copy- righted seal of the American Association of Medical Milk Commissions, Inc. The requirements in these Methods and Standards for the Production of Certified Milk shall be regarded as minimal and may be augmented by the require- ments of local Medical Milk Commissions. Any deviation from these Methods and Standards for the purpose of meeting local requirements or conditions, but without lowering fundamental standards, may be sanctioned but must be' acceptable to the Committee on Methods and Standards in conformity with the constitution and by-laws of the American Association. of Medical Milk Commissions, Inc. PAGENO="0062" 56 Sec. 2.Certified Milk (Unheated) - The Basic Product Certified Milk, so labeled without (1ualification, is a basic pro(lUct 811(1 must tie pure, cleati, fresh, nu- tritious milk in its natural state, not having been heated and without the ad(htion of coloring matter, or preservatives, nothing having beeti added and nothing taketi away. Unless otherwise labeled it is to be cow's milk. It must be the product of healthy animals and pro(luced and handled strictly in con- forinity with these Methods and Standards, and must meet bacteriological standards as specified in title 5, Sec. 2. It shall be free front objectionable odor and flavor. Any modification or processing of Certified Milk shall be plainly indicated on the label as herein- after specified or as iiiay be approved by the Com- mittee on Methods and Standards, during intervals between annual meetings of the Association, and subject to approval by the Council. Sec. 3. Certified Milk (Heated) - Pasteurized Certified Milk produced in accordance with these Methods and Standards may be subsequently pasteur- ize(l and labeled Certified Milk-pasteurized, it shall he pasteurized and bottled through equipment not for the handling of any other grade of milk or milk pro- duct except that, upon recommendation of the Milk Coinniission and after (tue consideration of each appli- cation, the Committee on' Methods and Standards may grant 1)crniii~sion for the milk to be pasteurized and bottled through freshly cleaned and sanitized equip- nient which may thereafter be used for other grades of milk. (Sec Title 2, Sec. 7). Whether proccessed or not every precaution shall be taken to insure that CertifiedMilk is not contaminated by any other milk and that it is as represented on the label. In any case tIme location, the processing and the milk-handling ~1imipnmtemmt, tIme methods use~l, and the standards main- taimied shall be subject to the~ontrol of the Milk Commission, 811(1 is their responsibility. Sec. 4. Certified Cream,..Certified Half and Half, and Certified Fat-free (Skim) Milk Alt requirements covering the production, handling and standards of Certified Milk, except those refer- ring to butterfat, shall also ~ipply to Certified Cream and Certifi(~d'Fat-Free (Skim) Milk. The percentage of butterfat in Certified Cream shall either be stated on the labels or conform to established local custom amid legal requirements. Certified half and half shall be made from Certi- fied Milk amid Certified Creammi. The percentage of PAGENO="0063" 57 butterfat in Certified Half and half shall be either stated on the label or conform to established loca! customs or lcgal requirements. Certified Fat.free.(Skirn) Milk is defined as skim milk produced by centrifugal separation of Certi Iled Milk to comply with individual state laws. Sec. 5. Special Certified Milks The productionof milk with special am~ niitrit~onal properties, may be sold as Certified Milk pro~/iding the fluid Whole milk, skim milk orcrca,n used s Certified and meets all the requirements of Methods and Stand- ards. The Methods and Standards for these products shall be in accordance with existing license agreements and must be approved by the local health authorities, Committee on Methods and Standards and Medical Milk Commissions. a. Certified Vitamin P Milk - Vitamin D Certified Milk is defined as whole Certified Milk rendered anti- rachitic by the! addition of a concentrate and shall be of sufficient vitamin D potency to show by bio- logical assay a content of at least 400 IJ.S.P. units per quart. it is suggested that each Medical Milk Cpm- mission shall make or have made such teats as will insure the maintenance at all times of the potency re- quired for Vitamin D Certified Milk produced under its certification, i.e., at least two biological assays per year. One of the two biological assays should he made in December or January and the other six months later. Producers of Vitamin D Certified Milk shall keep complete records covering the production of this product. These records are to be kept on file at the farm and with the Milk Commission. Any concentrate of Vitamin D used for thc production of Vitamin I) Certified Milk shall be a brand declared suitable for such purposes by. local, state or municipal h~alt1i agencies. * b. Certified Milk-Homogenized - Certified Milk- Homogenized may be produced and labeled with the approval of the Medical Milk Commission and the Committee on Methods and Standards of the Ameri- can Association of Medical Milk Commissions. it also may be labeled "Certified Milk-homogenized, soft curd" provided it maintains a curd tension below 15 grams. c. Fat-free (Skim) Milk with Vitamins A and D Added. - Certified Fat-free (Skim) Milk with vita- mins A and D added may be produced and labeled with the approval of the Medical Milk Commission and the Committee on Methods and Standards of the A.A.M.M.C. The vitamin D content of this milk shall PAGENO="0064" 58 (()nform with the specilications of Title 2, St~c. 5a. The vitamin A content shall be State(l on the label of the cap of each hot tie, as agree(l upon by the local Medical Milk Commissions. `Ibm' vitamin concentrates used shall be a brand declared suitable for such pur- ~ by local, state or municipal health agencies. d. Certified Low Sodium Milk. - A milk which is prothiced and handled in accordance with these Meth- 0(15 and Standards and treated so that its sodium content is reduced to less than 50 milligrams of so(Iium per quart, or contains less than 5 mg. sodium per 100 gins, or less than 12 mg. sodium per 8 oz. glass. e. Certified Acidophilus Milk. - A milk which is produced and handled in accordance with these Meth- ods aiim1 Sta n(iar(ls. The mimilk is inoculated with a pure culture of Lactobacillus Aci(Iophilus, and contains large tin tubers of therapeutically valuable, viable I ac!obacillmis Aci(lophilus cells. f. Other products made by culturing or churning Certified Milk or Cream. - Other products made b mmml Luring or churning Certified milk or cream may be labeled ``Made front Ccrti lied Milk" or ``Made from ( ert i iie(l creamit `. Sec. 6. Labeling Special Certified Milks LaI)cls br Special Certified Milks shall bear the Seal of time' American Association of Medical Milk Commission's. The wording for such labels shall be submitted to and approved by the Committee on Methods and Standards of the American Association of Medical Milk Conimnissions.SUdi prO(luCtS must be made tinder the Supi~rvision of the local Medical Milk Conimission. Sec. 7. Certified Goat's Milk Certified Coat's ~lilk is hereby defined to be the lacteal secretion obtained by the complete milking of one or morç healthy goats properly fed and kept, excluding that obtained within fifteen days before and five days after kidding, or such longer period as may be necessary to render the milk practically colostrum free; which contains not less than 10.7% of milk solids, and miot more than 89.3% of watery fluids, or less than 2.8% of milk faL The bacterial count for raw goat's milk shall not be more than 10,000 colonies SPC per ml and not more than 500 colonies per ml after pasteurization. The coliform requirement shall be less than 10 per ml on the raw milk and not more than 1 ~ ml after pasteurization. PAGENO="0065" 59 TITLE 3 Nutritional Value and Flavor of Milk Two important influences in maintaining the highest nutritional value and also the best flavor in milk, are, (1) the feeding of the cows, and (2) th~ care with which the milk is handled and processed. Both of these involve considerable detailed ktowlcdge, and application, but there are two key vitamins towards which special attention can be directed. Vitamin A serves very well as a good measure of the quality of the feeding program. Vitamin A in milk is very definitely influenced by the ration of the cow, and if feeds are produced so that they have a high vitamin A content, they will also tend to be high in other factors which may influence the quality of the milk. Likewise, the ascorbic acid (vitamin C) content of the milk can serve as a measure of the effectiveness of proper care in': handling and processing so far as nutritional valüe.is concerned. The forage crop feeds, hay, silage, and pastures sup- ply most of the vitamins and other nutrients which influence the quality of the milk, and also help to maintain normal health in the cows. The production of good forage crop feeds requires: proper soil fer- tility, adapted varieties of crops, harvesting at the best stage of growth, and for stored feeds, good preserva- tion and storage. The natural Vitamin A content of milk will vary from season to season due to. ration changes unless care is taken to see to it that cows get an adequate daily intake of Vitamin A or its pre- cursor, carotene. Only' pasture or green chopped forages can be depended upon to furnish Vitamin A activity as carotene, for much of the Vitamin A activity of harvested forages is lost during the first six months of storage. Thus it is necessary that lactating cows be furnished supplemental Vitamin A daily in their diets to insure healthy cows and milk that is. high in Vitamin A. The chief factors in the handling and processing of * milk. which affeèt its nutritional value are (I) Free- dom from contamination, (2) Oxygen content of the milk, (3) Length of time between production and use, (4) Heat' treatment, (5) Exposure to light Here again Certified Milk producers should apply the results of * the extensive studies which have been reported in this field. The test for ascorbic acid described in the Appendix provides a means of checking results along this line, * The flavor of milk is closely associated with its 52-266 O-85---3 PAGENO="0066" 60 nutritional value. The methods outlined for producing milk of high nutritional value arc also important for producing the best milk flavor. All rations fed to lactating cows shall be supple- mented with trace minerals in accordance with the latest recommendations of the National Research Council. TITLE 4 Organization and Duties of Medical Milk Conimissions Sec. 1. Organization A Medical Milk Commission may be appointed (1) by a recognized Medical Society, (2) by public health officials, (3) by the council of the A.A.M.M.C. which may itself serve as a Medical Milk Commission,. or (4) as provided for by law in the community where the milk is to be marketed. Before such a Commission shall be recognized under the terms of these Methods and Standards, it must be approved by vote of the Council of the American Association pf Medical Milk Commissions, Inc., and formal notification of such approval be issued by the President and Secretary of the above association. The Council of the Association may rescind such approval at any time for cause and after hearing. Sec. 2. Duties of Medical Milk Commissions a. Officers and Supervisors of Medical Milk Com- missions. - In addition to electing a President, Secre- tary and Treasurer, the Commission shall appoint the following Supervisors to enforce the Methods and Standards: A Physician, a Veterinarian, a Laboratory l)irector and a Sanitarian, who may or may not be members of the Commission. The Physician and the Veterinarian must be duly licensed practitioners. The Commission may delegate the duties of cnspection and enforcement to other Commissions certifying the same farms or dairies, or with the approval of the Committee on Methods and Standards of the American Association of Medical Milk Commissions, Inc., to State or Municipal Authorities. The Labors- tory Director must possess adequate chemical and bacteriological knowledge, and skill, and must have. access to the necessary laboratory facilities. At the discretion of the Commission the work of the Labora- tory Director may be divided among two or more properly qualified persons. The terms of employment PAGENO="0067" 61 ol the above men tionel Sn pervm)rs an (I I he means of (Ic fra yislg the cx uses of I heir W( )rk shi all he del er- mined by the Coninuss~on. these Supervisors shall be required to render to the Coinnussion and farms monthly reports of their inspections an (1 exa mi tions afl(I COpies. of these reports may be sent to every member of the Commission. All records of the Commission shall he opcmm to inspection at any) time by the Secretary of the American Association of Medical Milk Commissions, tue., or his daly author- ized representative. The above mentioned Supervisors of the Commis- sion shall perform time (In ties' hereinafter specified. b. Methods of Certification. - After the Commis- sioui has applied for and received a certificate oî recog- nition and approval signed by the Prcsi(Ient and the Secretary of the American Association of Medical Milk Commissions, Inc., it may receive application for certification from dairymen who desire to undertake the production of Certi fled Milk. i)airyincn produc- ing Certified Milk are hereinafter referred to as Pro- ducers. Uponreccipt of application for certification the Commission shall institute an investigation by its members and/or Supervisors to (letcrnline whether or not the applicant has proper interest, intentions, personnel, livestock and equipment for the successful production of Certified Milk. If the result of such, an investigation is favorable, time Commission uuiay (e1- ti fy the milk and shall enter into an agreement with the Producer to produ(~ Certified Milk under the Methods and Standards. The Secretary of the Ameri- can Association of Medical Milk Conuniissions, Inc., shall immediately be notified of such action, so that permits may be issued for licensed mann factnrcrs to supply the producer with approved Containers and closures and formal ack nowiedgment of certification may be issued. In this procedure it is understood that (1) certifica- tion is the responsibility of the Medical Milk Com- mission, (2) the Commission's certi Iieation shall eon- :`~ tinue as long as its standards and requirements are maintained but (3) certification of a Producer may be suspended at any time after due hearing by either the Commission or by the Council of the American As- sociation of Medical Milk Commissions, Inc., for fail- ure to operate in accordance with Methods and Standards or to meet financial obligations to the Commission orto the American Association of Medi- cal Milk Commissions, Inc., (4) full financial responsi- bility and liability for failure to meet the required standards for Certified Milk shall rest with the Pro- PAGENO="0068" 62 (lucers, (5) all money collected by the Medical Milk Commission from Certified Milk Producers shall be USe(l solely for the expt~nsi~~ of the Commission. c. Report of Medical Milk Commissions. - Every Medical Milk Commission shall rendet a quarterly re- port to the office of the Association, and also shall render special reports whenever requested to do so by the Secretary. Medical Milk Commissions shall promptly report to the Secretary of the Association any outbreak or epidemic of communicable disease suspected or knowii to be milk-borne in the communities where Certified Milk is produced or distributed so that the Association may be of all possible service. d. Advertising. - All advertising (including ex- hibits, billboards, posters, newspaper copy, printed matter and radio broadcasts) sponsored or promoted by the Certified Milk Producers' Association of America, inc., shall be subject to the approval of the Committee on Research and/or the Council of the American Associa ti on of Medical Milk Coni missio us, * Inc. All advertising, as specified above, sponsored or promoted by individual Certified Milk Producers shall be subject to the approval of their respective Medical Milk Commissions. TITLE 5 Laboratory Standards for Certified Milk Sec. 1. Supervision and Reports The maintenance of laboratory standards for Cer- tified Milk shall be under the supervision of the Lab- oratory Director of the Commission who shall be held responsible for the inspections and tests specified in Title 5. He shall promptly render monthly reports to the Commission and farms and shall immediately notify them if high bacterial counts or other question- able conditions are found. Sec. 2. Bacteriological Methods and Standards Routine bacteriological examinations shall be made at least once each week or more frequently as the Commission may direct. ~At least 50 er cent of sam- ples examined shall be roj~~anip cain- mna~ contain- em ~ delivered ~to consume dal!Jc_I~ept properly refn~èiit~J untilihey are exammned,yhich shall be as soon as possmb1e~ft~ ~èollection or within 24 hours. The methods used for bac~emf~IogicaI exaii~ir PAGENO="0069" 63 nations shall be those described in Append ices and those described in the latest edition of Standar(l Mctlunls for the l~xanunation oil )airy Prorlucts of [lie American Public I Iraltli Association when not in (Oil- Ilict Wi Lb these Methods and Standards. lli(~ examinations shall inclu(le: a. lotal bacterial colony counts (I) Certified Milk shall have a total eou nt o Inot nmiore than 1 0,000 colonies iwr miii. (2) (~rti fled Milk - ~j~urj ~I or Pasteurized Milk ma(lc from Certified Milk shall have a total count of not more than 10,000 colonies per nil, before J)astr~uriza- Lion, in samples taken at the pasteurizing 1l~t,mt, and not_mno~r(~,Jjiai1500, per ml. in route sam pies as de- livi r d to eu'.tom r~ (~ I ith 2 "e ( 7 for I) 0 ti ii colony counts for Certified Coat's Milk) h. `Coliform colony counts: (1) Certi fled Milk shall have a eohiform colony count of not nmmor~ iharul0 per ml.~ (~ Cciii. fled MiIk~'- pasteurized or Pasteurized Milk made from Certified l1llk"~lmaH have *a coli forum colony count of not more than 10 per ml. before pasteuriza- tion and not more than 1 per ml. in route samples as d livi r (I to COflSU~( N if counts excee(iing these standards are foum~d,' the following steps shall be taken immediately: (1) Samples obtained directly from the farm shall be cx- arnined; (2) If the counts on these samples are high, process samples from along the line of production shall be examined until the source of high counts is found; (3) If persistent difficulty is encountered in keeping the total .countof Certified Milk - pasteurized below 500 per ml. examine for thermoduric or1,ranlisms by methods described in Appendix See. 3. If counts within these standards are not restored within 10 days and maintained, `certification may be suspended. Once per month the Bacteriologist of each Milk Comniission shall make or have made by the: State Laboratory or other acceptable laboratory a titration of Brucella ag~utiniins in the wiley of the milk or. Ring Test from each Certified Milk Producer whether the milk is raw or pasteurized. Sec. 3. Physical and Chemical Methods and Standards L At a temperature of 60° F. (15°C.) Certified Milk shall have, a specific gravity of not less than 1.029 and contain not less than 12% of total solids including fat. b. Unless otherwise indicated on the label, it shall contain an average of 3.5 per cent butterfat with a tolerance for the average of 0.2 per cent above or below 3.5 per cent and a minimum of 3.3 per cent for individual samph~s. In case it is desired to nnain~ain an PAGENO="0070" 64 aVerage of 1)11 ttedat. above Or bil ow 3.5 per cent the average p~'~ cent of butterfat or the limits between which it fluctuates shall be stated on the cap or the eon tai tier, or by SOUI~ (lesignation wInch has legal standing is generally understood iii the community where the ittilk IS (list rihuted. In all cases the average of mi tterfat shall be base(l ti[)Oi1 not fewer titan ten santl)les over a period of not less tItan 60 (lays nor more thait 90 days. e. Certi lied ~ 111k - pasteti rizc(l shall show proper pasteurizati on as indicated by phospha tase tests. Sec. 4. Sediment and Flavor Tests It is recotitittended that se(l1ment and flavor test l)e reported on all samples with a required sediment test of No. I or better. Sec. 5. Detection of Microbial Inhibitants (Antibiotics) a. There shall be no antibiotics in Certified Milk, regardless of the route used for administering. b. `Flie ,nil k froni animals treated with antibiotics shall he withheld 7~ hours or until the mitilk is free of amitibiotics (see appendix). TITLE 6 Buildings and Equipment Sec. 1. Supervision and Reports All bucldings and equipment on a Certified Milk farm shall he under the supervision of the Sanitarian of the Commission who shall make a thorough inspec- (ion of the buildings, equipment and sanitary condi- tions ol the en tire dairy farm at least omice a riionth and more often if advisable, lie shall notify the Gout- mission of any (1uestionable con (Ii lions existing and shall l)rotnptly render monthly reports to the Cont- mission and farm where they shall be kept on file. Sec. 2. General a. Location of Buildings. . - Buildings in which GertUied Milk is produced and handled shall be located so as to insure good drainage and at sufficient distance front other buildings, dusty roads, cultivated and (lusty fields, and all other possible sources of con- tamination to safeguard the milk provided. In the case of unavoidable proximity to tiusty roads or fields, suitable arrangements shall be made to exclude dust. They shall he so constructed as to afford proper shel- ter. b. Surrounding of Buildings. - The barn lots and PAGENO="0071" 65 surroundings of all buildings shall be kept clean, free from accumulations of rubbish and all conditions con- ducive to fly breeding. They shall be kept graded and drained. Adcquatc and functioning drains to con- duct away the wastes from the barns and the dairy building shall be provided. All manure shall be stored or disposed of in such a manner to prevent breeding of flies therein. Manure shall not be piled or stored within 600 feet of the milking barii or dairy building except~ by other means or Systems approved 1y the Milk Commission. c. Extermination o. Flies and Other Insects~- In. addition to the elimination of fly-breeding conditions as provided in paragraph b, the frequent extermina- tion of flies and other insects in milking barns and dairy building shall be accomplished by spraying or equally effectiye methods. Insecticides and methods used shall be approved by the local milk commission. d. Exclusion of Rats and Vermin. - All necessary measures shall be taken to prevent the entrance of rats and vermin into banis and (Jairy l)uildings, and proper methods as approved by the Sanitarian shall be adopted for their destruction if they gain access. e. WaterSupply. The entire water supply shall be free from contamination and poiltition and shall be sufficient for all dairy purposes. It shall be pro- tected against flood or surface drainage. The purity of each source of supply shall be checked by bacteriolog- ical examinations according to standard methods of the American Public Health Association at equal intervals, at least three times a year and as often in addition as conditions indicate it to be necessary, and records of such examinations shall be filed at the farm and with the Commission for a period of one year. Samples for such examination shall be collected from outlets in the milk plant. When the water is obtained from a municipal supply, the records of the munici- pality or state tnay be accepted in lieu of th~ above requirements. No cross connections between potable and non-potable water systems shall be permitted. f. Drinking Fountains or Cups. - Sanitary drink- ing fountains or disposable drinking cups for the use of the employees shall be installed in convenient locations both for the stables and dairy buildings. g. Toilets. - There shall be one or more flush toilets connected to a public sewer system or to an individual sewage-disposal system. Such toilets and sewerage systems shall be constructed and maintained in accordance with local, county and state depart- ments of health. PAGENO="0072" 66 Such toilets shall be convenient to, but no~ open- ing into, the barn and milk room. All toilet rooms shall be kept clean and properly screened and have conveniently available lavatory facilities with running water, liquid or powdered detergent and individual toWels. l~tnployees shall be required to wash and dry their hands upon leaving toilet rooms. h. Employees' Homes, Dormitories and Boarding houses. - \Vhen employees live upon the premises their (lorinitories or boarding houses shall be con- structed and operated accor(liflg to plans approved by the certifying Commission. Adequate modern bathing and toilet facilities shall be provided for employees. i. Visitors. - Visitors shall be so conducted as to eliminate any possibility for contaminating or con- tacting the milk or sterilized equipment and bottles. They shall be excluded from the_milking barn and dairy building during milking and milk handling oper- atiotis. Arrangements for observing operations from outside these rooms may be provided. This pars- graph shall apply to members of employees' families, field employees or others not receiving the same medical supervision as the dairy employees, except official inspectors. j. Pollution. - A certified dairy should be a leader in the control of pollution .. and should use every means possible to protect our emwironmen t. Sec. 3. Cow Barns When cows are kept in other barns between milk- ings, these barns shall be so constructed as to provide a(lequate shelter. The floors shall be kept reasonably dry and clean. Regulations with respect to ventilation and windows (Title 6, Sec. 4, a, 3-4) shall apply also to cow barns except that in niild climates windows may be replaced by unglazed openings. Drinking and.. f(e(liIIg equipment shall be kept in a clean, sanitary.. cofl(litiolm. .* . Sec. 4. Milking Barn or Room, and Equipment a. Construction and Condition. - The milking barmi or room shall bc'construeted so as to facilitate keeping it in a clean, sanitary, well ventilated and lighted condition. It shall be kept in good repair and operating condition. (1) floors and gutters The floors shall `be made of concrete or other impervious and easily cleaned material and the gutters of.concrete only. `I'hey shall be properly graded afl(l drained. .(2) Interior walls and ceiling - These shall be 0. Jight color and made of smooth concrete, I)l~1st(~r, tile, rust resisting metal, or of well painted or varnished wood PAGENO="0073" 67 with (lust tight joints and capable of shedding water. Horizontal and slanting surfaces, winch might harbor dust or other accumulations, shall be avoided as far as possible. (3) Wi~idows and Lighting. In order to provide adequate light and sunshine, window areas in warm-barn environments should contain not less than 1/10th as much area as the floor space. In cnclose(I cold-barn environments, "skylight panels" in the roof should equal or exceed 1/20th of the floor area. In warm climates where loafing areas arc open on one or more sides, the "skylight panels" are unnecessary. Windows as such are not necessary in cold-barn en- *vironments. Minimum artificial lighting requirements are as follows: 100-watt of light for each 2-3 stalls in the milking facility, and * 100-watt of light for çach 1,000 square feet of floor space in the hedded area. (4) Ventilation and air space - Stables shall be ade- quately insulated `and provided with a functioning and adequate system of ventilation to minimize of- fensive odors and to prevent excessive condensation of moisture, and each cow shall be provided with a minimum of 60 square feet of space. Correspondingly less space may be providCd for goats. (5) Stanchions or ties - Stanchions or other forms of ties shall be of modern sanitary construction. They shall be so ar- ranged that droppings will fall for the most part into the gutter. Provision shall be made to keep cows standing between cleaning and milking. (6) Drinking cups and feed mangers - When drinking cups are used they shall be of modern sanitary construction. Feed mangers shall be of smooth concrete or other impervious easily cleaned material. (7) Feed mixing rooms - All feed shall be mixed in a separate room with dust tight wall and door if it adjoins the milking barn or room. b. Cleanliness. - The entire milking barn or room and equipment shall he kept in a clean sanitary condi- tion and free as possible from dust and all, other ac- cumulations. Only bedding which is clean, dry, ab- sorbent and reasonably free from mold and dust may be used in the milking barn. Soiled bedding' and~ manure shall be removed from the milking barn at least twice daily and the floor then swept and kept free of refuse. Where cows are not kept in the milking barn or room between milkings, the floors shall be washed down after each milking unless freezing temperatures exist.. PAGENO="0074" 68 Sec. 5. Milk Receiving Rooms A iiiilk receiving room is defined as any room or building located at or near the milking stanchions or nulking parlor, and used exclusively as a central col- lecting room for milk as brought from the barns. Such rooms shall conform to the same specifications as apply to the comistructipn, maintenance and cleanli- ness of the milk handling rooms in the dairy buildings. They shall be we11 screened, provided with automati- cally closing doors and shall not have open corn- municatiomi with the milking barns. In each milk receiving room, adjacent vestibule, or milking barn there shall be provided lavatory facilities with continuously running water or water with fo0t or arm control faucets, liquid or powdered detergent and individual (preferably paper) towels for the use of milkers. Sec. 6. Dairy Building A dairy building shall be provided for handling, processing and storing of milk and milk products and the cleaning, sterilizingand storing of milk equipment. a. Construction and Condition. The dairy build- ing shall be constructed so as to facilitate keeping it clean, sanitary, well ventilated and well lighted. It shall he kept in good repair and operating condition_ It shall not communicate directly with barns or dwell- ings. (1) Floors - The dairy building shall have smooth' floors of concrete or other water impervious and easily cleaned material. They shall be well graded and drained. (2) Interior walls and ceiling - These shall be of light cokred, smooth surfaced, impervious washabfe material. There shall be no objectionably * placed overhanging pipes or conveyors. (3) Openings - All openings shall be well screened and constructed SO as to exclude flies and other insects and vermin. All doors shall open outward if possible and be self closing. (4) Lighting and ventilation - The building shall be prcwidcd with adequate daylight and artificial light. It shall be well ventilated. (5) Ucanliness - all parts of the dairy building shall be kept clean and sanitary and the milk and equipment handling rooms shall be kept scrupulously clean, well painted and free ~fromn dust and odors. L Rooms Required. - If Certified Milk is pro- duced, processed and bottled on the same premises, the dairy building shall be provided with the following separate rooms suitably equipped: (1) One or more receiving rooms to be used exclusively for all Certified Milk brought to the dairy building and from which it PAGENO="0075" 69 .~liall be piped to the processing room unless the milk can be piped directly from the milking room to the processing room. (2) One or more rooms to he used exclusively for cooling, processing and packaging Cer- tified Milk or products therefrom. (3) One or more rooms for cleaning and sterilizing milk equipment and bottles. (If the hulk is produced for processing and bottling elsewhere, the above rooms may be coin- bined.) (4) There also shall be one or more refriger- ated rooms used exclusively for.storage of bottled or packaged milk or milk products. Offices, laboratories, rooms for storage of equip- ment and supplies used in the building, boiler rooms and toilet rooms may be located in this building. The latter two shall not communicate directly with the milk or clean equipment storage rooms. A properly constructed and isolated milking room in which COWS are kept only (luring milking may he located in the dairy building. c. Use. - The various rooms. mentioned above shall not be used for other purposes than those specified cxcep.t that clean, sterilized milk bo~tles and utensils may be stored for immediate daily use in the milk handling rooms. No animals other than cows within the milking room during milking shall be allowed in the dairy building. No. part of the dairy building may be used for dwelling or lodging. Sec. 7. Dairy Building Equipment and Bottles a. Necessary Equipment. - Adequate and efficient milk handling equipment and containers approved by the Commission shall be provided for producing, holding, processing, cooling, bottling and sealing of only Certified Milk and its products (See Title 2, Sec. 3) and for cleaning, sanitizing and refrigerating pur- poses. Adequate lavatory facilities with running water, liquid or powdered detergent and individual towels shall be conveniently to~ated in the milk handling an(l toilet rooms. b. Construction. - Milk handling equipment shall be constructed so as to be easily cleaned and give effective protection to the milk from contamination. Vats shall be solid tanks. All equipment shall. be of stainless steel or glass, except milking machine parts customarily made of nibher or plastic. All milk shall be carried through stainless steel or glass pipeline to a bulk tank. The milk should not he exposed to air or outside at any time. c. Condition. - All equipment shall be kept in PAGENO="0076" 70 goo(l repair dfl(l operating Cot1(litlOn. ,i\tilkitig machine rubber parts shall be. in sound sanitary condition. ll()t ties Shall be serVirea!)lV sound and undamaged. IA~nipuIent used in tutilk handling smut1 be replaced as soon as the inte?iOr surface is dented, or with open seams." - d. Cleaning and Sanitizing. - All milk handling equipment, milking machines and multi-use bottles shall he well clean'ed and sanitized after each use. Equipment, materials and methods used shall be ap- proved by the Commission. Methods shall include the following procedures: (I) Immediately after use rinse all equipment with cJeaiu cool water. (2) Next, thor- oughly clean alt equipment and multi-use bottles with a hot solution of a good soaptess cleaning detergent. (3) Rinse thoroughly with clean water. (4) Last, thoroughly sanitize with steam, boiling water, dry hot air, approved chemicals or other equally effective methods. (See Appendix, Sec 7) Approved paper cartons and/or polyethylene plastic bottles may be use(l. Automated washing equipment for C.I.P. cleaning shall he used following an appro~.ed sanitizing and cleaning procedure. Milking e~ui~hent shall be dis- mantled for cleaning and inspection once each week. Milking machines shall be so dismantled that all parts may be thoroughly cleaned and sanitized, care being takcn. to remove all milk-stone. Rubber parts shall be maintained in serviceably sound condition. Vacuum lines shall be kept in clean and. sanitary condition. After being sanitized, equipment and bottles shall be kept covered or. inverted in a room or cabinet free from (lust or other possible contamination. Milk l)Ottle CaSeS returned froni (lelivery routes or subjected to other contamination and to be used for hav~dling invurted sanitized bottles shall first be effec- .tively cleaned and sanitized. . . Thermometers shall be use(l on all steriliz~rs and mechanical bottle wash e~. They shall be checked for accuracy at frequent intervals, sped lied . by the onl viii lou, by a standard tustr(l thermometer. Rue-. ords of such checks and turn peratures main taincdshall be kept on file at thu farm. An atu Lornatie chemical sanitizing rinse shall he used in all me(:hatuical bottle washers as the final rinse. `l'hcsu' machines shall by operated according to the mann facturer's recom nwndations. \Vlieui chemical sanitizing solutions are used, eon- centrations and times of expusu re as recofli mended PAGENO="0077" 71 in the Appendix, shall be maintained. An approved test shall be provided and the solutions checked at frequent intervals, sped fled by the (o1n,nission, and record of such tests kept on iiie at the farm. Equip- ment sanitized with chemical sanitizing solu tions should not be rinsed with water after sanitizing Intl shall bewell drained before use. The final test of cleanliness and sterility shall be freedom front viable bacteria and visible foreign matter. PAGENO="0078" 72 TITLE 7 Veterinary Supervision of the Herd Sec. 1. Supervision and Reports lii e care an(l han(lliflg of animals shall be u nder the su pervision of the \`eterinarian srI erted by the Commission. lie shall make frequent inspections of the herd, and tiiake monthly reports to the Coin- mission on forms furnished by the National ( ) flier. lie shall file copies at the farm and immediatel notify the Commission of any outbreak of disease among the animals and of any (1ucstionable conditions in- volving their health and care. A veterinary inspection of the health of the herd shall be made at intervals of not more than one month. Each COW in milk shall be subjected to a careful physical examinati (ill ~It least oiit~ e~icli 111 i'flt Ii, giving special attention to the u(lder and external genitals. Sec. 2. Herd Management a. Identification of Cows. -- Ever~' cow in a Certi- fied Milk herd shall be ear-tagged or tattooed with a iHI ii~1 UT ~ Ii icli will prma tR ii len Li f~ her. )r other itirthi ol appro~ ed h~ the Milk ( .I~tii IiIi~iOti . Pru~ isii'ti shall he ticule for the replairtii.iit of lu~-t artags. IL herd Records. Kver~ cow in the herd shall be registered in a herd ree )rd which shall be acm rate1 v kept an(l readily accessible to the milk ( ~ i~sIOt) and official i I1slH( tors. Iliis record shall 111(1 u(le (lat es of en trance an (I departti re roni the herd, ser~ ire and freshening; (lates and results of Lu bereul in and Bru- celki testing, veterinary an (I bacteriological xa ruina- tions, abnormality of the milk as (leteeted by strip cup or other methods, ill ness, injuries~ and all other information of value to supervising agencies. The record for every cow shall be kept on file at the farm as lung as the cow is at the lariti and for at least six flU)ntlls thereafter. c. Milking and Calving Period. - Milk from all cows shal be excluded from human consumption for 5 (lays full ( )Wi iig pa rturiti on. It is recoin in ended that all cows receive a tiiiIiiflhiIIii (Iry p(i1o(l (if 45 days. d. Pastures and Yards. -- Pastures or* yards to ~vliich the cows have access shall be free from stagnant iiools and at so flleient (bstance from offensive con- (iitiOhii4_ so that the cows shall so ffer no had effects Irons thetis. Pastures or ~ar(is shall be free from in- fect ions agents and Irons vegetation whi ichi may a fleet the cows or their milk (leleteru)usl~ . Where milking PAGENO="0079" 73 animals arc l)erlna(icntly mai IitaiIIc(l ill opeti corrals, these corrals must be well drained and kept in a sani- tary. con (Ii Li on. `lii cy shall be regularly seraf)e(l 8n (I man tire han led away. It is i mporta ii t from t~ie stand- point of (liscase control that both crews and trucks doing this work shall not do similar cleaning on in- controlled dames. e. Feeding. - A well-balanced ration of high quality nutrients shall be used that is adequate in protein, energy, fiber, minerals and vitamins. The ration will be designed to maintain healthy cows and produce milk of ~normal composition and superior flavor. Thc mcthpd: of feeding shall be such as to not lower the quality or quantity of the milk produced. f. Bedding. - No moldy hay or straw, bedding from horse stalls or other unclean materials shall he used for bedding the cows. Only bedding which is clean, dry, absorbent and reasonably free from (lust may be used. Sec. 3. Disease Control a. Isolation of the Herd. - No hogs, horses, stray dogs, or fowls shall be allowed to come in or be in proximity to Certified Milk herds (cows or goats) in barns or yards except resident (logs and cats, which must be vaccinated annually against rabies and any other disease that applies to dogs and cats, at the discretion of the owner or veterinarian. No animals not known to be free from (I isease, and free I roni Brimeella in fection as shown by the blood test, or IIOI yet approved by the Veterinarian shall be allowed to come in contact with the Certified Milk herd in barns, yards or pastures. Other animals and fowl of the animal kingdom free from disease shall be kept on the premises and shall be under the supervision of the AA\IMC veterinarian. No cow shall be used to pro- (1)1(1 Certi fled ~lilk, that (101'S not have four heal I hv quarters, Wi (Ii thit following IX ceptio ii. A cow with a completely dry, non fu 1I(tioning If carter eati 1)1 used to pr0(lLi~~ ( erti fird Milk from the other Lb ne normal t~uarters (511. Title 8, Sect~on 3. Part 1)9) b. Admission to the Herd. ihe responsibility for admitting cows to the milking herd after inmr:hase or of readmitti ng them a fter freshening or a fter isolation because of disease, rests with the Veterinarian even though he may at times delegate certain (luties to other qualilled persons. I Ic shall avail himself of laboratory facilities when they are indicated. Every cow atimi tte(1 or readmitted to the milking herd shall he examined by an approved veterinarian or her milk shall be examined for total bacterial count, hemoly ti(: PAGENO="0080" 74 strel) t( )C( )cci an(l otli ~r ni~isti tis organ isnis by an proved bacteriologist. The milk of such animals shall 1101 1)e allowed to enter the Certi fled Milk supply until favorable veterinary or bacteriological reports have been received and placed in the herd record. c. Tuberculosis. ( ) nI v nega Live Ii erls in a modi - fied accredited area as designated liv the t . S. J)epart- merit of Agriculture Uniform Methods and Rules for Rovi tie luiberculosis kraulication. shall 1w used in the pro(luetton of Certified Milk. ~\ hen an application is made for certi hication, ever~ animal shall be tubercu- liii tcste(l. No animal shall be added to a herd pro- ducing Certi fled Milk unless such animal has origi- siated from a negativ herd in a mod lied accre(li ted area and has passed a tuberculin te~1 wi thin sixty (60) (lays prior to admission to the herd. Certified herds shall be retested for tuberculosis annually. All tuberculin tests shall be made by a veterinarian approved by the Commission and by the 1"ederal Bureau of Animal Industry. The dates of all herd tests shall be definitely ar- ranged by agreement between the Milk Commission and the supervising officials and a complete record of all tests shall be made by the veterinarian making the same and proniptly reported by him to the Secre- tary of the Commission. Ihese records shall be kept on file at the farm for one year and a summary of all such tests shall be niiade available to the American Association of Medical Milk Conirnissions for ~tatis- (na1 pu rh)uses. All reactors shall be reniove(l from the herd im- mediately 111)011 discovery an(1 the milk shall be dis- ear(led. The barns and exercise yards used by them shall be clea ned and disi n feeted in a man tier approved by the Commission. d. Brucellosis_ - All herds approved for the pro- duction of Certi lied Milk shall be o flicially accre(hite(l (certified Rrueehhosis free) and maintained as Bruce1- hx4is (lisease free and shall be teste(l at intervals riot to excee(l every iii netv (90) da~ s b the Ring Test in an accre(hi ted l3rn cellosis free state. `Fhie same herds shall have their blood sera tested for agglutinins at intervals riot 1)e exceed 12 months. i~ll herds producing Certi- fled Milk iii states that are not accredited Brucellosis free shall be tested by the Ri rig Test at intervals riot to eXer('(l t hirtv-fi~ e (3~i) days a 11(1 have 1)100(1 sera of all (`oWS ((stIll for aggl n ti nins at intervals riot to excee(J (, 11)01) ths. 1) B n'a('t ors an (I suspects to be de Inn ed unride r l'ederal Standards usi rig tested and approved pro- PAGENO="0081" 75 (`edures only. Rea(tors JUhISt lie iruniedia (ely removed from the herd for slaughter. Suspects are to he re- moved from the certified milking string and either 501(1 for slaughter or re-tested wi Eli in mi iii in urn thirty (30) day intervals 11 ntil tcs(e(l negative he lore re-admission to the milking string. (2) ~\he,i suspects are found in the herd, (he shall he re-tested at mtervals of not over thirty (3()) (lays. (3) All purchased herd a(lditions shall he tested at the time of entering the herd arid retested in 60 days. however, if COWS are purchased from officially accredited (Certified Brucellosis l'ree) herds, an of- ficial negative test made within 30 days of purchase shall qualify such COWS to enter the herd. (4) `Ihe interpretation of 1)100(1 a~lutiiial ion tests shall be that of the Animal and Plant I Iealtli hispectioii Service, U. S. i)epartrnent of Agrirult tin. (5) Tesls shall be ma(Ie under the su ~t~r~'isioii of such agents as shall be acceptable to the local Medica Milk Commission and the State health authorities Reports of such tests shall be sent immediately to il'. Milk Commission arid copies kept on file at the farri for one year. All provisions of this section (Title 7, Sec. 3, il shall apply to goat herds. (6) It is reeonlnier)(le(J that all rcl)laeenient (at ih~ shall be (ialfhood vaccinate(l for Brucellosis with Strain 19 vaccine. /~. Salmonella. - Milk from cows approved for th (production of (erti fied milk must be free from Sal ( monella organisms. \` (1) Cows that arc added to certified herds mus <`pass a negative Salmonella test and be certified free 0 ~thc organism prior to entering the milking line. / (2) All cows producing certified milk musE b (~ted for Salmonella organisms a nu ni m urn (if on time per year. 1. Withdrawals From the Milking String. - It i the duty of the farm superintendent or the herdsmai to se~ that any cow believed to be sick or disease shall immediately be isolated from other cows in th niilking string and that none of their milk shall entv the Certified Milk Supply. g. Mastitis and Abnormal Milk. - Any COW a' fected with, either acute or chrome mastitis shall li removed from the milking line and treated. Shii slrn miot be returned to the milking herd tititil her imsilk normal arid all residues front auhhiotie sources hay been eliminated from her body. PAGENO="0082" 76 Is. Notification of Veterinarian. - In the ever~t of (lie occurrence of a disease which appears to be of a ~eriosss character, or if a number of cows become sick at about the same tune, the dairyman shall withdraw stitli (0W5 from the litr(l . (lestrov (11(1 r milk, and itoh \ the Veterinarian immediately. i. Disposition of Dead Animals. - The carcass of any (lead animal whether diseased or not should he (lis1)ose(l of in a sanitary manner. Methods of disposal mimmist be approved by the local Medical Milk C)m- mission. I ,ocal and state regulations may determine to sonic extent how this is done. TITLE 8 Milking, Milk Han~t~, Transportation and t~ist'~ution Sec. 1. Supervision and Reports Milking, toil k handling, transportation and distri- hu tion of Certi lied Milk shall be under the supervision of the Sanitarian of the Commission who shall make friqitent inspections of the dairy at times when the alu )V~ operations are in progress. -lie shall render monthly reports of such inspec(~OøS to the Corn- mtme~sion and arm and shall immediately notify the tin Imsission of any questionable conditions existing on the tarni, or in the (listribution of the milk. Sec. 2. General a. Employees' Clothing. Milkers and other persons handling the milk shall wear clean white suits and caps or other suitable washable white and colored combinations approved by the local nulk commission, that shall he worn for no other purpose. They shall use not less than three freshly laundered suits and caps each week and these when not in USC shall be kept in a clean place, protected from dust and dirt. h. Things to Be Avoided by Employees. - Milkers and other handlers shall refrain from putting the hands to the nose and mouth. Evtuy~employee shall ~exercise great care to prevent milk contamination by droplet infection from nose and throat secretions. Em- ployees shall be required to wash and dry their hands upon leaving the toilet rooms. Spitting shall be pro- hibited in the parlors and in all parts of the dairy building where the milk is handled. These precautions are necessary to avoid possibility of any disease- producing bacteria getting into the milk. Smoking is prohibited during the time of milking and bottling. PAGENO="0083" 77 Sec. 3. Milking a. Protection of Milking Lqui~inient from Con- taininatioii. (I) ( Janing of IIiill~i1ig lar, blur milking. - ~`Oile(l l)(l(liIIg 11)(l Inanhir' shall lIe ri- moved from Ill milking barn at eat twice daily, and [lie floors shall hr sweilt and k1t free from re fuse. Such cleaning shall he done not less [harm one hon r before the milking [jill. (See Title ~, ~e 2, b) (2) Spraying to (lestroy flies. - Spraying or other efforts to eliminate flies ~liall le (loim(~ l)y materials and methods approved l)~ the Sanitarian; they should not be done (luring or immediately before milking. (3) Feeding hay after milking. - If hay is fe(' in the milking barn, it shall be brought into the narn only after milking. (4) All cows shall be milked into stainless steel or glass lines leading to a holding tank equipped with a recording thermometer. The milk shall be ccx~le(l promptly to 40 degrecs F. Provisions shall be made for prompt and effective cleaning and sterilization of the lines and equipment as soon as practical after the last cow has been milked. The lines and equipment riiust be given bactericidal treatment just prior to use for the subsequent milking. b. Preparation and Handling of Cows.. (1) Clipping. - Long haim shall be clipped from the udder and flanks of the Cows, and from the tail above the switch. The switch should be cut to clear the ground or platform by at least four inches. If this is not desirable with pure bred animals then the switch shall be washed often enough to keep it clean. * (2) Cleaning. - Every cow used in the produe- tion of Certified Milk shall be clean before milking. Whether cleaned by dry grooming or hosing, the cow's udder must be given particular attention by wiping * with. cloths used exclusively for this purpose. At the. tni of milking no water shall he running down tim udder and off the teats. (3) Examination of fore-milk. - At the time of even' milking and under t1I~ supei~ision of the herds- man . or some delegated m:omnpetent-and reliable lore- man, the first streams of milk from every teat shall be rejected. It i5 required that such milk shall he examined for evidence of mnastitis by examination of the fore-milk by means of a suitable strip cup or equally satisfactory method appruved b.y the Coin- mission. Such milk shall not he milked upon the floors or into the gutters of any stable or building where COWS arc allowed to he down or remain after PAGENO="0084" 78 milking. If any abnormal milk is disclosed by the strip cup, the milk from that cow shall be discarded and the cow shall be retnovc(I from the milking herd and shall not he returned until approved by the Vet- erinarian (See Title 7, Sec. 3, e and f). (4) Milking. - Milking shall be done rapidly and quietly and the cows shall be treated kindly. Managed or rapid milking procedure is recommended. (5) Milking three-quartered eOWS. - In tern. P V~CUU~ on the UOUSC(l teat cup through the use of a rubber cap or plug specifically manufactured for this l)tlrpose. This procedure will allow the milking ma- chine operator to nianipulate the unused teat cup as to prevent any possibility of contamination. (6) Milker'~s hands. - Adequate and conveniently located lavatory facilities shall be provided for the milkers. Immediately before milking, the hands oi the milkers shall he thoroughly washed an(l scrubbed, using detergents (liquid or powkre(l), running water and brush, and carefully dried on clean individual towels. `Ihe milkers' hands shall be clean and dry at all times, lie will not be required to wash his hands be- tween the operation of each cow unless his hands become soiled or wet. Sec. 4. Milk Handling and Processing a. Collecting and Filtering. Promptly after the milk of each cow is drawn, it shall be removed from the barn `to the milk receiving room and from there to the (lairy building. Milk shall be transporte(l from the milk receiving room to the dairy building con- veyed in approved sanitary vessel to the point of processing or bottling. The milk shall be passed through modern filters. A sufficient number of filters shall be proVi(le(l for every milking so that they may he changed frequently if necessary. Filtering may be (lone either in milk receiving rooms or in the dairy building. No filter shall be used at more than one milking. h. Cooling. - immediately after reaching the dairy buihuing the milk shall he cooled to a temperature below 40 degrees F., and except during process of pasteurization shall be maintained at a temperature above freezing and below 40 degrees F. until de. livere(l to the consumer. c. Processing, Bottling and Sealing. (1) Certified Milk shall be bottled and sealed by means of approved meehanieal ei1uipmmn'nt on the farm where it is 1)rOlltIer(l, e\('ept that wit I. the approval of the local Medical Milk Commission; Certified Milk PAGENO="0085" 79 from one farm may be processed and/or bottled at another Certified Milk farm and labeled with the cap of either farm. A producing farm may include a number of units und~r the same farm and Commission supervision. A certified producer may transport his milk in an insulated, stainless steel tank truck properly sanitized and in an insulated, refrigerated truck, to a processing plant other than a certified farm, its equipment, the methods used and the standards maintained shall be subject to the control of the local milk commission, and it is their responsibility. All such certified milk must be processed in sanitized equipment, bottled and sealed prior to any other grade of milk. The label* of this milk must carry the name of the Certified farm, the supervising milk commission, processor and distributor. Certified Milk in the finished package product must comply with standards for Certified Milk, in Title 5. (2) Milk bottle caps and other closures shall be stored in dust-tight packages in a clean room and shall at all times be handled in such a manner as to avoid contamination. After the milk has been cooled and bottled, the bottles shall be capped and sealed immediately with a closure approved by the Com- mittee of the American Association of Medical Milk Commissions, Inc. and in a manner satisfactory to the Certifying Commission. The bottle caps shall be un- contaminated and shall be applied only by a suitable capping machine which diminates the possibility of contamination. Outer milk bottle hoods shall be handled in such a manner as to avoid contamination of the, inner surface. Closures, shall be of sufficiently strong and durable material to withstand leakage or puncture dunng handling, transportation and delivery of the milk. They shall be of such form. that they will cover completely the pouring lips of the bottles and it is desirable that they shall be of such construction that when once removed they cannot be replaced upon. the bottles without detection. (3). Outer milk bottle closures whether made of .one or more layers of material and used without an additional plug cap are defined as single closures. * Those used over a plug cap are defined as double * closures. All types of milk bottle containers, caps or * closures shall be subject to approval by the local com- mission and the committee of the A.A.M.M.C. on Milk Bottles, Containers and Closures. Both the seal of the `A.A.M.M.C. and the script "Certified Milk" must appear on all Certified Milk outer closures. Block letter of the words Certified Milk is disapproved. PAGENO="0086" 80 (4) Paper, glass, plastic, or other approVe(I coil- tainers may be used for Certified Milk if they meet the requirements for glass bottles as described in paragi~aphs 2 and 3. - -- (5) Other or novel methods of milk handling, processing, packaging, storage or (listribu tion may be temporarily permitted by the Committee on Methods & Standards, subject to whatever controls and con- ditions it iiiay (leelli necessary. d. Labeling. - The approved container used shall be marked on their exposed surface with the approved copyrighted and seal of the American Association of Medical Milk Association of Medical Milk Commis- sions, Inc., the name of the Certifying Commission, the name of. the producing farm and other informa- tion as required by the local medical milk commission and the State or local boards of health. (See Title 8, Sec. 4, c) It is recommended that bottle closures he of the approved golden yellow color. The printing on exposed surface of the closure should be in legible type. Sec. 5. Transportation and Distribution a. Equipment. - During transportation, milk shall l)e kept properly cooled and the containers (bottles) shall be kept reasonably free from dust and dirt. Trucks, trays and crates shall be kept clean. The Medical Milk Commission shall exercise its authority to determijie the type of truck necessary to safeguard Certified Milk under the climatic conditions existing in its area. Approved shipping cases shall be used so that Certified Milk shipping cases shall be used so that Certified Milk can be properly cooled and main- tained i~t a low temperature. Ice shall come from approved sources free of coliforni contamination. b. Temperature. - Distributors handling Certified Milk must keep it at a temperature above the freezing point and below 450 F. from tIme time it is received until delivered to the consumer. This means that bottles shall be well packed in ice or refrigerated in warni weather, and shall not be allowed to freeze in cold weather. c. IJelivery Time Limit. - The milking in any con- secutive 24 hour period shall constitute a day's pro- duct. Certified Milk is a premium product and should be delivered to the consumer in the shortest possible time after production as determined by each individ- ual milk commission, with a maximum time limit of 144 hours (6 days) from the close of the day of pro- duction. This will insure proper distribution of the premium milk. However, it should be noted that Certi- PAGENO="0087" 81 fled 1\lilk is good after this (late. Extension of this time may be granted by the local nle(lical milk corn- mission with approval of the MethIO(lS and Standards Conrnii ttee. d. Bottles From Quarantined Homes. - Bottles shall not be collected from a house in which a com- municable disease exists except under conditions pre- scribed by the health authorities. Sec. 6. Preservation of Vitamins and Good FIavo~ In the handling, holding and distribution of milk, oxidation reactions may take place which tcntj, to destroy ascorbic acid (vitamin C), to cause the (level- opmcnt of oxidized flavor and possibly to cause other less noticeable effects. To avoid these results the folowing precautions shall be observed: The milk shall only be allowed to come into con tact with properly cleaned and sanitized rubber ni ilk ing parts, stainless, steel or glass. If chlorine solution is used for sterilizing equipment or utensils, it must be thor- oughly drained out before milk is allowed to enter. In the handling of milk IWO IC~ssary exposure to sunlight shall be avoided and when delivered to the custmner the milk shall be placed where it will be protected from sunlight. (See also htle 3.) As a control on the extent of oxidation changes in milk, ascorbic acid tests, as described in Appendix, See. 9, are recomlnen(le(l. TITLE 9 Personnel, Medical Supervision, etc. Sec. 1. Supervision and Reports The Physician appointed by the Commission shall have medical and hygienic supervision of all em- ployees and all other persons on a farm or plant pro- ducing or processing Certified Milk. lIe shall make reports to the Commission and farms, as hereinafter indicated in this Title 9. Sec. 2. Duties of the Physician a. Medical Examinations. - Every person to be employed in the dairy, (lorflhitories, or boarding house in any capacity whatsoever shall be under the super- :%i$IOI~ of the Physician and may be in receipt of a medical examination report card before. I he employee begi us work. The phvsicia ii in taking the hi story a recording his exam iu)atioii shloLul(l bear in ~im uuud rsl)eOiallv, such; a~ tuberculosis, typhoi(l fever and PAGENO="0088" 82 other enteric diseases, an(l the streptococeal and staphylococcal in fections. No person with active tul)erculosis 5110111(1 he hire(1 ilil x-ray examination an(l/or skiii test is mandator~'. Persons with a past history of typhoid fever should not he hired until the physician is satisfied that he is not a carrier of typhoid organisms. A stool examination for typhoid bacillus and other enteric pathogenic organisms shall be made. A throat culture should be made to rule Out a (Ii phtlieria carrier, and when indicate(l for hemolytic organisms. It is recommended that for the informa- tion of the physician every new employee shall have his blood tested by the VDRL or equivalent test. Satisfactory evidence of recent successful vaccination or immunity against smallpox shall be presented. After successful vaccination an employee shall not be allowed to milk or handle cows until vaccination has healed. All members of the families of employees on the farms and other contacts shall be under the super- vision of the Physician. Employees working in the niilki ng and plant area or who are in close contact wi LIi the milk shall he examined liv a physician every ninety (90) (lays. At other times the Physician shall cond net such medical e xa mi nations of employees or other pei~ons on the farm as he or the Milk Com- mission think necessary and have suitable laboratory tests made whenever it is deemed advisable. He shall see that fresh and reliable specimens are furnished to the laboratory. All examinations shall be Cofl(lUcted by laboratories and physicia mis a ppoin ted a mid ap- proved by the Commission and satisfactory to the health authorities. Complete records shall be filed with the Commission. b. Medical Inspection. - The physician may visit the farm if he or the Commissi n deems it advisable. lie shall be given an opportunity to examine and interview all employees and residents of the farm, and shall report to the Milk Commission upon its blank forms supplied for that purpose. This report shall be countersigned by the farm owner or superintendent and ~ 1°l1Y shall be kept on file at the farm for one \ear. C! Special Examinations. - Upon report from the kmim~ owner or superintendent of a farm or upon in- lornialion from any other source, that any illness or carrier state capable of transmission by milk is sus- to exist on tIme farm, or among the employees, of the farmmm. it shall lu Lime dii t~ of the Physician to take inmniediate steps to safeguard tIme milk. The Pimysieiaim shall examine tiim patient or suspect and PAGENO="0089" 83 ~t~urc In msel I. tIi~I(. (lie person is atten(le(l by i physi- cia ii Iii good stan (Ii tig. .llie li)Vsieiaii shall iirotii ph v report any ease o I contagious disease to the ( ominis- sioti and the propi~r heal (Ii aut liorities and shall see that (lie patient is removed from (lie prenlises or that adequate quaranti II'~ is established and inaintai ned. Sec. 3. Duties of the Farm Owner or Superintendent It is the duty of the fariti owiur or superintendent to exclude from work and contact with the cows or in (lie handling of ittilk or of milk utensils any, em- ployee who tiiay have sore throat, fever, (liarrhea, skiti eruptwn or acute respiratory in fiction, to notify the Pitysiciati and to follow such instructions as the Miysieian Illay give. Sec. 4. Duties of Employees It is the (luty of every eiliployec to report iiiiinedi- ately to the farm owner or superintendent any illness which he ittay have, such as sore throat, fever, diarrhea ski,, eruption, or acute respiratory infection and also to report such ill ness to the Physician at the ti inc of his inspection. lail nrc of an employee to make such a report and to follow the directions received is to be regarded as sufficient cause for his (lisnhissal. Sec. 5. Management of Communicable Infections No persons a If eted with any communica ide disease which may b~ transniitted through iiiilk, or who has recently been exposed to such in fection shall be eiii~ ployed in the produ(:tion or handling of Certified Milk. No person known to be a carrier of any coni- municable disease known to be milk-borne shall he eiiiployed or reside on a Certi lied Milk fariii. Persons known or suspected to have had typhoid fever shall not be employed except with the approval of the Milk Commission and with the knowledge and consent of the proper health authorities. In the evetit that any person employed or residing on a Certified Milk farm becomes affected with any disease which titay be transmitted through iiiilk such persons shall inimed- iatelv be removed (rout the fartut or properly isolated tinder the direction of the Physician and the Milk Coni~uiissioii and the proper health authorities notified. Sec. 6. Records of Employees In order that records may be readily available for inspection by proper officials there shall be kept on the dairy premises as well as in the Commission Office a record of every employee which shall give his PAGENO="0090" 84 iianie ali(I address . . . date of dO ploy iIidfl t, 1115 mcdi- cal history, results of physical examination by time l'hysieian, and time results of army laboratory tests. `lime Physician may check this record against the tune hook or ti iiii record. Any al)pl meant for dip1 oyment on a Certified Milk farm or il ii ciii pl ny di' wlm 0 may be rejected or dis- charged l)ecausc of being a carrier of pathogenic organisms of diseases transmissible through milk shall be reported by the Conmimmission to tIme Secretary of the Anmerican Association of Medical Milk Coni- iimissi otis, lii c. `lIme ~emritarv of (lie \ssociatioii mas' report [lie lathes of' such i imdi'~ iii miab- It) all the \led ical Milk Commissions of (1w As5uciation. PAGENO="0091" 85 APPENDIX Approved Laboratory Methods and Recommendations Sec. 1. Total Bacterial Counts TotiLl bacterial counts of Certified Milk shall be made by the agar plate method. The amounts of milk inoculated into these plates shall be 0.1 and 0.01'ml., or in such amounts as to insure plates containing more than 30 colonies and fewer than 300 colonies. See latest edition of th~ American Public Health Associa- tion, Inc., Standard Methods for the Examination of Dairy Products,. or as outlined under Section 4, page Sec 2 The Determination of Coliform Organisms The presence of these organisms in unpasteurized milk usually indicates unclean milking, contaminated Utensils or improper handling of milk. Rarely they ~rnay. come from infected udders. Their presence in pasteurized milk indicates improper pastcuri'i.ation or contamination of the milk after pasteurization. Prop- erly pasteurized milk should contain no organisms of the coli-aerogenes group. The direct plating and over laying with medium of 1 ml. amounts of Certified Milk is desoxycholate agar or violet red bile agar is recommended, since this gives a direct enumeration of coli and aerogenès colonies of characteristic redcolor and makes unnecessary further. confirmatory tests unless it is desired to differentiate coIl from aerogenes organisms. The growth of all Gram positive organisms is inhibited, or greatly re- tarded by this medium. For further details see latest edition of A.P.H.A. Standard Methods for Exaniina- lion of Dairy Products. Sec. 3. Heat-Resistant Bacteria in Milk a. Thermophilic.spore-forming bacteria. Seldom or never are spore.forming bacteria found in the cow's udder. Milk drawn from the udder under the cleanest conditions should contain few or no bacterial sp9rcs. Cow manure and dust contain many spores, as may dirty milking utensils. The finding of bacterial spores in milk, therefore, indicates contamination from one of the above sources. Bacterial spores are not killed by pasteurization. If miLk is heated at 80° C. (176° F.) for 15 minutes, the vegetative bacteria are killed and only the spores remain alive. Many of these spores PAGENO="0092" 86 ire from ~uiaerohic I) eLena an(1 islien grown in milk mm ruler nmmaerohn condit ions ~m lien produce gas or co- agulation amid sometimes (IlgeStion of the milk. ihe following ti~st is a mo(hulcation of that de- sen bed l)y \Veinzirl. into clean, dr~ test Lu bes plugged with cotton, place ~ibøimt 2 ml. of pet~o1atum and sterilize them iii the hot air oven at 160° CL (320° F.) or over br at least ont~ hour, or until the cotton be- gins to turn brown. Ten ml. of each iiiilk to he tested are pipetted into each,of 10 of the above tubes. The tubes of milk arc then heated in a water bath at 80° C. (176° 1".) for 15 minutes. During this time the petrolatuni melts arid Conies to the surface of the milk. The tubes of milk are then to be cooled to room temperature and incubated for 72 hours. Gas forming in the milk raises the petrolatum up the side of the tube. l)igestion is indicated by clearing of the milk. Certified Milk should rarely show gas formation; coagulation or digestion in any of the tubes. Other grades of milk, whether pasteurized or raw, usually show gas formation, coagulation or digestion in most 0.1 the tubes. A negative tube is o~j~jn which the milk shows no evidence of growth, whatever. b. Thermoduric.non.spore.forming bacteria. Cer- tain non-spore-forming bacteria are resistant to pas- teurization and may ~ausc high counts in pasteurized milk. Such bacteria niay accumulate in milking ma- chine part~, cooling, bottling or even pasteurizing equipmenL Some may infect the udder of the cow. They may pass unnoticed in grades of pasteurized milk which are allowed to have counts of several thousands per ml., but not in Certified Milk-pas- ten rized which must have a count of not more than 500 per m~1. lo deternune the presence of thermdduric bacteria heat a sample of milk, in. a well stoppered tube in a water bath at 62.8° C. (145° F.) for 30 minutes and then plate out 0.1 ml. in Trypticase-Soy agar (BBL) containing 0.2% of dextrose or Standard Method agar. Then incubate plates for 48 hours at 350 C. (950 F.) and `make counts. Any: form of Certified Milk should seldom show any colonies. Thermoduric bacteria may be eliminated by thorough cleaning and sterilization of milking machines and milk handling equipment amid withdrawal of infected cçws from the milking line. Sec~ 4. Examination for Hemolytic Streptococci~ Deep colonies in1kh~ood agar pla~s are necessary for the recognition and differentiation of streptococci. The surface inoculation of blood agar plates is not PAGENO="0093" 87 satisfactory. Blood agar plates poured as here recom- mended may also serve for determining the total bac- terial count of milk and in fact, for Certified Milk, blood agar is sometimes a more suitable medium. If blood agar is to ~be used for making total counts, use only 5% of blood in the agar. The agàr used shall be a meat infusion agar, as described in Standard Methods for the Examination of Dairy Products; latest edition, or Trypticase-Soy agar (BBL) without. dcx trose, or Heat Infusion Agar (Difco). Samples of milk should be diluted 1:10 and 1:100 in sterile salt solution (0.85% NaCI). One ml. amounts of these dilutions shall be pipetted into sterile Pctri dishes. To the melted agar cooled to between 45° C. (112° F.) and 50° C. (122° F.), add 5% of sterile defi- brinated horse or rabbit blood; human, cow or sheep blood may be used if one has familiarized himself with the appearances produced in them. The blood is im- mediately well mixed with the agar and 10 to 12 ml. are: poured into the Petri dishes containing the milk. The Petri dishes shall be rocked immediately to insure uniform mixing of the milk with the medium. When the agar has solidified the plates shall be incubated in an inverted position at 35° C. (95° F.) The Petri dishes shall be 9Y2 to 10 cm. in diameter and shall have glass or plastic tops; porous tops may not be used. The plates should he examined after incubation overnight and again after incubation for another day. Beta hemolytic streptococci produce about the deep colonies clear colorless zones of hemolysis. When studied under the low power of the microscope beta zones of hemolysis should show no blood corpuscles remaining next to the deep colony. In the examina- tion of blood agar plates it cannot be assumed that all colonies with beta zones are streptococci since certain strains of staphylococci, colori bacilli ~and other or-. ganisms may also be hemolytic. Gram stained smears from' the colonies or from subcultures from' ,the colonies must be:examined. For the identification of hemolytic streptococci two methods are' availible, the' cultural' method and the serological method. CUL- TURAL METHOD - For strongly presumptive diag- nosis1 (1) from the blood agar plates fish deep beta' bemolytic colonies: (2) inoculate from the same colony, or from, a broth culture of the colony into `Brown, J. H.: Significance of the Hemolytic Strep- tococci Found ~n Milk. Cornell Vet. 1937, XX- .VH,l0o.. , , PAGENO="0094" 88 (a) 1%. dextrose broth, (b) sorbitol broth and (d) hip- purate broth.2 Strains which are sorbitol-negative, hippurate-negative and which attain a pH not lower than 4.8 in dextrose broth after incubation for 48 hours are to be suspected of being human pathogens (usually serological Group A, occasionally Group C). Such straitis shall be sent promptly to the nearest Refer~nce' Laboratory of the A.A.M.M.C. for further study and, if possible, should, also be studied by the local Commission Laboratory. instructions as to de- tails and for further study may be obtained from the Committee on Methods and Standards of the A.A.M.M~C. The hemolytic mastitis streptococci of serological Group B are sorbitol-negative and hippur- ate-positive. There are also many non-hemolytic mnastitis streptococci. The so-called animal strains of hemnolytic streptococci or serological Group C, less frequently a cause of mastitis, are sorbitol-positivc and hippuratc-negative, as are also those of Group E by the usual methods of testing. Hemolytic strepto- cocci of serological Group D attain a final acidity of pH 4.0 to 4.5 in dextrose broth, are variable in their sorbitol and hippurate reactions, do not lyse human flbrin, and arc resistant to the temperature of pas. teurization. SEROLOGICAL METHOD - When suit. able Group-specific immune sera are available hemoly- tic streptococci may be. rapidly identified by the preciptin method of Lancefleld. ~ A simplified tech- nique4 makes possible the identification of the' sero- logical Group within 24 hours after the colonies are fished from the blood agar plate, and with a minimum of expense and labor; A description of the technique may be obtained from" the Committee on Methods and Standards of the A.A.M.M.C. Since cultural study is necessary for the identification of species within the groups, strains of streptococci found to belong to Groups A or C should be sent to the nearest Regional Laboratory of the A.A.M.M.C. for further study. So far as is known only Group A hemolytic strep- toco~ci have ca~ised milk-borne epidemics of septic 2Ayers, S. H., and `Ri~pp, P.: Differentiation of Hemolytic Streptococci from Human and Bovine Sources by the Hydrolysis of Sodium Hippurate. Jour. Inf. Dis. 1932, XXX, 388. 3Lancefleld, R. C.: A Serological Differentiation of Human `and other Groupsof Hemolytic Strepto- cocci. J. Exper. Med., 1933, 199, LVII, 571. 4Brown, J. H.: Simplified Method for Group~ng Streptococci by the Precipitin Reaction, J.A.M.A., 1938, CXI, 310. PAGENO="0095" 89 sore ~throat or scarlet fever.5, If any cow should be found tO harbor GroupS A heinólytic streptococci si~c shaII~.be imniediately and permanently renu)ved from the herd. The milk from cows harboring (;roisi~ C streptococci shall not. be used in CertifiedMilkpro- duction,. and such animals shall be segregated from the milking herd. Cows harboring strçptocod~i of Group B shall be regarded as carriers Of mastitis strep- tocou.i and putt ntmal ~ourtts of inft.ctiomi for olin r animals in the herd. Where facilities permit it is recommended that at least once a month samples of milk should be taken from groups of about 10 cows or from the milking pails before they are emptied into the receiving tank; that these samples should be diluted 1:20 with sterile salt solution (0.85% NaCI), plated in blood agar and ~.tudicd for hunolvtmt ~trt ptocolL cm In cast thc pri s ence of streptococci pathogenic for man is suspected in any of the group sampks milk from the individual cows of this group should be cultured and any.:eow found to harbor time organisms should be permanently removed from thç herd. This same procedure is to be adopted if at any time there is any reason to suspect that pathogenic streptococci may have gained en- trance to the milk supply or that ammy ~ases of milk- borne streptococcal disease have appeared among con- sumers of the milk, or. that there may be present in the herd cows shedding large numbers of bacteria in their milk. This same procedure is of value in the differential study of mastitis organisms. In the routine streptococcus survey of milkers and other personnel, swabs from the throat (and nose, if advisable) shall be sent promptly to the laboratory and there cultured by some such method as the following: (1),Plac~ the swab into a test tube of about 5 ml. of broth ahd shake off the bacteria. One s~nahl loop of the broth suspension mnoculatid into a 10 or 12 ml. tube of melted blood agar prepared as de-. scribed above, usually makes a proper dilution for a good plate which should contain not more than 100 to 200 colonies of all kinds. (2) Streak the swab across one edge of the solidified surface of a nutrient agar plate (preferably infusion agar without blood or. dextrose, as described above). With the wire loop streak the material from the original streak over the remaining surface of the agar. Over the inoculated 5Tdlet, W S and Garner, R L The Fmbrmnolytmc Activity of Hemoly tic Streptococci, J. Exp. Mcd., 1935, LVIII, 483. PAGENO="0096" 90 surface pour not more than 5 ml. of melted blood ~igar prepared as described above. After incubation of the plates deep colovtio~ with beta zones of henio- lysis are to be fished and the, streptococci identified as described above. Sec. 5. Suggested Routine Bacteriological Procedure The following procedures will answer the purposes for the. routine bacteriological examination of Certi-. fled Milk. 1. Plate 0.1 ~nd 0.01 ml. of milk in blood agar for total count and the detection of hemolytic streptococci. 2. Plate 1 ml. of milk in desoxycholate agar, or violet red bile agar, for detection of coliform bacteria. 3. Prepare 10 tubes of 10 ml. of milk under petrolatuan for the spore tests as described. 4. If the counts arc high, examine for thermophihic and tlier- anoduric bacteria (Appendix, Sec. 3, a; Sec. 3, b). `Sec. 6. Diagnosis and Control of Mastitis To supplement physical examination by the vet- erinarian, bacteriological examination of the milk and evi(lenee obtained by USe of the strip cup, the follow. ing tests are valuable aids for the diagnosis of mastitis but no one of theni alone need be regarded as con- clusive unless it is strongly positive; the ph of the milk a~ determined by the use of brom-thymol blue or hrorn-cresol purple, determination of chlorides, the catalase test, the California Mastitis Test, the rennct test, leucoc~te count, milk sediment test, smears from milk sediment or incubated milk samples, the hlotis test. For further information see, "Bovine Mastitis", Schalm, 0. W.; Carroll, E. j. and Jam, N. C. (lea and Feibiger,-.1971), and for screening technics see the latest (~(lition of `~Standard Methods for the Examination of Dairy Products," Walter, W. C. (Ani. Public I lealth Association, Inc., 1967). It has been proven that the cow's udder is most readily infected after milking by the growth of bac- teria up through the teat canal in' the residue of milk which may a~ernain at the teat opening in the canal. Cleaning the teats after milking is a rational prophy- lactic procedure for the prevention of udder infection.. The following procedure is suggested: Use a chlorine solution, 250 ppm; or losan, .25 p~nn; or any approved teat-dip; and spray or dip each teat after milking. lithe teats are dipped, `each teat should be dipped its full length into a cup of any above solution; all four teats may be dipped into the same cup, but a fresh quantity should be used for each c?w. PAGENO="0097" 91 Sec. 7. Sanitizing Methods and Materials a. High Temperatures.- This method of sanitizing equipment is efficient if properly (lone but worthless if the recomniended' times and temperatures are not maintained. Steam confined in a suitably constructed cabinet or closed piece of equipment sanitizes effec- tively but whemi allowed to escape freely into the open mimay be ineffective. The following conditions should be maintained: (I) Steammi - Exposed for at least 15 minutes to a temperature of at least 2000 F'. (93.30 C.) in a cabinet or in closed equipment provided with a thermometer Jocated in the coolest area. (2) hot Water - Exposed for at least 5 minutes in water maintained at 190° F. (87.8° C.) or abo~'e at the outlet as indicated by properly placed thermometers. (3) Dry heat - Exposed for at least 30 minutes to a temperature not less than 225° F'. (1070 C.) in a properly designed dry heat cabinet or room equipped with a thLriilomLttr in tlit. tookst arca this txpo~urc should include neither the heating-up nor cooling time. It also implies that the equipment shall be moist when placed in the cabinet or room. b. Chemical Sanitizing Agents. - The reconunenda- tions of the manufacturer should he followed in using these preparations provided they meet Milk Commission and health [)epartmuent requi remflentS. (1) Chlorine and quarternary amnmoruum disin- fectants - The following prinriples shiomil d be kept in mind; (a) A concentrated forum of the sanitizing agent should be obtained, known to have high stability arid efhlciericy. (b) Fresh solutions of these products, par- ticularly chlorine, should be prepared for each opera- tion during the day. (c) Equipment must be clean and free from organic matter since these agents are rapidly inactiv~~ted by organic matter, and are ineffective un- less brought into intimate contact with the bacteria. (d) Soaps and many synthetic organic (letergents have been found to reduce the effectiveness of quarternary ammnomIiuni~ disinfectamits and should not he used in :solutions with these agents: tri-sodiu in l)liosphate may be used. (c) Caution in the use of chlonmme solutions should be observed to prevent corrosion of metal surfaces. (f) The following concentrations of these chemical disin fecting agents are recommended for dairy sanitizing purposes: 100 ppm, for the soak method of treatment. 200 ppm. for the flow method of treatment. 300 ppm. for the spray method of treatment. .50-100 ppm. for final nnse of bottles washe(l by mechanical bottle washers operated with caustic treatment. 52-266 0-85-4 PAGENO="0098" 92 20()-30() ppm. in rinses for cows u(ltlcrs and as a hand rinse. (2) Caustic solution in mechanical bottle washers - Cleaning and sanitizing of multi-use bottles is of extreme importance because of possible contamina- tion' from many sources during distribution. In opera- tion of mechanical bottle washers there is an essential relationship between temperature, time of contact and concentration of the caustic solution. The time of contact for each particular washer should be ob- tained from the manufacturer, accurate thermometers kept in use and a test set used regularly to maintain proper solution strength. For a contact of 5 minutes a caustic solution strength of 3% at 1300 F. (54.40 C.) is generally recommended. (3) Caustic or lye solutions for rubber parts of milking machine tc.at cup assemblies - A concentra- tion of from 0.3 to 0.5% is recommended. This type of solution is generally preferable to other commonly used sanitizing solutions because it possesses the property of dissolving casein and fat residues, particu- larly in machines that are not completely disas- sembled after each use. Sec. 8. Determination of Curd Tension of Milk (American Dairy Science Association)' Reagent: The coagulant consists of 008N hydro- (:hloric acid to which U.S.I'. (1:300) dry pepsin has been added in the ámóunt of 450 mgms. per 100 ml. This solution may be kept refrigerated and away from light for not more than 10 days, but in case of doubt, results obtained with it must be checked against results obtained using a freshly prepared coagulant. Apparatus: The instrument used in me~suring the curd tension shall indicate in grams2 the force neces- sary to cut the coagulum obtained as described below, using the standard type of knife. The motion of the knife or the vessel containing the coagulum shall be automatic and at the rate of one inch in 7 to 8 seconds, obtained by lowering the knife or by raising the vessel containing the coaguluin. The sensitivity of. the instrument shall be such that readings can be made to an accuracy of + or - 1.0 gram. Note: The Hill method of determining the curd tension of milk is described in editions of Methods and Standards previous to 1941. 1J. Dairy Science, 1941, XXIV 825. 2Submarinc Signal Co. Curd Tension Meters made priorto July 1941 do not read in grams. Reading `may be converted to grams by multiplying by 1.10. PAGENO="0099" 93 Standard Knife lli~ knif shall t,oiisist of ut,ht radial blades, each having 9/16 inches of lineal cutting edge and being 0.020.inches thick, spaced equally and enclosed by a circular ring blade 1 3/4. inches outside diameter, 3116 inches high and 0.031 inches thick. The radial blades shall be attached t~ inside of the circular ring blade and extend upward above it 2 1/16 inches, being reduced to a width of 5132 `inches above the circular ring blade. Their upper cdges shall be curved inward' andattached to a central spindle 5/16 inches in diameter. The lower or cutting edge of the circular ring blade shall be tapered from the outside at an angle of 30 degrees to the knife axis, to a dull knife edge. The lower or euttin~edgcs of the radial blades shall `be, tapered on each side at an angle of 15 degrees to th~ knik axis tb a dull knif edgc. 1h cutting; edges of the ring blade and tl~e radial blades shall lie approximately in the same plane, deviating not more than, 1/32 inches~ The total linear cutting edge. of the, knife shall be 9.8 inches 0.10 inches. All joints shall be mortised and soldered smoothly and the knife tonstructed' of a noñ-corrosiv,e metal. Coagulation Vessel: The vessel used for coagulating the milk shall be a heavy walled glass jar 3 to 4 inches high (inside) having an inside diameter of 2 3/8 inches + or - 1/8 inch.1 Sampling Pipette: `l'he pipette used for measuring and adding the milk sample to the jar containing the coagulant shall be one made to deliver 100 ml., which has had the tip removed and which empties by gravity in approximately 4.5 secori (Is. Water Bath: A suitable water bath shall be used to temper the jars containing the coagulant before the sample of milk ,is added and to hold the milk and coagulant at the proper temperature `during the co- * agulating period. Thç water levd shall come up on the outside of the jar to a point no lower than the * milk and coagulant level on the inside of the jar. The volume of water shall be such that the temperature * does not change more than 1.00 F. `during the 10 minute penod of cosgulation and preferablyshould be agitated. Procedure: Introduce 10 ml. of the coagulant into the coagulation v~cl and set the vessel in the water bath at 950 F~. (35° C.) The vessel containing the co- agulant should be tempered for no less than 3 minutes before introducing tli e milk samj.de. ` * The undiluted milk to be tested `is tempered to 950 F. (350 C.), as experience dictates, being'careful not to exceed 1000 F. (37.80 C.) in the process. lime PAGENO="0100" 94 tempering ShOLIld be ~icconiplishcd in a five minute period immediately preceding the pipetting of the sample. Introduce 100 ml. of the sample into the coagulation vessel, using the tipless 100 ml. pipette. The following and doubtless other jars meet these specifications, W. M. Welch Scientific Co., Chicago, No. 4612A (8 oz~); Central Scientific Co., Chicago No. 10396 (7~4 ozs.); Owens Illinois Glass Co., Toledo, Mayonnaise jar (8 ozs). This is to he accomplished by holding the pipette vertically over the center of the vessel and blowing the sample from the pipette as rapidly as possible. No further mixing of the vessel contents is to be employed and the vessel should not be disturbed in the water bath. Place a watch glass or other suitable covering over the vessel immediately. hold the contents of the coagulation vessel at 950 F. + or - 1.00 F. for 10 minutes, the time in the water bath being adjusted so that the cutting of curd by the standard knife occurs at the expiration of 10 minutes + or - 30 seconds from the time the sample was placed in the coàgu!ation Vessel. Reading Results: The curd tension reading is the maximum reading which is obtained at the moment the knife penetrates the surface of the coagulum. The test shall he made in duplicate or triplicate and results, to he acceptable must not deviate more than 5 per cent front the average. The average of the results, so chccking~ constitutes the curd tension of the sample. Sec. 9. Titration of Ascorbic Acid in Milk (New Jersey Agricultural College) Dye Solution: To 0.2 grams of 2-6 dichloropheno- lindo1~hcnol' in a small beaker add 50 ml. of hot distilled water. Break up the lumps with a stirring rod. Decant the (lye solution through a filter and add more water to the undissolved dye in the beaker. Repeat until all is dissolved, then add water to make 1 liter of solution. The solution should be stored in the cold, must be standardized every day and should not be used after it is two weeks old. Metaphosphate Solution: Dissolve 5.0 grams of metaphosphoric acid in 50 ml: of distilled water and add sodium hydroxide solution to adjust the reaction to phi 8.0 to 9.0, This solution is stable. Immediately before using addS 1.5 ml. of glacial acetic acid to 10 ml. of the metaphosphate solution. lasted as 2-6 dichlorobenzenoneindophenol by the l~astinan Kodak Co. The sodium salt of this corn- ~OL1 1111 can also be Lised. Sharp, P. F.: Rapid Method for the Quantitative PAGENO="0101" 95 Determination of Reduced Ascorbic Acid in Milk. J. Dairy Sciences, 1938, XXI, 85. Garret, 0. F.:: Determination of Ascorbic Acid (Vitamin C) in Milk. `J. Milk Tech., 1938, I, 37. Lorenz, A. L., and Arnold, L. J.: Standardization of 2-6 dichlQrop~enolindoplIenol Dye with Ferrous Compound. 1nd~ & Eng. Chem. Anal. Ed., 1938, X, 687. Traum, J. and Henry, B. S.: Boric Acid for the Preservation of Milk Naturally Infected with Brucehla abortus, J. Inf. Dis., Nov. 1930, 47, p. 380. Standardization of Dye Solution: Weigh exactly 0.50 grams of regent grade Mohr's salt (FcSO4 (NH4)2 S04.6H20), dissolve in distilled water, add 20 ml. of glacial acetic, and make UI) to I liter with distilled water. This solution is stable for at least 6 `days~ To 10 ml. of this solution add 4 drops of the metaphosphate solution and titrate with the dye solution to a faint, pink color, visible for 30 seconds. For a blank add 5 drops of acetic acid to a volume of water equivalent to the ml. of the salt solution plus the dye solution used in the titration. Titrate the blank with the dye solution and subtract the reading from the titration of the ~alt solution. One milligram of Mohr's salt is equivalent to 0.2247 mg. of ascorbic acid. Procedure: To 10 ml. of milk add 1 ml. of acidified metaphosphate solution and 10 ml. of distilled water. Titrate with the (lye solution to a faint pink, visible for 30 seconds. For a blank use milk to which 2 parts per million of copper as copper sulfate has been added 24 hours previously. Sec. 10. Tests for Brucella Agglutinins in Milk Preservation and Shipment of Milk Samples. - .\lilk samples for agglutination tests may be taken into one. ounce screw-cap bottles, containing about one- half thimbleful of boric acid crystals. The boric acid arrests the growth of bacteria, preventing souring of the milk, but does not interfere with the titration of agglutinins. Such samples may be sent through the mail without refrigeration. If samples are fresh and refrigerated the addition of boric acid is not necessary. a.. Titration `of Agglutinins in Whey. Antigen. - A smooth strain of l3rucella ahortus is grown in a suitable medium. From this growth aeon- centrated .suspension is made in 0.85% NaCI contain- ing 0.5% phenol. For use in the tests, this suspension is diluted with the NaCl.phcnol solution to a turbidity at which a wire loop, bent at a right angle, just (Jisap- PAGENO="0102" 96 pears from view when lowered 2 cm. into a tube of the antigen (reading 2 with the Gates turbidimeter.) For further information regarding the preparation or availability of suitable antigen communicate with the Central Office, 405 Lexington Ave., New York 17. N.Y. Preparation of the Whey. - 0.5 ml. of 1% aqueous solution of rennet is mixed with 5 ml. of milk drawn from beneath' the cream after the milk has been cen- tri:fuged or has stood until the cream has risen. The milk and rennet must be mixed immediately and al- lowed to clot with the test tube in a slanting position. Place time slanted tube in a 56° C. (132° F.) water bath for 30 minutes or incubate for 2 hours at 37° C. (98.5° F.) Without shaking the tube and by means of a capillary pipette carefully remove about 1 ml. of dear whey. The Test: - In clean, serological test tubes, free of scratches, dilute the whey as follows: Tube 1. 0.6 nil. of NaCI-phenol solution + 0.4 ml. of whey Tube 2. 0.5 ml. of NaCI-phenol solution + 0.5 ml. from tube 1. Tube 3. 0.5 ml. of NaCl-phenol solution + 0.5 ml. from tube 2 Tube 4. 0.5 ml. of NaQ-phenol solution + 0.5 ml. from tubc3 Tube 5. 0.5 ml. of NaCl-phenol solution (no whey; ncgative.control) Discard 0.5 ml. from tube 4, thus leaving 0.5 ml. in each tube. Add 0.5 ml. of diluted antigen to each tube; the tithes, thus containing whey dilutions of 1/5, 1/10, 1/20 and 1/40 respectively. (In testing the milk of-individual cows, higher dilutions of whey are used.) Incubate the tubes for 18 to 24 hours. Do not shake the tube.s during the last 12 hours of incubation. Reading of Results. - Read first by looking down through the tops of the tubes. A compact sediment, as seen in tube 5, is negative; a diffuse sediment, often with curled edges, is positive. After this observation the tubes may be shaken and viewed with a hand lens. A smooth suspension is negative; visible clumps `indi- cate a positive reaction. Interpretation. - For herd milk, a positive result in any tube is indication for testing composite samples of milk from groups of about 10 cows, to be followed by testing the milk or blood of individual anintals within positive groups. For the milk of individual cows, a positive result in whey dilutions of 1/20 or teyond should be. followed by testing the milk from individual quarters and the blood of the cow. PAGENO="0103" 97 b. The Ring Test For. Whole Milk. - Place one drop of the Ring1~est antigen in the bottom of a sniall (Wassermann) test tube, taking care not to allow the antigen to ma down the side of the tube. Add about 1 cc. of the whole milk to be tested. (To homogenized or skim miIk~add 5 or 7 drops of negative cream). Immediately mix thoroughly and allow to stand undisturbed in a . moderately warm place (37° C. (98.5° F.) incubator of water bath if available) for 30 minutes to 1 hours. The antigen is a heavy suspension of dyed Brucella organisms. If the reaction is positive the dyed, agglutinated bacilli will rise with the cream and present a purple cream layer. If the reaction is negative the bacilli remain dispersed in the underlying milk and the cream layer is uncolored. After proper dilution with 0.85% salt solution con- taining 0.5% phenol the Ring Test antigen may also be used for the titration of agglutinins in whey as described above. . If the herd milk gives a positive ring test, composite samples of milk from groups of about 10 cows should be tested, to be followed by testing the milk or blood of individual animals within the positive groups. In taking' milk samples for ring testing care must be taken' to use clean containers free from contamination by other milk. Sec. 11. Detection of Microbial Inhibitants (Antibiotics) `rhis procedure is designed for the qualitative 1 de- tection of small quantities of penicillin in milk. The test organism, Sarcina lutea (A.T.C.C. 934 l),.is main- tained on agar2 slants and transferred every 2 weeks. For the detection of the most minute quantities of other antibiotics more sensitive test organisms3 should be used. Prepare an organism suspension as follows: Streak an agar slant heavily with time organism and incubate, for 24.. hours at 26° C. (790 F.) Wash the growth off with several ml. of nutrient broth4, trans- fer to the surface of 300, ml. of seed agar, in a Biux bottle, and spread evenly over the surface with the aid of sterile glass heads. Incubate for 24 hours at.26° C. (79°F.) Wash the growth from the agar with 20 ml. of nutrient broth. Ad~ust the vol u inc of this hulk sums- pension so that it eon tains approximately 2.8 x .100 viable organisms per ml. as determined by plate count or turbidimetrie measurement. Before the actual test, determine by trial plates time amount of adjusted bulk suspension to he added to yeast-beef agar5 to obtain the optimum sensitivity. [sing this method, zones of inh i hi tion shoti Id hi obtained from in ilk containing PAGENO="0104" 98 as little as 0A)0~ U nits per uti. ( enerally, 0.3 to 0.5 niL. of the inoculum per 100 nil, of agar is satisfactory. Fo prepare the Petri dishes, add 10 ml. of agar2 to sterile plates, distribute the media evenly, and allow to harden on a perfectly levelsurfaçe. The Petri dishes shall be 100 mm. in diameter and 20 mm. deep and shall have porcelain covers glazed on the outside or cover lids with filter pad inserts. The plates should be covered at all times except when media and samples are being introduced. Add the appropriate amount of inoculum to yeast.beef agar5 which has been melted and cooled to 48° C. (1200 F.), mix thoroughly, and add 4.0 ml. to each plate. Immediately distribute the agar evenly by tilting the plates from side to side with a circular motion. Allow to harden and use the plates the same day. Tile milk shall he tested usingeither stainless steel cylinders of filter paper discs. The cylinders 6sliall have an outside diameter of 8 mm., an inside (hanleter of 6 mm. and a height of 10 mm., all dimensions plus or minus 0.1 mm. Using sterile for. c~j~s~,a cylinder dropping de~iôe place a number of cylind~tis on the inoculated agar surface. Fill 2 or more cylinders with the milk sample. The paper discs7 shall be Y2 inch in diameter. Using sterile for- ceps to hold a disc, immerse it in the milk for a second, withdraw it, shake off any remaining droplets with a snap of the wrist, and place the disc on the surface ol the inoculated agar~ Use 2 or more discs for each santple. Include on each plate as a control, a milk sample containing 0.01 unit of penicillin per ml. Incubate the plates at ~6° C. (79° F.) for 16 to 18 hours, after which they are inspected. Certified Milk produces no zones of inhibition around the cylinders or discs. This method was worked out in collaboration with the Division of Antibiotics, Food and Drug Admini- stration, U. S. Department of Health, Education, and Welfare. PAGENO="0105" 99 1Quantitive procedures for penicillin and other anti- biotics~are given in "Assay Methods of Antibiotics" by Grove and Randall, M. D. Publications, Inc., 1955, New York~ 2Peptone 0.6%, pancreatic digest of casein `.0.4%, yeast extract 0.3%, beef extract 0.15%, dextrose 0.1%, agar 1.5%, final pH 6.5-6.6. This and the two subsequent media are available in dehydrated form from Baltimore Biological Laboratory, Inc., Balti- more 18, Md., or Difco Laboratories,' Inc., Detroit 1,Michigan. 3The recommended organisms are B. cereus `var mycoides (A.T.C.C. 11778) for the tetracyclines, B. subtilis (A.T.C.. 6633) for the streptomycins, M. flavus(A.T.C.C.' 10240) or S. subflava (A.T.CC. 7468) for. hacitracin, M.1pyogenes var a~bus (A.T~ C.C. 12228) for. neomycin, and Bord. bronchi- septica (A.T.C.C. 4617) for polymyxin. 4Peptone 0.5%, yeast extract 0.15%, beef extract 0.15%, 8OdiUm chloride 0.35%, dextrose 0.1%, di- potassium phosphate 0.368%, monopotassium phosphate 0.132%, final pH 7. 5Peptone 0.6%, yeast extract 0.3%, beef extract `0.15%, dextrose 0.1%, agar, 1.5%, final pH 6.6. 6Availablè from the S & L Metal Products Corp., 25 Lafayette St., Brooklyn 1, N. Y. 7Available from Carl Schicicher and Schucll Co., New York, N. Y., S and S No. 740-E. PAGENO="0106" 100 METHODS AND STANDARDS FOR THE PRODUCTION OF THE AMERICAN ASSOCIATION OF MEDICAl MIlK COMMISSIONS, INC. PAGENO="0107" 101 METHODS AND STANDARDS FOR THE PRODUCTION OF L. Allen McDonough, M.D. President THE AMERICAN ASSOCIATION OF MEDICAL MILK COMMISSIONS, INC. 960 Johnson Ferry Road, N.E. Atlanta, Georgia 30342 Phone 404-255-1701 Paul N. Fleiss, M.D. Secretary and Treasurer 1842 Hillhurst Los Angeles, California 90017 Charles M. Ozanian, D.V.M. Chairman of the Board Revised 1984 PAGENO="0108" 102 INTRODUCTION Certified Milk Producers have a 91 year history of producing nutri- tious safe, clean milk. Throughout the years the Certified producers have endeavored to produce the highest quality milk in the dairy industry. They have always been leaders in utilizing modern dairy technology. They have alw~y~ complied with Federal, State and local regulations. The American Association of Medical Milk Commissions will always demand that the Certified producers continue to produce the best possible milk and milk products, and where possible improve upon them. Our goal is that Certified Milk and Certified Milk products continue to be health promoting and safe. The American Association of Medical Milk Commissions, Inc. will continue to sponsor research that will help produce the best quality milk and milk products. Since milk products make up approximately 25% of the American diet (the per capita consumption being about 6 oz. milk a day) we intend that by monitoring their products, the Certified producers will give us products that will improve the health, strength and intelligence of the American people. (Adopted by the American Association of Medical Milk Commissions, Inc. - June, 1984) PAGENO="0109" 103 CONTENTS TITLE 1 HISTORICAL INTRODUCTION I TITLE 2 DEFINITION OF CERTIFIED MILK 2 1. Definition 2 2. Raw Certified Milk, the Basic Product 2 3. Pasteurized Certified Milk 2 4. Certified Crleam, Half and Half and Non-Fat Milk 2 5. Special Certified Milks 3 6. Labeling.Special Certified Milks 3 7. Certified Goat's Milk 3 TITLE 3 NUTRITIONAL VALUE AND FLAVOR OF MILK 4 TITLE 4 MEDICAL MILK COMMISSIONS 4 1. Organization 4 2. Duties of Medical Milk Commissions 5 TITLE 5 LABORATORY STANDARDS 6 1. Supervision and Reports 6 2. Bacteriological Methods and Standards 6 3. Physical and Chemical Methods and Standards 7 4. Sediment and Flavor Tests 7 5. Detection of Microbial Inhibitants (Antibiotics) 7 TITLE 6 BUILDINGS AND EQUIPMENT 8 1. Supervision and Reports 8 2. General 8 3. Barns 4. Milking Barn or Room and Equipment 9 5. Milk Receiving Rooms 10 6. Dairy Building 10 7. Dairy Building Equipment and Bottles 11 TITLE 7 VETERINARY SUPERVISION 12 1. Supervision and Reports 12' 2. Herd Management 13 3. Disease Control 13 TITLE 8 MILKING, PROCESSING, DISTRIBUTION 15 1. Supervision and Reports 15 2. General 15 3. Milking 15 PAGENO="0110" 104 4. Milk Handling and Processing . 16 5. Transportation and Distribution 18 6. Preservation of Vitamins and Good Flavor 18 TITLE 9 PERSONNEL, MEDICAL SUPERVISION 18 1. Supervision and Reports 18 2. Duties of the Physician 18 3. Management of Communicable Infections 19 4. Records of Employees 19 APPENDIX APPROVED LABORATORY METHODS AND RECOMMENDATIONS 20 PAGENO="0111" 105 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 1 Title 1 Historical Introduction Certified Milk had its origin in the medical profession. In 1893 Dr. Henry L. Coit of Newark, N.J. formulated a plan whereby he and his colleagues might obtain for infant feeding a supply of clean, safe, pure nutritious milk, the best which the knowledge of the time could produce. In accordance with this plan the Medical Society of Essex County, N.J. appointed a Medical Milk Commission which entered into contract with a dairyman (Stephen Francisco of Caldwell, N.J.) willing and able to produce this milk which was to be "certified" by the Commission and labeled with the copyrighted and trademarked name "Certified Milk". Other medical soci- eties soon followed the example of the Essex County Medical Society and by 1909 there were 58 local Medical Milk Commissions, functioning in dif- ferent parts of the country; each formulating its own methods and standards but showing a remarkable-similarity in fundamental requirements. In 1907 most of these local commissions were organized into the Ameri- can Association of Medical Milk Commissions, Inc. which had for its objects the adoption of uniform methods and standards for the production of Certi- fied Milk and the extension of the movement throughout the country. Four standing committees were appointed: Medical Examination of Employees; Chemical Standards; Bacteriological Standards; and Veterinary Inspections and Protection Against Tuberculosis. The personnel of these committees, giving their services without pay for many years for the development of methods and standards is cause for pride: Doctors W. H. Park, M.J. Rosenau, D.L. Edsall, L.L. Van Slyke, Henry Dwight Chapin, Rowland G. Freeman, M.P. Ravenel, Francis H. Slack, A.R. Ward, Leonard Pearson and others. These committees submitted reports which were adopted by the associations and in 1909 were published in the form of "a Manual of the Working Methods and Standards for the use of the Medical Milk Commission." Since that time the Methods and Standards have been revised from year to year at the annual conventions of the American Association of Medical Milk Commis- sions, Inc. in accordance with the advancing scientific knowledge. Certified Milk has retained a position of leadership in the dairy industry which has exerted an influence far greater than volume of its sales may indicate. It's the object of this Association to retain this leadership and it's the belief of its members that regardless of what subsequent treatment may be given to milk, improvements of the product as to safety and nutritional factors can best be accomplished at the source of production. It is the belief of the Association that Certified Milk is the highest grade of milk obtainable. Recognition of the standing of the Association is to be found in the laws of many states and municipali- ties which require that Certified Milk shall be produced in accordance with the Methods and Standards as currently published by the American Association of Medical Milk Commissions (or words to that effect) and by a similar definition which occurs in the United States Public Health Service Milk Ordinance. PAGENO="0112" 106 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 2 Title 2 Definition of Certified Milk Sec. 1. CERTIFIED MILK IS PRODUCED BY DAIRIES OPERATED IN ACCORDANCE WITH THE METHODS AND STANDARDS ADOPTED BY THE AMERICAN ASSOCIATION OF MEDICAL MILK COMMISSIONS, INC. It is produced under the direct supervision of local Medical Milk Commissions or other agencies recognized and approved by the A.A.M.M.C. Herein the term "Medical Milk Commission" may be under- stood to apply to any such recognized and approved agency. Only milk produced in accordance with the Methods and Standards and by approved dairies shall be labeled CERTIFIED MILK and shall bear the copyrighted seal of the American Association of Medical Milk Commission, Inc. The requirements in these Methods and Standards for the Production of Certified Milk shall be regarded as minimal and may be augmented by the requirements of local Milk Commissions. Any deviation from these Meth- ods and Standards, without lowering fundamental standards, may be sanc- tioned but must be acceptable to the Committee on Methods and Standards in conformity with the constitution and by-laws of the American Association of Medical Milk Commissions, Inc. Sec. 2. Raw Certified Milk - The Basic Product CERTIFIED MILK IS A BASIC PRODUCT AND MUST BE PURE, CLEAN, FRESH, NUTRITIOUS MILK IN ITS NATURAL STATE, NOT HAVING BEEN HEATED, AND NOTHING HAVING BEEN ADDED OR TAKEN AWAY. Unless otherwise labeled it is to be cow's milk. It must be produced and handled strictly in conformity with these Methods and Standards. It shall be free from objectionable odor and flavor. Any modification or processing of Certified Milk shall be plainly indicated on the label as hereinafter specified. Sec. 3. Pasteurized Certified Milk Certified Milk produced in accordance with these Methods and Standards may be subsequently pasteurized and labeled Pasteurized Certified Milk. It shall be pasteurized and bottled through equipment not for the handling of any other grade of milk or milk product except that, upon recommendation of the Milk Commission and after due consideration of each application, the Committee on Methods and Standards may grant permission for the milk to be pasteurized and bottled through freshly cleaned and sanitized equip- ment of milk. (See Title 2, Sec. 7.) Whether processed or not every precau- tion shall be taken to insure that Certified Milk is not contaminated by any other milk. In any case the location, the processing and milk- handling equipment, the methods used, and the standards maintained shall be subject to the control of the Milk Commission. Sec. 4. Certified Cream, Certified Half and Half, and Certified Non-Fat (Skim) Milk PAGENO="0113" 107 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 3 All requirements covering the production, handling and standards of Certi- fied Milk, except those referring to butterfat, shall also apply to Certi- fied Cream and Certified Non-Fat (Skim) Milk. The percentage of butterfat in Certified. Cream shall either be stated on the labels or conform to established local custom and legal requirements. Certified Half and Half shall be made from Certified Milk and Certi- fied Cream. The percentage of Butterfat in Certified Half and Half shall be either stated on the label or conform to established local customs or legal requirements. Certified Non-Fat (Skim) Milk is defined as non-fat milk produced by centrifugal separation of Certified Milk to comply with Federal or state laws. Sec. 5. Special Certified Milks The production of milk with special and nutritional properties, may be sold as Certified Milk providing the fluid whole milk, non-fat milk or cream used is Certified and meets all the requirements of Methods and Standards. The Methods and Standards for these products shall be approved by the local health authorities, Committee on Methods and Standards and Medical Milk Commissions. a. Certified Vitamin D Milk - is defined as whole Certified Milk with the addition of 400 USP units of Vitamin D per quart. b. Certified Pasteurized-Hombgenjzed Milk - may be produced and labeled in accordance with these Methods and Standards. c. Certified Non-Fat (Skim) Milk with Vitamins A and D added - may be produced and labeled in accordance with these Methods and Standards. d. Certified Low Sodium Milk - may be produced and labeled in accor- dance with these Methods and Standards and is treated so that its sodium content is reduced to less than 50 milligrams of sodium per quart, or contains less than 5 mg. sodium per 100 gms. or less than 12 mg. sodium per 8 oz. glass. e. Certified Acidophilus Milk - may be produced and labeled in accor- dance with these Methods and Standards and is inoculated with a pure cul- ture of Lactobacillus Acidophilus. f. Other products made by culturing or churning Certified Milk or Cream - may be labeled "Made from Certified Milk" or "Made from Certified Cream." Sec. 6. Labeling Special Certified Milks Labels for special Certified milks may bear the Seal of the American Association of Medical Milk Commissions. The wording for such labels shall be submitted to and approved by the committee on Methods and Standards of the American Association of Medical Milk Commissions. Such products must be made under the supervision of the local Medical Milk Commission. Sec. 7. Certified Goat's Milk Certified Goat's Milk is hereby defined to be the lacteal secretion obtained by the complete milking of one or more healthy goats properly fed and kept, excluding that obtained within fifteen days before and five days after kidding, or such longer period as may be necessary to render the PAGENO="0114" 108 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 4 milk practically colostrum-free which contains not less than 10.7% of milk solids, and not more than 89.3% of watery fluids, or less than 2.8% of milk fat. The bacterial count for raw goat's milk shall not be more than 10,000 colonies S.P.C. per ml. and not more than 500 colonies per ml. after pasteurization. The coliform requirement shall be less than 10 per ml. on the raw milk and not more than 1 per ml. after pasteuriza- tion. Title 3 Nutritional Value and Flavor of Milk Two important influences in maintaining the highest nutritional value and also the best flavor in milk are, (1) the feeding of the cows, and (2) the care with which the milk is handled and processed. Both of these involve considerable detailed knowledge and application, but there are two key vitamins towards which special attention can be directed. Vitamin A in milk is very definitely influenced by the ration of the cow, and if feeds are produced so that they have a high vitamin A content, they will also tend to be high in other factors which may influence the quality of the milk. The forage crop feeds, hay, silage and pasture supply most of the vitamins and other nutrients which influence the quality of the milk, as well as helping to maintain normal health in the animals. The production of good forage crop feeds requires: proper soil fertility, adapted vari- eties of crops, harvesting at the best stage of growth, and for stored feeds, good preservation and storage. The natural vitamin A content of milk will vary from season to season due to ration changes unless care is taken to see that animals get an adequate daily intake of vitamin A or its precursor, carotene. Only pasture or green chopped forages can be depended upon to furnish vitamin A activity as carotene, for much of the vitamin A activity of harvested forages is lost during the first six months of storage. The chief factors in the handling and processing of milk which affect its nutritional value are (1) Freedom from contamination, (2) oxygen content of the milk, (3) length of time betwen production and use, (4) heat treatment and (5) exposure to light. Here again Certified Milk produc- ers should apply the results of the extensive studies which have been reported in this field. The flavor of milk is closely associated with its nutritional value. The methods outlined for producing milk of high nutritional value are also important for producing the best milk flavor. All rations fed to lactating animals shall be supplemented with trace minerals in accordance with the latest recommendations of the National Research Council. Title 4 Organization and Duties of Medical Milk Commissions Sec. 1. Organization PAGENO="0115" 109 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 5 Medical Milk Commissions may be appointed (1) by a recognized Medical Society, (2) by public health officials, (3) by the Board of Trustees of the A.A.M.M.C. which may itself serve as a Medical Milk Commission or (4) as provided for by law in the community where the milk is to be marketed. Before such a Commission shall be recognized under the terms of these Methods and Standards, it must be approved by vote of the Board of the American Association of Medical Milk Commissions, Inc., and formal notification of such approval be issued by the president and secretary of the above association. The Board of the Association may rescind such approval at any time for cause and after hearing. Sec. 2. Duties of Medical Milk Commissions a. Officers and Supervisors of Medical Milk Commissions. In addition to electing a president, secretary and treasurer, the Commission shall appoint the following supervisors to enforce the Methods and Standards: a physician, a veterinarian, a laboratory director and a sanitarian who may or may not be members of the Commission. The physician and the veteri- narian must be duly licensed practitioners. The Commission may delegate the duties of inspection and enforcement to other Commissions certifying the same farms or dairies, or with the approval of the Committee on Method and Standards of the American Association of Medical Milk Commissions, Inc. to state or municipal authorities. The laboratory director must possess adequate chemical and bacteriological knowledge and skill, and must have access to the necessary laboratory facilities. At the discre- tion of the Commission the work of the laboratory director may be divided among two or more properly qualified persons. The terms of employment of the above mentioned supervisors and the means of defraying the expenses of their work shall be determined by the Commission. These supervisors shall be required to render to the Commission and farms monthly reports of their inspections and examinations and copies of these reports may be sent to every member of the Commission. All records of the Commission shall be open to inspection at any time by the secretary of the American Association of Medical Milk Commissions, Inc., or his duly authorized representati ye. The above mentioned Supervisors of the Commission shall perform the duties herinafter specified. b. Methods of Certification. After the Commission has applied for and received a certificate of recognition and approval signed by the president and secretary of the American Association of Medical Milk Com- missions, Inc., it may receive application for certification from dairy- men who desire to undertake the production of Certified Milk. Dairymen producing Certified Milk are herinafter referred to as Producers. Upon receipt of application for certification, the Commission shall institute an investigation by its members and/or supervisors to determine whether or not the applicant has proper interest, intentions, personnel, live- stock and equipment for the successful production of Certified Milk. If the result of such an investigation is favorable the Commission may certify the milk and shall enter into an agreement with the producer to preduce Certified Milk under the Methods and Standards. The secretary PAGENO="0116" 110 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 6 of the American Association of Medical Milk Commissions, Inc. shall insti- tute an investigation by its members and/or Supervisors to determine whether or not the applicant has proper interest, intentions, personnel, livestock and equipment for the successful production of Certified Milk. If the result of such an investigation is favorable, the Commission may certify the milk and shall enter into an agreement with the producer to produce Certified Milk under the Methods and Standards. The secretary of the A.A.M.M.C. shall immediately be notified o such action, so that permits may be issued for licensed manufacturers to supply the producer with approved containers and closures and formal acknowledgement of certi- fication may be issued. In this procedure it is understood that (1) certification is the responsibility of the Medical Milk Commission, (2) the Commission's certi- fication shall continue as long as its standards and requirements are maintained but (3) certifications of a Producer may be suspended at any time after due hearing by either the Commission or by the Council of the American Association of Medical Milk Commissions, Inc. for failure to operate in accordance with the Methods and Standards or to meet financ- ial obligations to the Commission or to the American Association of Medi- cal Milk Commissions, Inc., (4) full financial responsibility and liabil- ity with the Producers and (5) all money collected by the Medical Milk Commission from producers shall be used solely for expenses of the Commis- sion. c. Report of Medical Milk Commissions. Every Medical Milk Commission shall render a quarterly report to the office of the Association, and also shall render special reports whenever requested to do so by the secretary. Medical Milk Commissions shall promptly report to the secretary of the Association any outbreak or epidemic of communicable disease suspected or known to be milk-borne in the communities where Certified Milk is produced or distributed so that the Association may be of all possible service. Title 5 Laboratory Standards for Certified Milk Sec. 1. Supervision and Reports The maintenance of laboratory standards for Certified Milk shall be under the supervision of the laboratory director of the Commission who shall be held responsible for the inspections and tests specified in Title 5. He shall promptly render reports to the Commission and farms and shall immediately notify them if high bacterial counts or other ques- tionable conditions are found. Sec. 2. Bacteriological Methods and Standards Routine bacteriological examinations shall be made. These samples shall be properly refrigerated until they are examined, which shall be as soon as possible after collection or within twenty-four (24) hours. The methods used for bacteriological examinations shall be those described in the Appendix. PAGENO="0117" 111 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 7 The examinations shall include: (a) Total bacterial colony counts: (1) Certified Milk shall have a total count of not more than 10,000 colo- nies per nil. (2) Pasteurized Certified Milk shall have a total count of not more than 10,000 colonies per ml. before pasteurization, in samples taken at the pasteurizing plant, and not more than 500 per ml. in finished product samples. (see Title 2, Sec. 7 for bacterial colony counts for Certified Goat's milk.) (b) Coliform colony counts: (1) Certified Milk shall have a coliform colony count of not more than 10 per ml. (2) Certi- fied Pasteurized Milk shall have a coliform colony count of not more than 10 per ml. before pasteurization and not more than 1 per ml. in finished product samples. If counts exceeding these standards are found, the following steps shall be taken immediately: (1) Samples obtained directly from the farm shall be examined; (2) If the counts on these samples are high, process samples from along the line of production shall be examined until the source of high counts is found; (3) If persistent difficulty is encountered in keeping the total count of Certified Pasteurized Milk below 500 per ml., examine for thermoduric organisms. If counts within these standards are not restored within ten (10) days and maintained, certification may be suspended. Once per month the Bacteriologist of each Milk Commission shall make or have made by the State Laboratory or other acceptable laboratory a titration of Brucella agglutinins in the whey or the milk or Ring Test from each Certified Milk Producer whether the milk is raw or pasteurized. Sec. 3. Physical and Chemical Methods and Standards a. At a temperature of 60 degrees F. Certified Milk shall have a specific gravity of not less than 1.029 and contain not less than 12% of total solids including fat. b. Unless otherwise indicated on the label, it shall contain an average of 3.5 percent above or below 3.5 percent and a minimum of 3.3 percent for individual samples. In case it is desired to maintain an aver- age of butterfat above or below 3.5 percent the average percent of butter- fat or the limits between which it fluctuates shall be stated on the cap or the container, or by some designations which have legal standing and is generally understood in the community where the milk is distributed. In all cases the average of butterfat shall be based upon not fewer than ten samples over a period of not less than 60 days nor more than 90 days. c. Certified Pasteurized Milk shall show proper pasteurization as indicated by phosphatase tests. Sec. 4. Sediment and Flavor Tests It is recommended that sediment and flavor tests be reported on all samples with a required sediment test of No. 1 or better. Sec. 5. Detection of Microbial Inhibitants (Antibiotics) a. There shall be no antibiotics in Certified Milk, regardless of the route used for administering. b. The milk from animals treated with antibiotics shall be withheld 72 hours or until the milk is free of antibiotics. PAGENO="0118" 112 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 8 Title 6 Buildings and Equipment Sec. 1. Supervision and reports All buildings and equipment on a Certified Milk Farm shall be under the supervision of the Sanitarian of the Commission who shall make thorough inspections of the buildings, equipment and sanitary conditions of the entire dairy farm. He shall notify the Commission of any questionable conditions existing and shall promptly render reports to the Commission and farm where they shall be kept on file. Sec. 2. General a. Location of Buildings. Buildings in which Certified Milk is pro- duced and handled shall be located so as to insure good drainage and at sufficient distance from other buildings, dusty roads, cultivated and dusty fields, and all other possible sources of contamination to safeguard the milk provided. In the case of unavoidable proximity to dusty roads or fields, suitable arrangements shall be made to exclude dust. They shall be so constructed as to afford proper shelter. b. Surrounding of Buildings. The barn lots and surroundings of all buildings shall be kept clean, free from accumulations of rubbish and all conditions conducive to fly breeding. They shall be kept graded and drained. Adequate and functioning drains to conduct the wastes away from the barns and the dairy building shall be provided. All manure shall be stored or disposed of in such a manner to prevent breeding within 600 feet of the milking barn or dairy building except by other means or systems approved by the Milk Commission. c. Extermination of Flies and Other Insects. In addition to the elimination of fly-breeding conditions as provided in paragraph b, the frequent extermination of flies and other insects in milking barns and dairy buildings shall be accomplished by spraying or equally effective methods. Insecticides and methods used shall be approved by the local Milk Commission. d. Exclusion of Rats and Vermin. All necessary measures shall be taken to prevent the entrance of rats and vermin into barns and dairy buildings, and proper methods as approved by the Sanitarian shall be adop- ted for their destruction if they gain access. e. Water Supply. The entire water supply shall be free from contamin- ation and pollution and shall be sufficient for all dairy purposes. It shall be protected against flood or surface drainage. The purity of each source of supply shall *be checked by the bacteriological examinations according to standard methods of the American Public Health Association at equal intervals, at least three times a year and as often in addition as conditions indicate it to be necessary, and records of such examinations shall be filed at the farm and with the Commission for a period of one year. Sampeles for such examination shall be collected from outlets in the milk plant. When the water is obtained from a municipal supply, the records of the municipality or state may be accepted in lieu of the above requirements. No cross connections between potable and non-potable water systems shall be permitted. f. Drinking Fountains or Cups. Sanitary drinking fountains or dispos- able drinking cups for the use of the employees shall be installed in convenient locations both for the stables and dairy buildings. PAGENO="0119" 113 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 9 g. Toilets. There shall be one or more flush toilets connected to a public sewer system or to an individual sewage-disposal system. Such toilets and sewerage systems shall be constructed and maintained in accor- dance with local, county and state departments of health. Such toilets shall be convenient to, but not opening into, the barn and milk room. All toilet rooms shall be kept clean and properly screened and have conveniently available lavatory facilities with running water, liquid or powdered detergent and individual towels. Employees shall be required to wash and dry their hands upon leaving toilet rooms. h. Employees Homes, Dormitories and Boarding Houses. When employees live upon the premises their dormitories or boarding houses shall be con- structed and operated according to plans approved by the certifying com- mission. Adequate modern bathing and toilet facilities shall be provided for employees. i. Visitors. Visitors shall be so conducted as to eliminate any possibility for contaminating or contacting the milk or sterilized equip- ment and bottles. This shall apply to members of employees' families, field employees or others not receiving the same medical supervision as the dairy employees, except official inspectors. j. Pollution. A certified dairy should be a leader in the control of pollution and should use every means possible to protect our environ- ment. Sec. 3. Barns When animals are kept in other barns between milkings, these barns shall be so constructed as to provide adequate shelter. The floors shall be kept reasonably dry and clean. Regulations with respect to ventilation and windows (Title 6, Sec. 4, a, 3-4) shall apply also to animal barns except that in mild climates windows may be replaced by unglazed openings. Drinking and feeding equipment shall be kept in a clean, sanitary condi- tion. Sec. 4. Milking Barn or Room and Equipment a. Construction and Condition. The milking barn or room shall be constructed so as to facilitate keeping it in a clean, sanitary, well ventilated and lighted condition. It shall be kept in good repair and operating condition. (1) Floors and gutters - The floors shall be made of concrete or other impervious and easily cleaned material and the gutters of concrete only. They shall be properly graded and drained. (2) Interior walls and ceiling - These shall be of light color and made of smooth con- crete, plaster, tile, rust resisting metal, or of well painted or varnished wood with dust tight joints and capable of shedding water. Horizontal and slanting surfaces, which might harbor dust or other accumulations, shall be avoided as far as possible. (3) Windows and Lighting - In order to provide adequate light and sunshine window areas in warm-barn environ- ments should contain not less than 1/10th as much area as the floor space. In enclosed cold-barn environments, "skylight panels" in the roof should equal or exceed 1/20th of the floor area. In warm climates where loafing areas are open on one or more sides, the "skylight panels" are unnecessary. Windows as such are not necessary in cold-barn environments. Minimum arti- ficial lighting requirements are as follows: 100-watt of light for each PAGENO="0120" 114 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 10 2 - 3 stalls in the milking facility, and 100-watt of light for each 1,000 square feet of floor space in the bedded area. (4) Ventilation and air space - Stables shall be adequately insulated and provided with a function- ing and adequate system of ventilation to minimize offensive odors and to prevent excessive condensation of moisture, and each cow shall be provi- ded with a minimum of 60 square feet of space. Correspondingly less space may be provided for goats. (5) Stanchions or ties - Stanchions or other forms of ties shall be of modern sanitary construction. They shall be so arranged that droppings will fall for the most part into the gutter. Provision shall be made to keep cows standing between cleaning and milking. (6) Drinking cups and feed mangers - When drinking cups are used they shall be of smooth sanitary construction. Feed mangers shall be of smooth concrete or other impervious, easily cleaned material. (7) Feed mixing rooms - All feed shall be mixed in a separate room with dust tight wall and door if it adjoins the milking barn or room. Cleanliness. The entire milking barn or room and equipment shall be kept in a clean, sanitary condition and free as possible from dust and all other accumulations. Only bedding which is clean, dry, absorbent and reasonably free from mold and dust may be used in the milking barn. Soiled bedding and manure shall be removed from the milking barn at least twice daily and the floor then swept and kept free of refuse. Where cows are not kept in the milking barn or room between milkings, the floors shall be washed down after each milking unless freezing temperatures exist. Sec. 5. Milk Receiving Rooms A milk receiving room is defined as any room or building located at or near the milking stanchions or milking parlor, and used exclusively as a central collecting room for milk as brought from the barns. Such rooms shall conform to the same specifications as apply to the construc- tion, maintenance and cleanliness of the milk handling rooms in the dairy buildings. They shall be well screened, provided with automatically closing doors and shall not have open communication with the milking barns. In each milk receiving room, adjacent vestibule, or milking barn there shall be provided lavatory facilities with continuously running water or water with foot or arm control faucets, liquid or powdered deter- gent and paper towels for the use of milkers. Sec. 6. Dairy Building A dairy building shall be provided for handling, processing and stor- ing of milk and milk products and the cleaning, sterilizing and storing of milk equipment. a. Construction and Condition. The dairy building shall be construc- ted so as to facilitate keeping it clean, sanitary, well ventilated and well lighted. It shall be kept in good repair and operating condition. It shall not communicate directly with barns or dwellings. (1) Floors - The dairy building shall have smooth floors of concrete or other water impervious and easily cleaned material. They shall be well graded and drained. (2) Interior walls and ceiling - These shall be of light colored, smooth surfaced, impervious washable material. There shall be no objection- ably placed overhanging pipes or conveyors. (3) Openings - All openings shall be well screened and constructed so as to exclude flies and other insects and vermin. All doors shall open outward if possible and be self PAGENO="0121" 115 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 11 closing. (4) Lighting and ventilation - The building shall be provided with adequate daylight and artificial light. It shall be well ventilated. (5) Cleanliness - all parts of the dairy building shall be kept clean and sanitary and the milk and equipment handling rooms shall be kept scrup- ulously clean, well painted and free from dust and odors. b. Room Required. If Certified Milk is produced, processed and bot- tled on the same premises, the dairy building shall be provided with the following separate rooms suitably equipped: (1) One or more receiving rooms to be used exclusively for all Certified Milk brought to the dairy building and from which it shall be piped to the processing room unless the milk can be piped directly from the milking room to the processing room. (2) One or more rooms to be used exclusively for cooling, processing and packaging Certified Milk or products therefrom. (3) One or more rooms for cleaning and sterilizing milk equipment and bottles. (If the milk is produced for processing and bottling elsewhere, the above rooms may be combined.) (4) There also shall be one or more refrigerated rooms used exclusively for storage of bottled or packaged milk or milk products. Offices. Laboratories, rooms for storage of equipment and supplies used in the building, boiler rooms and toilet rooms may be located in this building. The latter two shall not communicate directly with the milk or clean equipment storage rooms. A properly constructed and isolated milking room in which cows are kept only during milking may be located in the dairy building. c. Use - The various rooms mentioned above shall not be used for other purposes than those specified except that clean, sterilized milk bottles and utensils may be stored for immediate daily use in the milk handling rooms. No animals other than those being milked shall be allowed in the dairy building. No part of the dairy building may be used for dwel- ling or lodging. Sec. 7. Dairy Building Equipment and Bottles a. Necessary Equipment. Adequate and efficient milk handling equip- ment and containers approved by the Commission shall be provided for pro- ducing, holding, processing, cooling, bottling and sealing of only Certi- fied Milk and its products (See Title 2, Sec. 3) and for cleaning, saniti- zing and refrigerating purposes. Adequate lavatory facilities with running water, liquid or powdered detergent and individual towels shall be conveniently located in the milk handling and toilet rooms. b. Construction. Milk handling equipment shall be constructed so as to be easily cleaned and given effective protection to the milk from contamination. Vats shall be solid tanks. All equipment shall be of stain- less steel or glass, except milking machine parts customarily made of rubber or plastic. All milk shall be carried through stainless steel or glass pipeline to a bulk tank. The milk should not be exposed to the open air at any time. c. Condition. All equipment shall be kept in good repair and operat- ing condition. Milking machine rubber parts shall be in sound sanitary condition. Bottles shall be serviceable sound and undamaged. Equpment used in milk handling shall be replaced as soon as the interior surface is dented, or with open seams. PAGENO="0122" 116 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 12 d, Cleaning and Sanitizing. All milk handling equipment, milking machines and multi-use bottles shall be well cleaned and sanitized after each use. Equipment, materials and methods used shall be approved by the Commission. Methods shall include the following procedures: (1) Immediately after use rinse all equipment with clean cool water. (2) Next, thoroughly clean all equipment and multi-use bottles with a hot solution of a good soapless cleaning detergent. (3) Rinse thoroughly with clean water. (4) Last, thoroughly sanitize with steam, boiling water, dry hot air, approved chemicals or other equally effective methods. Approved paper cartons and/or polyethylene plastic bottles may be used. Automated washing equipment for C.I.P. cleaning shall be used follow- ing an approved sanitizing and cleaning procedure. Milking equipment shall be dismantled for cleaning and inspection once each week. Milking machines shall be so dismantled that all parts may be thor- oughly cleaned and sanitized, care being taken to remove all milk-stone. Rubber parts shall be maintained in serviceably sound condition. Vacuum lines shall be kept in clean and sanitary condition. After being sanitized, equipment and bottles shall be kept covered or inverted in a room or cabinet free from dust-or other possible contamin- ati on. Milk bottle cases returned from delivery routes or subjected to other contamination and to be used for handling inverted sanitized bottles shall first be effectively cleaned and sanitized. Thermometers shall be used on all sterilizers and mechanical bottle washers. They shall be checked for accuracy at frequent intervals, speci- fied by the Comission, by a standard tested thermometer. Records of such checks and temperatures maintained shall be kept on file at the farm. An automatic chemical sanitizing rinse shall be used in all mechanical bottle washers as the final rinse. These machines shall be operated accord- ing to the manufacturer's recommendations. When chemical sanitizing solutions are used, concentrations and times of exposure as recommended, shall be maintained. An approved test shall be provided and the solutions checked at frequent intervals, specified by the Commission, and record of such tests kept on file at the farm. Equipment sanitized with chemical sanitizing solutions should not be rinsed with water after sanitizing but shall be well drained before use. The final test of cleanliness and sterility shall be freedom from viable bacteria and visable foreign matter. Title 7 Veterinary Supervision of the Herd Sec. 1. Supervision and Reports The care and handling of animals shall be under the supervision of the Veterinarian selected by the Commission. He shall make frequent inspec- tions of the herd, and make monthly reports to the Commission. He shall file copies at the farm and notify the Commission of any outbreak of dis- ease among the animals and of any questionable conditions involving their health and care. A veterinary inspection of the health of the herd shall be made at intervals of not more than one month. Each animal in milk shall be subjected to a careful physical examin- ation at least once each month, giving special attention to the udder and external genitals. PAGENO="0123" 117 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 13 Sec. 2. Herd Management a. Identification. Every animal in a Certified milk herd shall be ear-tagged or tattooed with a number which will permanently identify her, or other method approved by the Milk Commission. Provision shall be made for the replacement of lost eartags. b. Herd Records. Every animal in the herd shall be registered in a herd record which shall be accurately kept and readily accessible to the Milk Commission and official inspectors. This record shall include dates of entrance and departure from the herd, service and freshening; dates and results of tuberculin and brucella testing. The record for every animal shall be kept on file at the farm as long as she is at the farm and for at least six months thereafter. c. Milking and Parturition. Milk from all animals shall be excluded from human consumption for 5 days following parturition. It is recommended that all animals receive a minimum dry period of 45 days. d. Pastures and Yards. Pastures or yards to which the animals have access shall be free from stagnant pools and at sufficient distance from offensive conditions so that the animals shall suffer no bad effects from them. Pastures or yards shall be free from infectious agents and from vegetation which may affect the animals or their milk deleteriously. Where animals are permanently maintained in open corrals, these corrals must be well drained and kept in a sanitary condition. They shall be regularly scraped and manure hauled away. It is important from the standpoint of disease control that both crews and trucks doing this work shall not do similar cleaning on uncontrolled dairies. e. Feeding. A well-balanced ration of high quality nutrients shall be used that is adequate in protein, energy, fiber, minerals and vitamins. The ration will be designed to maintain healthy cows and produce milk of normal composition and superior flavor. f. Bedding. Only bedding which is clean, dry, absorbent and reason- ably free from dust may be used. Sec. 3. Disease Control a. Isolation of the Herd. No animals not approved by the Veterinarian shall be allowed to come in contact with the Certified Herd in the barns, yards or pastures. No cow shall be used to produce Certified Milk that does not have four healthy quarters, however, a cow with a completely dry, nonfunctioning quarter can be used to produce Certified Milk from the other three normal quarters (see Title 8, Sec. 3, Part b, 5). b. Admission to the Herd. The responsibility for admitting animals to the milking herd after purchase or of readmitting them after freshening or after isolation because of disease, rests with the Veterinarian even though he may delegate certain duties to other qualified persons. Every cow or goat admitted or readmitted to the milk herd shall be examined by an A.A.M.M.C. approved veterinarian. The milk of such animals shall not be allowed to enter the Certified milk supply until favorable veter- inary reports have been received. c. Tuberculosis. Only negative herds in a modified accredited area as designated by the U.S. Department of Agriculture Uniform Methods and Rules for Bovine Tuberculosis Eradication, shall be used in the production of Certified Cows Milk. When an application is made for certification, every cow shall be tuberculin tested. No cow shall be added to a herd PAGENO="0124" 118 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 14 producing Certified Milk unless such animal has originated from a negative herd in a modified accredited area and has passed a tuberculin test within sixty (60) days prior to admission to the herd. Certified herds shall be retested for tuberculosis annually. All tuberculin tests shall be made by a veterinarian approved by the Commission and by the Federal Bureau of Animal Industry. The dates of all herd tests shall be definitely arranged by agreement between the Milk Commission and the supervising officials and a complete record of all tests shall be made by the veterinarian making them and promptly reported by him to the secretary of the Commission. These records shall be kept on file at the farm for one year and a summary of all such tests shall be made available to the American Association of Medical Milk Commissions for statistical purposes. All reactors shall be removed from the herd immediately upon discovery and the milk shall be discarded. The barns and exercise yards used by them shall be cleaned and disinfected in a manner approved by the Com- mission. d. Brucellosis. All herds approved for the production of Certified Milk shall be officially accredited (certified brucellosis free) and main- tained as brucellosis disease free. Herds shall be tested at intervals not to exceed every ninety (90) days by the Ring Test in a accredited brucellosis free state. The same herds shall have their. blood sera tested for agglutinins at intervals not to exceed twelve (12) months. All herds producing Certified Milk in states that are not accredited brucellosis free shall be tested by the Ring Test at intervals not to exceed thirty- five (35) days and have blood sera of all animals tested foragglutinins at intervals not to exceed six (6) months. (1) Reactors and suspects to be defined under Federal Standards using tested and approved procedures only. Reactors must be immediately removed from the herd. Suspects are to be removed from the Certified milking string and re-tested within minimum thirty (30) day intervals until tested nega- tive before re-admission to the milking string. (2) All purchased herd additions shall be tested at the time of enter- ing the herd and retested in sixty (60) days. However, if animals are purchased from an officially accredited (certified brucellosis free) herd, an official negative test made within thirty (30) days of purchase shall qualify such animals to enter the herd. (3) The interpretation of blood agglutination tests shall be that of the Animal and Plant Health Inspection Service, U.S. Department of Agriculture. (4) Tests shall be made under the supervision of agents acceptable to the local Commission and the state health authorities. Reports of such tests shall be sent to the Milk Commission and copies kept on file at the farm for one (1) year. (5) It is recommended that all replacement cattle shall be calfhood vaccinated for Brucellosis with Strain 19 vaccine. e. Withdrawals from the Milking String. It is the duty of the farm superintendent or the herdsman to see that any animal thought to be sick or diseased shall be immediately isolated from other animals in the milking string and none of their milk shall enter the Certified milk supply. f. Mastitis and Abnormal Milk. The milk from any animals with either acute or chronic mastitis shall be withheld and not used for human consump- tion until her milk is normal and all antibiotic residue has been elim- PAGENO="0125" 119 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 15 mated. g. Notification of Veterinarian. In the event of the occurrence of a disease which appears to be of a serious nature, or if a number of animals become sick at about the same time, the dairyman shall withdraw such animals from the herd, destroy their milk and notify the Veterinarian immediately. h. Disposition of Dead Animals. The carcass of any dead animal whe- ther diseased or not should be disposed of in a sanitary manner. Methods of disposal must be approved by the local Medical Milk Commission. Local and state regulations may determine to some extent how this is done. Title 8 Milking, Processing and Distribution Sec. 1. Supervision and Reports Milking, milk handling, transportation and distribution of Certified Milk shall be under the supervision of the Sanitarian of the Commission who shall make frequent inspections of the dairy at times when these opera- tions are in progress. He shall render monthly reports of such inspections to the Commission and farm and shall notify the Commission of any question- able conditions existing on the farm or in the distribution of the milk. Sec. 2. General a. Employees Clothing. Milkers and other persons handling the milk shall wear clean suits and caps approved by the local milk commission, which shall be worn for no other purpose. They shall use not less than three freshly laundered suits each week and these when not in use shall be kept in a clean place, protected from dust and dirt. b. Things to be Avoided by Employees. Milkers and other handlers shall refrain from putting hands to the nose and mouth. Every employee shall exercise great care to prevent milk contamination by droplet infec- tion from nose and throat, secretions. Spitting shall be prohibited in the parlors and in all parts of the dairy building where the milk is han- dled. Smoking is prohibited during the time of milking and bottling. Sec. 3. Milking a. Protection of Milking Equipment from Contamination. (1) Cleaning of Milking Barn Before milking. Soiled bedding and manure shall be removed from the milking barn at least twice daily and the floors shall be swept and kept free from refuse. Such cleaning shall be done not less than one hour before milking (see Title 6, Sec. 2, b). (2) Flies. Efforts to eliminate flies shall be done by materials and methods approved by the Sanitarian. They should not be done during or immediately before milking. (3) Feeding Hay After Milking. If hay is fed in the milking barn, it shall be brought into the barn only after milking. (4) All animals shall be milked into stainless steel or glass lines leading to a holding tank equipped with a recording thermometer. The milk shall be cooled promptly to 40 degrees F. Provisions shall be made for prompt and effective cleaning and sterilization of the lines and equipment as soon as practical after the last animal has been milked. The lines must be given bactericidal treatment just prior to use for the subsequent milking. PAGENO="0126" 120 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 16 b. Preparation and Handling of Animals. (1) Clipping. Long hairs shall be clipped from the udder and flanks and from the tail above the switch. The switch should be cut to clear the ground or platform by at least four inches. If this is not desirable with pure bred animals then the switch shall be washed often enough to keep it clean. (2) Cleaning. Every animal used in the production of Certified Milk shall be clean before milking. Whether cleaned by dry grooming or hosing, the animal's udder must be given particular attention by wiping with cloths used exclusively for this purpose. No water shall be running down the udder and off the teats when milking. (3) Examination of fore-milk. At every milking the first streams of milk from every teat shall be regected. It is required that such milk shall be examined for evidence of mastitis by a method approved by the Commission. Such milk shall not be milked upon the floors or into the gutters of any stable or building where animals are allowed to lie down or remain after milking. If any abnormal milk is disclosed, the milk from that animal shall be discarded and she shall be removed from the milking herd and not be returned until approved by the Veterinarian. (see Title 7, Sec. 3 e and f.) (4) Milking. Milking shall be done rapidly and quietly and the animals shall be treated kindly. Managed or rapid milking procedure is recommended. (5) Milking Three-quartered Cows. Interupt vacuum on the unused teat cup through the use of a rubber cap or plug specifically manufactured for this purpose. This procedure will allow the milking machine operator to manipulate the unused teat cup as to prevent any possibility of contami- nation. (This section shall also apply to goats with an unused teat.) (6) Milkers' Hands. Adequate and conveniently located lavoratory facilities shall be provided for the milkers. Immediately before milking, the hands of the milkers shall be thoroughly washed and scrubbed, using detergents (liquid or powdered), running water and brush, and carefully dried on clean individual towels. The milkers' hands shall be clean and dry at all times. He will not be required to wash his hands between the operation of each cow unless his hands become soiled or wet. Sec. 4. Milk Handling and Processing a. Collecting and Filtering. Promptly after the milk of each cow is drawn, it shall be removed from the barn to the milk receiving room and from there to the dairy building. Milk shall be transported from the milk receiving room to the dairy building conveyed in an approved sanitary vessel to the point of processing or bottling. The milk shall be passed through modern filters. A sufficient number of filters shall be provided for every milking so that they may be changed frequently if necessary. Filtering may be done either in milk receiving rooms or in the dairy build- ing. No filter shall be used at more than one milking. b. Cooling. Immediately after reaching the dairy building the milk shall be cooled to a temperature below 40 degrees F., and except during the process of pasteurization shall be maintained at a temperature above freezing and below 40 degrees F. until delivered to the consumer. PAGENO="0127" 121 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 17 C. Processing, Bottling and Sealing. (1) Certified Milk shall be bottled and sealed by means of approved mechanical equipment on the farm where it is produced, except that with the approval of the local Medical Milk Commission, milk from one farm may be processed and/or bottled at another Certified farm and labeled with the cap of either farm. A producing farm may include a number of units under the same farm and Commission supervision. A certified producer may transport his milk in an insulated, properly sanitized stainless steel tank truck to a processing plant other than a certified farm. Its equipment, the methods used and the standards main- tained shall be subject to the control of the local milk commission. All such certified milk must be processed in sanitized equipment, bottled and sealed prior to any other grath of milk. The label of this milk must carry the name of the Certified farm, the supervising milk commission, processor and distributor. Certified Milk in the finished package product must comply with standards for Certified Milk, in Title 5. (2) Milk bottle caps and other closures shall be stored in dust- tight packages in a clean room and shall at all times be handled in such a manner as to avoid contamination. After the milk has been cooled and bottled, the bottles shall be capped and sealed immediately with a closure approved by the Committee of the American Association of Medical Milk Commissions, Inc. and in a manner satisfactory to the Certifying Commis- sion. The bottle caps shall be uncontaminated and shall be applied only by a suitable capping machine which eliminates the possibility of contam- ination. Outer milk bottle hoods shall be handled in such a manner as to avoid contamination of the inner surface. Closures shall be of suffi- ciently strong and durable material to withstand leakage or puncture during handling, transportation and delivery of the milk. They shall be of such form that they will cover completely the pouring lips of the bottles and it is desirable that they shall be of such construction that when once removed they cannot be replaced upon the bottles without detection. (3) Outer milk bottle closures whether made of one or more layers of material and used without an additional plug cap are defined as single closures. Those used over a plug cap are defined as double closures. All types of milk bottle containers, caps or closures shall be subject to approval by the local commission and the committee of the A.A.M.M.C. on milk bottles, containers and closures. Both the seal of the A.A.M.M.C. and the script `Certified Milk" must appear on all Certified Milk outer closures. Block letters of the words Certified Milk is not approved. (4) Paper, glass, plastic or other approved containers may be used for Certified Milk if they meet the requirements for glass bottles as described in paragraphs 2 and 3. (5) Other or novel methods of milk handling, processing, packaging storage or distribution may be temporarily permitted by the Committee on Methods and Standards, subject to whatever controls and conditions it may deem necessary. d. Labeling. The approved container used shall be marked on their exposed surface with the approved copyrighted seal of the American Associ- ation of the Medical Milk Commissions, Inc., the name of the Certifying Commission, the name of the producing farm and other information as re- quired by the local medical milk commission and the state or local regula- tory agencies. PAGENO="0128" 122 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 18 Sec. 5. Transportation and Distribution a. Equipment. During transportation, milk shall be kept properly cooled and the containers (bottles) shall be kept reasonably free from dust and dirt. Trucks, trays and crates shall be kept clean. The Medical Milk Commission shall exercise its authority to determine the type of truck necessary to safeguard Certified Milk under climatic conditions existing in its area. b. Temperature. Distributors handling Certified Milk must keep it at a temperature above the freezing point and below 45 degrees F. from the time it is received until delivered to the consumer. c. Delivery Time Limit. The milking in any consecutive 24 hour period shall constitute a day's product. Certified Milk is a premium product and should be delivered to the consumer in the shortest possible time after production as determined by each individual milk commission. It should be noted that Certified Milk is good past this date. Sec. 6. Preservation of Vitamins and Good Flavor In the handling, holding and distribution of milk, oxidation reactions may take place which tend to destroy ascorbic acid (vitamin C), to cause the development of oxidized flavor and possibly to cause other less notice- able effects. To avoid these results the following precautions shall be observed: The milk shall only be allowed to come into contact with properly cleaned and sanitized rubber milking parts, stainless steel or glass. If chlorine solution is used for sterilizing equipment or utensils, it must be thoroughly drained out before milk is allowed to enter. In the handling of milk unnecessary exposure to sunlight shall be avoided and when delivered to the customer the milk shall be placed where it will be protected from sunlight. Title 9 Personnel, Medical Supervision, etc. Sec. 1. Supervision and Reports The Physician appointed by the Commission shall have medical and hygienic supervision of all employees involved with the production of Certified Milk. He shall report to the Commission and farms. Sec. 2. Duties of the Physician a. Medical Examinations. The Physician, in taking the history and recording his examination, should note any diseases which may be spread from person to person. No person with active tuberculosis should be hired; and x-ray examination or skin test is mandatory. Persons with a past his- tory of typhoid fever should not be hired until the physician is satisfied that he is not a carrier of typhoid organisms. A stool examination for typhoid bacillus and other enteric pathogenic organisms shall be made. Throat cultures should be made to rule out a diptheria carrier, and when indicated for hemolytic organisms. It is recommended that for the informa- tion of the Physician every new employee shall have his blood tested by the VDRL or equivalent test. Employees working in the milking and plant PAGENO="0129" * 123 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 19 area or who are in close contact with the milk shall be examined by a. physician at least every ninety (90) days. At other times the Physician shall conduct such medical examinations of employees or other persons on the farm as he or the Milk Commission think necessary and have suitable laboratory tests made whenever it is deemed advisable. All examinations shall be conducted by laboratories and physicians appointed and approved by the Commission and satisfactory to the health authorities. Complete records shall be filed with the Commission. b. Medical Inspection. The Physician may visit the farm if he or the Commission deems it advisable. He shall be given an opportunity to examine and interview all employees and residents of the farm and shall report to the Milk Commission. This report shall be countersigned by the farm owner or superintendent and a copy shall be kept on file at the farm for one year. c. Special Examinations. Upon report from the farm owner or super- intendent of a farm or upon information from any other source, that any illness or carrier state capable of transmission by milk is suspected to exist on the farm, or among the employees of the farm, it shall be the duty of the Physician to take immediate steps to safeguard the milk. The Physician shall examine the patient or suspect and assure himself that the person is attended by a physician in good standing. The Physician shall promptly report any case of contagious disease to the Commission and the proper health authorities and shall see that adequate quarantine is established and maintained. Sec. 3. Management of Communicable Infections No persons affected with any communicable disease which may be trans- mitted through milk, or who has recently been exposed to such infection shall be employed in the production or handling of Certified Milk. No person known to be a carrier of any communicable disease known to be milk- borne shall be employeed or reside on a Certified Milk farm. Persons known or suspected to have typhoid fever shall not be employed except with the approval of the milk Commission and with the knowledge and consent of the proper health authorities. In the event that any person employed or residing on a Certified Milk farm becomes affected with any disease which may be transmitted through milk such persons shall be immediately removed from work. Sec. 4. Records of Employees In order that records may be readily available for inspection by proper officials there shall be kept on the dairy premises a record of every employee which shall give his name and address, date of employment, his medical history, results of physical examination by the Physician and the results of any laboratory tests. Any applicant or any employee involved with the production of Certi- fied Milk who may be rejected or discharged because of being a carrier of pathogenic organisms of diseases transmissible through milk shall be reported by the Comission to the secretary of the A.A.M.M.C., Inc. The secretary of the Association may report the names of such individuals to all the Medical Milk Commissions of the Association. 52-266 0-85--S PAGENO="0130" 124 METHODS AND STANDARDS FOR THE PRODUCTION OF CERTIFIED MILK Page 20 Appendix Approved Laboratory Methods and Recommendations To maintain those qualities of dairy products not discernible by the consumer, it is necessary to perform tests which must be done by labor- atory procedures. The ultimate aim of these procedures shall be to provide a product in which the original nutritive qualities, flavor and appearance have been preserved and to ensure that no harmful organisms or substances are present to adversely affect the consumer. An acceptable methodology must be found and adhered to. The American Association of Medical Milk Commissions, Inc. elects to utilize in full, the procedures and standards found in the latest edition of "Standard Methods for the Examination of Dairy Products" published by the American Public Health Association, 1015 Eighteenth Street, N.W., Washington, D.C. 20036. PAGENO="0131" 125 Dr. FLEISS. OK. Mr. WAXMAN. Mr. Dannemeyer. Mr. DANNEMEYER. Dr. Bolton, are you familiar with the salmo- nella outbreak from properly pasteurized milk that occurred in Ar- izona, and also the outbreak of salmonella infection that occurred from improperly pasteurized milk in Kentucky? Dr. BOLTON. I think I probably have those in my files. I know I have the improperly pasteurized one, but these were again out- breaks or epidemics. Epidemics are unusual, meaning clusters as Dr. Fierer mentioned, with the milk. You are talking about a spo- radic thing here. Mr. DANNEMEYER. The point of your testimony was that pasteuri- zation is the cure-all for this prospective menace from the contin- ued availability of certified raw milk. And you are conceding that pasteurized milk does cause salmonella outbreaks. Dr. BOLTON. First of all, sir, I did not say pasteurization was the cure-all. Pasteurization is a step forward in the annals of public health insofar as protecting people from pathogenic organisms. But if equipment doesn't work properly or if milk is grossly contami- nated or standards are not up to par, you can get sick from pas- teurized milk. You stand a greater chance of getting sick, however, according to all the data we have, from drinking raw milk than pasteurized milk. Mr. DANNEMEYER. Dr. Bolton, are you aware of the 800-some, of yersinia enterocolitica, a pathogenic organism not unlike salmonel- la found in three or four different cities in pasteurized milk? Dr. BOLTON. I am aware of that, yes. There have been epidemics again with pasteurized milk. Mr. DANNEMEYER. On the logic that you are following, if I under- stand it, to get rid of the menace to the public from the continued availability of certified raw milk you suggest we pasteurize milk. Now, you are conceding that notwithstanding pasteurization of milk in these United States we are continuing the manifest cases of illness? Dr. B0LT0N. No, extremely rare, sir, with pasteurized milk. Mr. DANNEMEYER. Couldn't it also be said that the claims of ill- ness from salmonella and certified raw milk are extremely rare? Dr. BOLTON. When the risk studies have been done, they show that raw milk drinkers have something like a 53, or is it 153 times greater risk of getting salmonella dublin infections than people who do not drink it. Mr. DANNEMEYER. You know, if the goal is a perfect world, wouldn't it be logical to also ban pasteurized milk? Dr. BOLTON. No, it would be logical to pasteurize milk and have good standards of dairy cleanliness so you would try to cover your bases both ways, because you cannot make safe raw milk. I will dis- agree with you and with Dr. Fleiss because we know that cattle carry this organism. No matter how clean you make the dairy, and it is good they do, and I wish all dairies were good about their standards of cleanliness, but it is going to break down somewhere. It is as if so what if a few people die from raw milk, we really should not take this so lightly, however. We need to take all avail- able precautions we can about a food meant to be consumed in a raw state. PAGENO="0132" 126 Mr. DANNEMEYER. Are you saying that somebody has died, that the proximate cause of the death was the consumption of certified raw milk? Dr. BOLTON. In my opinion, yes, many people. Mr. DANNEMEYER. OK. Do you know a gentleman by the name of Dr. Werner, an offi- cial? Dr. BOLTON. Yes, and I have talked to Dr. Werner about his depo- sition which you probably have in hand there. Mr. DANNEMEYER. Dr. Werner said he was unaware of any person who actually died from consumption of raw certified milk. Are you aware of that? Dr. BOLTON. Dr. Werner's deposition has been cut up in pieces there. If you read the entire part of his statement given in the dep- osition, you would see that he explained he is an epidemiologist and that the evidence is there, that he has not personally gone out and investigated each of these to establish the causal relationship. Mr. DANNEMEYER. I think the-- Dr. BOLTON. He is an epidemiologist, sir. Mr. DANNEMEYER. I think the statement I made is a fair state- ment of what he said. Dr. BOLTON. I think you are cutting up his statement and not giving his full statement. Mr. DANNEMEYER. He said he was unaware of any person who actually died from consumption of raw certified milk. Are you de- nying Dr. Werner said that? Dr. BOLTON. I talked to Dr. Werner about this very point about 2 days ago. He was really upset about this because he saw it on the flyer sent out to the people to get them in here for this meeting today. He said. They cut up my deposition. I went into a lengthy discussion about the epidemio- logic proof linking this, and they go in and zero in on one little statement. Mr. DANNEMEYER. He made his statement under oath, didn't he? Dr. BOLTON. That is an incomplete statement, sir. I would sug- gest you look at his whole statement, whole deposition. Mr. WAXMAN. If the gentleman will yield to me, I have a letter dated February 12, 1985, from S. Benson Werner, M.D., Medical Epidemiologist, Department of Health Services, State of California. He would like to have that letter inserted into the record. I have not had a chance to review it, but as I understand, Dr. Werner is making clarifications. His letter is titled, "Re: false and misleading propaganda directed by Alta-Dena Dairy." I think this letter would be further elucidation of Dr. Werner's position. So, since he is not here, we have whatever document my colleague has and this letter that we will also put in the record. [The information follows:] PAGENO="0133" 127 DEPARTMEHT OF HEALTH SERVICES February 12, 1985 Congressman Henry A. Vaxman 2418 Rayburn Office Building Washington, D.C. 20515 RE: False and Misleading Propaganda Distributed by Alta Dena Dairy Dear Congressman: As I was personally cited in the attached propaganda/petition entit1ed~ "Keep Government Out of Our Refrigerators," I would like to point out rather serious misstatements of fact in the information distributed by Alta Dena in advance of your Subcommittee's scheduled meeting in Los Angeles on Wednesday, February 13, 1985. (A copy of the propaganda/petition is attached.) Despite what was written, the association between certified raw milk use and Salmonella dublin infection in California is statistically indisputable, large, and causal. These important findings were supported by an independent study of California's data by the UCLA School of Public Health (that was con- ducted with funds that were provided, incidentally, by the Los Angeles County Medical Milk Commission which certifies Alta Dens's milk). In a study of S. dublin cases which occurred outside of California, the Centers for Disease Control independently confirmed that raw milk was the only implicated risk factor. There is no doubt thatthat "not one" but many individuals have become infected by drinking raw milk. The epidemiologic, statistical, and laboratory evidence are irrefutable despite dairy allegations to the contrary as stated on the attachment. As we have emphasized, S. dublin cases associated with use of raw milk have not appeared in outbreak form in California but have occurred sporadical~v, and the pathogen appears to attack those exposed individuals in our population who have infirmities or who are either very young or very old, although healthy people are certainly at risk as well. We estimate over S million people in California meet our criteria for compromised health status--a substantial proportion of the State's population. Finally, despite what was stated, the overwhelming majority of milkborne outbreaks of salmonellosis (and of campylo- bacteriosis too, for that matter) have been due to raw milk, not pasteurized milk. A conservative estimate is that more than 9O~f all milk produced in this country is pasteurized but that more than 90% of all milkborne outbreaks have been due to raw milk. lhesc and other issues are covered far more fu]l~ in a written statement submitted for your hearing by this State's Infectious Disease Section. Sincerely yours, SBW:FRM S. Benson Werner, M.D. Enclosure--- MedicmlEpidemiologtst Infectious Disease Section PAGENO="0134" February 1985 Dear Friend: Once again Alta-Dena Certified Dairy and raw certified milk are under attack. This time, Congressman Henry Waxman is hold- ing hearings at U.C.L.A. in Los Angeles to ban raw certified milk. (See enclosed flyer for date, location and time.) While testimony can only be received from those invited by Congressman Waxman, the hearings are open to the public and your visible support can make a difference. The issue of freedom of choice and the future availability of raw certified milk needs your support. Please attend and write to Congressman Waxman so your voice can be heard (see enclosed petition). Thank you for your support. Si ncerely, ~ .~~-~-2~-- THE STUEVE FAMILY ALTA-DENA CERTIFIED DAIRY cr 128 `The da~ryttsat cares about your health PAGENO="0135" 129 KEEP OOVERNMENT OUT OF OUR REFRIOER4TORS ATTEND IN PERSON THE SUB-COMMITTEE ON HEALTH & ENVIRONMENTS HEARINGS TO BAN RAW CERTIFIED MILK: WEDNESDAY, FEBRUARY 13, 1985 at 9:00 am to 3:00 pm U.C.L.A. CAMPUS, MARION DAVIES CHELDREN'S CLINIC, MOSS AUDITORIUM 404 HILLGARD STREET, ROOM A2-342 LOS ANGELES, CALIFORNIA YOUR SUPPORT IS NECESSARY TO PROTECT THE FUNDAMENTAL RIGHT OF FREEDOM OF CHOICE HEARINGS ARE UNDERWAY AT THE STATE AND FEDERAL LEVEL THAT MAY BAN THE SALE AND DIS- TRIBUTION OF RAW CERTIFIED MILK. WE DEMAND TO KNOW WHY. THESE ARE THE FACTS: * 120,000 PEOPLE CONSUME OVER 250,000 GLASSES OF RAW CERTIFIED MILK DAILY IN CALIFORNIA. THERE HAS NEVER BEEN ONE CASE OF ILLNESS FROM THE CONSUMPTION OF RAW CERTIFIED MILK IN OVER 30 YEARS. * S. BENSON WERNER, M.D., STATE DEPARTMENT OF HEALTH, SAYS THAT HE DOES NOT KNOW OF ONE PERSON WHO HAS BECOME ILL FROM CONSUMING RAW CERTIFIED MILK, NOR DOES HE KNOW OF ONE OUTBREAK FROM RAW CERTIFIED MILK IN 30 YEARS. * THE ONLY OUTBREAK OF SALMONELLA FROM MILK OCCURRED FROM PROPERLY PASTEURIZED MILK IN ARIZONA AND IMPROPERLY PASTEURIZED MILK IN KENTUCKY. * PASTEURIZATION DESTROY ESSENTIAL ENZYMES, VALUABLE IMMUNE FACTORS AND NUTRI- ENTS. * RAW CERTIFIED MILK IS, AND HAS BEEN, THE SAFEST, MOST WHOLESOME FOOD PRODUCT AVAILABLE TO MAN, BAR NONE! If you can't attend the hearings, please sign and send the petition below. * * * * * * * * * * * * * * * * * * * PETITION * * * * * * * * * * * * * * * * * * * UNDERSTANDING THAT SOME DIETS AND PHYSICAL CONSTITUTIONS PREFER AND REQUIRE RAW MILK, I SUPPORT THE CONTINUED SALE AND DISTRIBUTION OF RAW CERTIFIED MILK AND RAW CERTIFIED MILK PRODUCTS. DAlE: ____________________ SIGNED: ____________________________________________________ NAME ADDRESS CITY, STATE, ZIP CODE _______________________________________________________________ Mail: Congressman Henry Waxman, 2418 Rayburn House Office Building, Washington, D.C. 20515. Or, call him at (213) 651-1040, Los Angeles Office or (202) 225-4952, Washington, D.C. Office 2/85 PAGENO="0136" 130 Mr. DANNEMEYER. Dr. Bolton, are you familiar with the campylo- bacter infection associated with certified milk in Atlanta, GA, which occurred between May and June, 1981, and further that the culture survey failed to document the presence of the organism campylobacter in the suspected milk? Dr. BOLTON. Finding it in milk is a difficult process. Later you will have a chance to talk to John Orsborn, with the Department of Food and Agriculture for California. The techniques for recover- ing compylobacter are difficult. As a matter of fact, isolating it from human beings has been very, very difficult until about the last 4 to 5 years. The techniques for recovering it from milk have now been per- fected, and they have a sanitarian or laboratory technician with the California Department of Food and Agriculture who has finally perfected a technique to get this out. This is where they have liter- ally planted the germ in a sample of milk and said OK, let's see you grow it out of there. We just mixed it in. So, it has been diffi- cult, but it is coming on line now. It is like with this outbreak where the kids here went to the dairy, drank raw milk; the kids who in British Columbia went to a raw milk dairy, drank it, got campylobacter. As a matter of fact, these dairy epidemics of campylobacter with school field trips cropped up in British Columbia, Georgia, California, so much so that this week the U.S. FDA has mailed a special alert to the health departments all over the U.S.A. saying: Tell your school departments if kids go on field trips to dairies of any sort, caution the teachers that under no circumstances are the children to consume any raw milk products at these dairies. This just hit the mail or is just hitting the desk of the various health departments throughout the country this week. Mr. DANNEMEYER. Of course, there are other sources for campy- lobacter besides milk? Dr. BOLTON. Of course, person-to-person spread and other ways. But these are bunched-up cases. Most of the time we had sporadic cases of campylobacter, but we get 10 or 12 kids 2 days atter a visit to a raw milk dairy who are sick with high fever and bloody diar- rhea. And it is no fun, sir. Mr. DANNEMEYER. Dr. Fierer, what is your response to this? I think you told us in your testimony that you had three patients die. Dr. FIERER. That is right. Mr. DANNEMEYER. That manifested salmonella dublin, is that right? Dr. FIERER. Yes. Mr. DANNEMEYER. How many serotypes of salmonella are there known to medical science? Dr. FIERER. Probably 1,000. Mr. DANNEMEYER. And dublin is just one of them, isn't it, really? Dr. FIERER. Dublin is one of them, yes, as is typhoid. Mr. DANNEMEYER. Are you familiar with where salmonella dublin is in the list of 10 or 20 most commonly reported salmonel- las to the CDC Atlanta, GA? Dr. FIERER. Yes. PAGENO="0137" 131 Mr. DANNEMEYER. Where is it? Dr. FIERER. Way down. Mr. DANNEMEYER. How far down? Dr. FIERER. Oh, it is down among the infrequently isolated orga- nisms. Mr. DANNEMEYER. For instance, in 1978, the records of CDC dis- close, I think, that the top source of salmonella was typhimurium, with a little over 10,000 cases; No. 20 was branderop, of 204 cases. Salmonella dublin didn't make the top 20, did it? Dr. FIERER. No; but if you made a list of people dying from sal- monella infections, you would find dublin in the top 10. Mr. DANNEMEYER. Have you made that list? Dr. FIERER. Yes. Mr. DANNEMEYER. Have you? Dr. FIERER. Yes. Mr. DANNEMEYER. And? Dr. FIERER. That is in the State of California. I have not made it for the United States. Mr. DANNEMEYER. And what period of time did this list include? Dr. FIERER. Last couple of years. Mr. DANNEMEYER. All right. Have you published that? Dr. FIERER. No. Mr. DANNEMEYER. Then in 1979, the 10 top salmonella typhimur- ium with 10,000, No. 1, and 592 for s. anatum. Salmonella dublin was down that year, too? Dr. FIERER. Yes. Mr. DANNEMEYER. In fact it is fairly low, it is so small it is not even listed in terms of-it is not in the top 10 or 20, is it, sir? Dr. FIERER. That is true in terms of total isolates, that is certain- ly true. Mr. DANNEMEYER. One of these three people that you say, pa- tients of yours that died, did one have AIDS? Dr. FIERER. One had AIDS, one had chronic lymphocytic leuke- mia, and one had malignant melanoma carcinoma. Mr. DANNEMEYER. Is it your testimony that in those three cases you have just described that the proximate cause of the death of those patients was the consumption on their part of certified raw milk? Dr. FIERER. Two of them. The AIDS patient survived the salmo- nella infection. He was hospitalized in intensive care for approxi- mately a month with respiratory failure as a result of it. He did get better. He got AIDS from a blood transfusion. We didn't know he had AIDS. He was a previously healthy man. He left the hospi- tal and then came back in with pneumocystis pneumonia and died. I don't see anything funny about that. I don't see why people are laughing. People have died. Mr. DANNEMEYER. I didn't laugh, sir. Dr. FIERER. I know you didn't. Mr. DANNEMEYER. You know, I think the interest of members of the audience to your testimony was the fact that to a layman when you described the illnesses these three patients had, to suggest that the proximate cause of the death was to consumption of certified raw milk, raised a question of credibility. PAGENO="0138" 132 Dr. FIERER. It does? I don't understand who here is a physician who can decide proximate cause of death. Mr. DANNEMEYER. That is for triers of fact to resolve. But I think-- Dr. FIERER. Oh. Mr. DANNEMEYER. In two of the cases you say the proximate cause was consumption of certified raw milk. Is that right? Dr. FIERER. Salmonella dublin infection, yes, that was in people who drank raw milk. Mr. DANNEMEYER. Was that the cause listed on the death certifi- cate? Dr. FIERER. Yes. Mr. DANNEMEYER. Did you sign the death certificate? Dr. FIERER. No. Mr. DANNEMEYER. Was the physician who did sign the death cer- tificate someone you knew? You were the treating physician, weren't you? Dr. FIERER. I was the infectious disease consultant. We have a teaching hospital and I am a professor of medicine. The resident signed the death certificate. Mr. DANNEMEYER. How long had these two patients who died been suffering from the diseases that you described that they had prior to death, roughly? Dr. FIERER. The lady with a chronic lymphocytic leukemia had it for about 1 year; the man who had the malignant melanoma, I don't know how long he had it. I am sorry. Mr. DANNEMEYER. How long had these patients been consuming certified raw milk? Dr. FIERER. The woman who had the leukemia had been drinking raw milk for at least 2 years. The man who had the melanoma, I can't tell you. He came in in a coma from meningitis, and I never had a chance to talk to him. Mr. DANNEMEYER. Would you agree with the statement that for a single case of salmonella infection it would be very difficult to determine the source because there are a lot of risk factors in- volved? Dr. FIERER. That general statement, yes. Mr. DANNEMEYER. You also agree with the statement that though people cook meat and poultry, for the most part statistics show people are still contracting salmonella from meat and poultry or from cross-contamination or improper handling and storage of it? Dr. FIERER. I wouldn't know whether it is most but certainly some. Mr. DANNEMEYER. I have no other questions, Mr. Chairman. Mr. WAXMAN. Dr. Bolton, you showed us a sign from the city and county of San Francisco. I assume that was an ordinance adopted by San Francisco? Dr. BOLTON. Yes; it was. Mr. WAXMAN. As a warning to people, certainly to certain high- risk individuals not to purchase raw milk. Dr. BOLTON. Yes. Mr. WAXMAN. Yet you advocate a ban. Why don't you advocate a warning? PAGENO="0139" 133 Dr. BOLTON. A warning label on cigarettes has done no good. A warning label on raw milk, unless it is very striking, that says this product can kill you, or this product has potentially lethal side-ef- fects, with a biohazard sticker or something that is very eye-catch- ing, people will not pay much attention to it. I really think it would be better if you are not going to ban it, to at least have people have to sign a paper like if I am going to send somebody in for an operation and a surgeon is going to put tubes in the child's ear or take out his appendix. The parents sign a paper saying that the doctor explained this procedure and the risks and benefits, and I understand them and I authorize the doctor to go ahead. If you were going to sell it and not take it off the shelves, I think a statement is necessary that would outline the health risk of it to be signed by the purchaser saying I have read all this and I don't care, I will take my chances. Mr. WAXMAN. I guess the question is whether you think patients have adequate information about the risks and benefits of raw milk? Dr. BOLTON. Absolutely not. Mr. WAXMAN. The question then is if we added the warning label would they have that information available to them and should we say to them notwithstanding the fact that they have that informa- tion that they can disagree if they want to take their chances. Dr. Fierer, do you have any thoughts on that? Dr. FIERER. I really don't know whether a warning label would do any good. If that was proposed I would support it. Mr. WAXMAN. As opposed to nothing? Dr. FIERER. As opposed to nothing, definitely. Mr. WAXMAN. We have had suggestions like when children might go on a field trip. Their informed judgment is not the judg- ment we usually accept as an informed judgment. I guess there are other complications. But I was interested in your reaction. Dr. BOLTON. A warning label will really do it. We are dealing with a toxic waste problem. You have a product contaminated with a biologic toxic waste. It is an intermittent contamination even in the face of good sanitation. Would you really want an infant formu- la to stay on the market if you knew it was intermittently contami- nated by a harmful chemical? Obviously the answer is no. You say what about harmful bacteria? Should we look at that differently from the way you look at a deadly chemical? Mr. WAXMAN. Your testimony indicates-let me review it. The Academy of Pediatrics has become more concerned about the ques- tion of raw milk lately because of an increasing incidence of illness in recent years. Is that correct? Dr. BOLTON. That is true. Mr. WAXMAN. Is it an increasing incidence? Dr. BOLTON. Yes; but still not in great numbers. In California maybe 20 or so pediatric cases this year. A percentage of them have lymphoma, things like this, leukemia. But the tack of saying, well, so many other people die from getting other salmonella, or else from some other thing, why be concerned about this, is like saying why be concerned about somebody running over somebody with a car when thousands of people get run over by buses or something like this. PAGENO="0140" 134 You have to take every child's life as a sacred thing and say this child deserves the protection of our society, of our public healthful department to try to see to it that the child has clean milk. Mr. WAXMAN. Do you know of any evidence that raw milk is more healthy for you? Dr. BOLTON. I know of absolutely no evidence to that effect. I have studied the-this has been reviewed by Dr. Helen Swener- ton of U.C. Davis, by the CDC, and in literature search other people, and with the exception of the proponents of raw milk-basi- cally the industry and their allies-the majority of the medical lit- erature I have read indicates that there is less than 10 percent bind up in certain ingredients or certain things that are not really biologically important anyway because these things come from other sources in the human diet. There is no basic nutritional dif- ference between them. Mr. WAXMAN. We have heard a lot about salmonella. Is that the only organism to worry about when we are talking about raw milk, Dr. Fierer? Dr. FIERER. No. There are others. I concentrated on salmonella dublin in particular because it is such a serious illness for the people, at least in California, who acquire it. But you have heard there is a long list of organisms that can be acquired from raw milk including Listeria, Yersinia, et cetera. These organisms differ somewhat in that they are widely distributed through the food chain and there are plenty of other sources for them. Mr. WAXMAN. Dr. Bolton, one last question. Is the Academy con- cerned about the promotion of raw milk for infants? Dr. BOLTON. We have been very concerned. Mr. WAXMAN. All three of you gentlemen seem to think raw milk is inappropriate for infants. It is not a good food for them. They are the most susceptible to the disease. Do you have any com- plaint that there is a certain amount of encouragement for raw milk for infants? Dr. BOLTON. Yes; in the advertisements which you have stated and I have copies of those things describing it as the perfect food for infants. I feel that is a very dangerous thing to do. The Acade- my has an official statement on this that says for raw milk, except for the mother's own breast milk, raw milk should not be fed to the infant at any time. Mr. WAXMAN. I have no further questions. Do you have any others? Mr. DANNEMEYER. Yes. Dr. Fierer, the records of the CDC disclose in 1981 there were 2,456 cases of food poisoning from salmonella of all types. Dr. FIERER. You mean epidemics? Mr. DANNEMEYER. They classified them as attributable to food, part of an outbreak. That was the classification. Dr. FIERER. All right. Mr. DANNEMEYER. The largest number in 1981 came from chick- en. Now, since we are concerned about the adverse impact on humans from salmonella, in your instance you are talking about certified raw milk which produced in that same year-according to the records of the CDC-26 cases. PAGENO="0141" 135 Dr. FIERER. What year is this? Mr. DANNEMEYER. In 1981 the CDC reports 26 related to milk, 122 related to chicken. Now if the logic of your view says to get rid of the 26 cases that came from milk, pasteurize it or get rid of it, shouldn't we also ban chicken? Dr. FIERER. That is a list of food-related epidemics. When the epi- demic occurs you know something has gone wrong because that is out of the ordinary. What that tells me is that it is a very easy thing to prepare chicken incorrectly and, in effect, a lot of people do. Mr. DANNEMEYER. From the standpoint of-- Dr. FIERER. That is not a day-to-day threat. Mr. DANNEMEYER. Since we are looking out for the health of our consumers, we have a responsibility, those of us in Government, and if our goal is eradication of salmonella-- Dr. FIERER. That is not my goal. Mr. DANNEMEYER. Then to be consistent shouldn't we eliminate any food product that has produced salmonella food poisoning? Dr. FIERER. I couldn't go about telling you how to do that. That is not my goal. That is an unrealistic goal. Mr. DANNEMEYER. What do you mean? Dr. FIERER. To eliminate all salmonella infections is an unrealis- tic goal. I would never attempt it. Mr. DANNEMEYER. That is puzzling. Dr. FIERER. Why? Mr. DANNEMEYER. Why would salmonella from chicken be less inimical to the health of humans than salmonella from milk? Dr. FIERER. For one thing, as I thought I emphasized, one of the infections that is acquired from milk is salmonella dublin, which is potentially lethal; whereas you never get that from chickens. Most of the chicken infections, chicken-associated infections are relative- ly self-limited cases of gastroenteritis. It would be nice if we didn't have them, but they are one of the plagues of mankind that we live with. That will be my major point. Mr. DANNEMEYER. In other words, salmonella, you agree, is a ubiquitous substance. Is that right? Dr. FIERER. Not ubiquitous. Mr. DANNEMEYER. All right. How about pork, 120 cases in 1981. Shouldn't we ban pork? Dr. FIERER. I don't think there was a single case of salmonella dublin from pork. Mr. DANNEMEYER. Egg nog, 74. Shouldn't we get rid of egg nog? Dr. FIERER. I don't know about egg nog. Mr. DANNEMEYER. How about shellfish? Dr. BOLTON. I would like to comment on this if I could. Mr. DANNEMEYER. If you wait, I will come to you next. Dr. BOLTON. OK. Mr. DANNEMEYER. Forty cases from shellfish. Shouldn't we get rid of that? Dr. FIERER. We should try to control it, and I think the public health authorities have. Its a major source of hepatitis in the United States. Most public health authorities attempt to control raw shell fish. PAGENO="0142" 136 Mr. DANNEMEYER. Turkey, for instance, produced 455 cases. Shouldn't we get rid of turkey? Dr. FIERER. No; I wouldn't say that. Mr. DANNEMEYER. Dr. Bolton, let's take another year, 1980; 2,381 cases of salmonella food poisoning reported to the CDC in that year. Take 1978, it might be a better year for comparison. In that year there were all together 33 cases of salmonella food poisoning, and 23 of them related to pasteurized milk. That is to be contrasted with pork, producing 850 cases in 1978. Shouldn't we get rid of pork? Dr. BOLTON. If you take everything that you have mentioned there and say, are we really balancing things, and so are we talk- ing about getting rid of milk? No; we are talking about making it safe by heat treatment or pasteurizing. The thing that makes chicken and pork safe for consumption is cooking. Mr. DANNEMEYER. Wait a minute, notwithstanding the cooking, whatever preparation was involved by the preparer, the records of the CDC disclose that in 1978 there were 379 cases from turkey, 850 from pork, 147 from beef. In other words, we consumers have almost reached the point where we cannot be trusted with our own food preparation, and in order to improve the lot of the lives of all of us, we should, if the goal is elimination of salmonella, get rid of all these food products that produce salmonella, shouldn't we? Dr. BOLTON. No, sir; you should heat-treat them, pasteurization, heat treatment. You cook pork. You cook chicken. If you don't cook pork, not only are you going to get salmonella, but you will stand a good chance of getting trichinosis and a lot of other problems. But the breakout there is the cooking factor. When you go into that, OK, we will suffer pasteurized milk out- breaks, this will happen. Or if it is not properly done or cleanliness breaks down, certainly no system is perfect. But one of the things that girls are taught and that boys are taught and that other people are taught is you don't eat pink chicken. If you get chicken improperly prepared-- Mr. DANNEMEYER. What you just said, nothing's perfect in this world, isn't that really the crux of this controversy? It strikes me that people of a persuasion of yourself and Dr. Fierer-good-mean- ing, well-intentioned people, I concede that-are attempting to assert a standard of performance or achievement for in this case certified raw milk, in terms of its ability to be consumed by a con- sumer, and that you are ignoring a vast majority of other food products that are available to consumers on the tables of people of California. Dr. BOLTON. I will not give you that point. We are not sitting back saying it is OK to have salmonella in these other places. You try to cook and control this by heating because heating will control or kill the salmonella. Mr. DANNEMEYER. In 1 year, if I could find it, we had CDC re- porting that the source of salmonella was water in 78 cases of sal- monella poisoning. From water. Dr. BOLTON. That happened to be related to a cistern where there were birds roosting on the roof. The drain water was collect- ed in the cistern and consumed by the people. PAGENO="0143" 137 You should go back and look at the epidemics you quoted be- cause you are using rough statistics. Mr. DANNEMEYER. In 1979 there were 200 cases from hospitals, and to be consistent should we shut down hospitals? Dr. BOLTON. Salmonella will spread in hospitals if people don't wash their hands carefully or if the food is not prepared carefully. Salmonella can be transmitted person to person. It's a big factor. You must wash your hands. Mr. DANNEMEYER. Would it follow we should shut down the hos- pitals in America and we can stop salmonella? Dr. BOLTON. No. You have to get people to wash their hands, sir. Mr. DANNEMEYER. Well, the point is there is nothing perfect in this world. Dr. BOLTON. So you are going to spot us so many leukemics and lymphoma patients and say, OK, let them die because it is not a perfect world? No. You try to protect those people. Mr. DANNEMEYER. Let me ask you one other question, if I may. Are you familiar with those who claim that there is a nutritional loss from the pasteurization of milk? I am not asking if you agree with those. Are you familiar with those claims? Dr. BOLTON. I have read their claims and the counterclaims I have read. I happen to believe the counterclaims. My opinion is dif- ferent from Dr. Fleiss, but I have reviewed this and I believe there is no great nutritional loss from pasteurization. The health risk is greater. Mr. WAXMAN. Let me admonish the audience that we won't have any reactions. You are guests here, and this is a public meeting; but we are not asking for public reactions to statements made by the witnesses. That would be inappropriate. Mr. DANNEMEYER. Dr. Fierer, are you familiar with the claims of people who have done research, scientific research, who assert there is a significant nutritional loss from the process known as pasteurization of milk? Dr. FIERER. I am. You sent me some of them yourself. Mr. DANNEMEYER. Did you read them? Dr. FIERER. Oh, yes. Dr. Fri~iss. And you have concluded that they are lacking in what? Dr. FIERER. In scientific merit. Mr. DANNEMEYER. In your opinion. Dr. FIERER. Yes. Mr. DANNEMEYER. Thank you very much. Mr. WAXMAN. Thank you, Mr. Dannemeyer. Gentlemen, thank you very much for your testimony. We now call our third panel. I regret that the Los Angeles De- partment of Health Services was unwilling to permit Dr. Shirley Fannin, chief of the county communicable disease control, to par- ticipate in this hearing. We do have Dr. James Chin, who is chief of the Infectious Disease Section of the California Department of Health Services; Dr. Morris Potter is a veterinary epidemiologist from the Centers for Disease Control, and Dr. Patton Smith, who is assistant director, Division of Animal Industry, California Depart- ment of Food and Agriculture. Dr. Smith is accompanied by Dr. PAGENO="0144" 138 John Orsborn, who is chief of venterinary and laboratory services. Also, Dean Thomas is president of Delst Chemical Co. & Research Inc. I would like to welcome all of you to this hearing. We have on the list John Adams of the National Milk Producers Federation, to testify after this, but he will have to leave, so I would like to have Mr. Adams, National Milk Producers Federa- tion, come forward at this time, if he would. We are aware of the fact you have a tight schedule. We hoped to have had you up earlier, but I will ask you to give us your testimo- ny first and see if there are questions, and we can allow you to leave. STATEMENT OF JOHN ADAMS, DIRECTOR, MILK REGULATORY AND ANIMAL HEALTH AFFAIRS, NATIONAL MILK PRODUCERS FEDERATION Mr. ADAMS. Thank you very much, Mr. Chairman, I appreciate your courtesy. I am John Adams. I am director of milk regulatory and animal health affairs of the National Milk Producers Federation, located at 1840 Wilson Boulevard, Arlington, VA. The National Milk Producers Federation is a national farm com- modity organization representing nearly all of the several hundred dairy marketing cooperatives serving this Nation. These coopera- tives and their producer members market a significant volume of all of the milk sold commercially in the United States. The membership of the federation has long supported the need for pasteurization of all milk and milk products sold to consumers. Not only has the federation recognized the basic necessity of pas- teurization for the protection of the public health, the federation has also been actively involved in developing and supporting the National Conference on Interstate Milk Shipments since its incep- tion in 1950. The NCIMS is an organization of State governments and the Food and Drug Administration, who jointly participate in the National Conference on Interstate Milk Shipments known as NCIMS. This national conference is held every 2 years to develop the Grade A pastuerized milk ordinance and conference procedures. These documents serve as a basis for reciprocity agreements be- tween the states governing milk shipments and receipts. They also form the basis of a sound cooperative State-Federal program de- signed to protect the public health from the cow to the consumer. This program has been cited by the second National Conference on Food Protection as a model for the entire food industry. Without the requirement of pasteurization, no comparable public health program can exist for the consumption of raw milk. Seldom, if ever, has there been such an overwhelming array of scientific evidence indicting raw milk consumed in a raw state. Seldom, if ever, has there been such an array of universal public support for banning the sale of raw milk in interstate commerce for beverage consumption. The entire milk industry, both producer organizations and proc- essors, support such a ban. Federal agencies, State governments and consumer organizations have registered continued concern PAGENO="0145" 139 that no action has been taken at the federal level to ban the sale of unpasteurized products sold to consumers. The FDA Hearing Clerk's file is replete with resolutions, letters of concern and scien- tific evidence supporting a prohibition of the sale of unpasteurized milk and milk products sold directly to consumers. Yet, for unsub- stantiated reasons, there has been no concrete action taken by Health and Human Services to prohibit the sale of a food which continues to pose a public health threat. If there were not such a simple way of reducing or eliminating such a public health threat as pasteurization would provide, per- haps we could understand the delay. However, in the face of all the scientific evidence indicting unpasteurized milk, it is unconscion- able that no action has been taken by HHS to lift the stay imposed by FDA in 1974. This stay has continued to permit the interstate shipment and sale of unpasteurized milk and milk products for direct sale to consumers. We are therefore, encouraged by the ruling of U.S. District Court Judge Gerhard Gesell on January 14, 1985. As a result of the court's direction, we hope HHS will proceed to clear the way for FDA to propose regulations which will require all milk and milk products moving in interstate commerce for direction human con- sumption to be pasteurized. We are hopeful that this subcommittee can support such a much needed requirement which is so essential for protecting the public health. There are no sound or justifiable public health or scientific rea- sons for not requiring pasteurization of all milk and milk products sold in final packaged form to consumers. To do otherwise will con- tinue to undermine the great progress which has been made in this Nation to produce and market very safe and wholesome pasteur- ized milk and pasteurized manufactured milk products. Mr. Chairman, I referred to the scientific evidence. You have re- ceived that. Obviously there are different opinions regarding the evidence, but I have prepared and would like to submit for the record, a number of references which perhaps will add to the al- ready complete FDA hearing record: One is a reprint from the Journal of the American Medical Asso- ciation entitled, "Unpasteurized Milk-the Hazards of a Health Fetish" by Morris Potter, and you will hear him speak today. In this review, the hazards and purported benefits of raw milk con- sumption are reviewed to "help the practicing physician and other health professionals more fully appreciate the risk posed to human health by raw milk." Quoting further from the comment section of his review, which I hope everyone has read: The relative merits of raw and pasteurized milk have been debated for at least 90 years. In this period, the theoretical health benefits of raw milk have never with- stood careful scientific scrutiny. I would like to acknowledge for your benefit that in this particular review article, the situation dealing with nutritional benefits is dealt with. I think if you will read that, there are differences, but the differencesare less than 10 percent and are not considered statistically significant at the 5 percent level. So I think we need to be careful when we talk about nutritional benefits because the scientific scrutiny of the nutritional benefits has not stood up in terms of the statistical relationships. Conversely, since October 19, 1984, when the review article was published in JAMA, we know of at least one documented and reported outbreak of salmonella found in raw milk sold in southwestern Oregon. Based on a news release dated November 15, 1984, PAGENO="0146" 140 issued by the Oregon State Health Division, salmonella dublin was isolated from Reservation Ranch brand raw milk bottled on November 5 in Smith River, CA. A routine sample of this milk was reported to have been received in the Food and Dairy Division Laboratory, Oregon Department of Agriculture on November 6 and the presence of salmonella dublin was confirmed on November 15th. According to this release, "Oregon has experienced several raw milk associated disease outbreaks since 1978 involving salmonella dublin, salmonella typhimurium and camphylobacter jejuni." Therefore, the "Oregon State Health Division recommends that only pasteur- ized milk and other dairy products be used." Mr. Chairman, a Federal regulation banning interstate shipment of raw milk for direct beverage consumption would assist a number of States which deem it necessary or desirable to restrict or ban the sale of unpasteurized milk and milk products within their own governing boundaries. There have been few times when so many from all sectors of the public, whether producer, consumer or professionally oriented, have realized the necessity to take action to protect the public health. The great majority of those in the dairy industry realize that protection of the public health is and must continue to be our most important consideration. At a time when so much public at- tention is focused on the need to protect the public health and pro- vide a safe and wholesome food supply, it is unconscionable that we continue to delay action to provide protection for the public against sale of unpasteurized milk or milk products in interstate commerce for direct beverage consumption. Thank you very much. [Mr. Adams' prepared statement and reprint referred to follow:] PAGENO="0147" 141 National Milk Producers Federation Mr. Chairman, my name is John B. Adams. I am Director of Milk Regulatory And Animal Health Affairs of the National Milk Producers Federation, located at 1840 Wilson Boulevard, Arlington, Virginia. The National Milk Producers~ Federation is a national farm commodity organization representing nearly all of several hundred dairy marketing cooperatives serving this Nation. These cooperatives and their producer members market a significant volume of all the milk sold commercially in the United States. The membership of the Federation has long supported the need for pasteuri- zation of all milk and milk products sold to consumers. Not only has the Fede- ration recognized the basic necessity of pasteurization for the protection of the public health, the Federation has also been scti~ely involved in developing and supporting the National Conference on Interstate Milk Shipments (NCIMS) since its inception in 1950. The NCIMS is an organization of state governments and the Food and Drug Administration who jointly participate in the "National Conference on Interstste Milk Shipments" known as "NCIMS." This national con- ference is held every two years to develop the Grade "A" Pasteurized Milk Ordinance and "Conference Procedures." These documents serve as a basis for reciprocity agreements between the States governing milk shipments and receipts. They also form the basis of a sound "Cooperative State-Federal program designed to protect the public health from the cow to the consumer. This program has been cited by the secoiid National Conference on Food Protec- tion as,a model for the entire food industry. Without the requirement of pasteurization, no comparable public health program can exist for the con- sumption of raw milk, PAGENO="0148" 142 Seldom, if ever, has there been such an overwhelming array of scientific evidence indicting raw milk consumed in a "raw" state. Seldom, if ever, has there been such an array of universal public support for banning the sale of raw milk in interstate commerce for beverage consumption. The entire milk industry, both producer organizations and processors, support such a ban. Federal agencies, State governments and consumer organi-' zations have registered continued concern that no action has been taken at the Federal level to ban the sale of unpasteurized products sold to consumers. The FDA Hearing Clerks file is replete with resolutions, letters of concern and scientific evidence supporting a prohibition of the sale of unpasteurized milk and mIlk products sold directly tà consumers. Yet, for unsubstantiated reasons, there has been no concrete action taken by Health and Human Services to prohibit the sale of a food which continues to pose a public health threat. If there were not such a simple way of reducing or eliminating such a public health thi~eat as pasteurization would provide, perhaps we could under- stand the delay. However, in the face of all the scientific evidence indicting unpasteurized milk, it is unconscionable that no action has been taken by HHS to lift the stay imposed by FDA in 1974. This stay has continued to permit the interstate shipment and sale of unpasteurized milk and milk products for direct sale to consumers. We are, therefore, encouraged by the ruling of 13.5. District Court Judge Gerhard Gesell on January 14, 1985. As a result of the Court's ~1irection, we hope 11115 will proceed to clear the way for FDA to propose regulations which will require all milk and milk products moving in interstate commerce for direct huñian consllmption t9 be pasteurized. We are hopeful that this Subcommittee can support such a much needed requirement which is so essential for protecting the public health. PAGENO="0149" 143 There are no sound or justifj~able public health or scientific reasons for not requiring pasteurization of all milk and milk products sold in final pack- aged form to consumers. To do otherwise will continue to undermine the great progress which has been made in this Nation to produce and market very safe and wholesome pasteurized milk and pasteurized manufactured milk products. Mr. Chairman, Ihave referred in my statement to the scientific evidence which supports an MRS ban on the interstate sale of unpasteurized milk and milk products for direct consumer consumption. Most of this evidence is now a part of the FDA hearing record. We have prep~red, however, several references which may provide additional supporting evidence for a ban on interstate shipment of raw milk for direct human consumption, so I would ask that these references be included along with my statement for the hearing record. One of these references is a reprint form the Journal of the American Medical Association entitled "Unpasteurized Milk-The Hazards of a Health Fetish" by Morris Potter and associates (CDC, Atlanta, Georgia published in JAMA, October 19, 1984-Vol. 252, No. 15). In this review, the hazards and purported benefits of raw milk consumption are reviewed to "help the practicing physician and other health professionals more fully appreciate the risk posed to human health by raw milk." Quoting further from the comment section of this review: "The relative merits of raw and pasteurized milk have been debated for at least 90 years. In this period, the theoretical health benefits of raw milk have never withstood careful scientific scrutiny." "Epidemic richets and scurvy and the other dire consequences of milk pasteurization prophésized by early raw milk advocates have not occurred." "Conversely, the fact that raw milk presents a substantially greater inherent risk of infectious disease has been demonstrated repeatedly." "Surprisingly, the controversy continues." PAGENO="0150" 144 Since October 19, 1984 when the review article was published in JAMA, we know of at least one documented and reported outbreak of Salmonella found in raw milk sold in Southwestern Oregon. Based on a News Release dated November 15, 1984 issued by the Oregon State Health Division, Salmonella dublin was isolated from Reservation Ranch brand raw milk bottled on November 5 in Smith River, California. A routine sample of this milk was reported to have been received in the Food and Dairy Division Laboratory, Oregon Department of Agriculture on November 6 and the presence of Salmonella dublin was confirmed on November 15. According to this release, "Oregon has experienced several raw milk-associated disease outbreaks since 1978 involving Salmonella dublin, Salmonella typhimurium and Camphylobacter jujuni. Therefore, "The Oregon State Health Division recommends that only pasteurized milk and other dairy products be used." Mr. Chairman, a Federal regulation banning interstate shipment of raw milk for direct beverage consumption would assist a number of states which deem it necessary or desirable to restrict or ban the sale of unpasteurized milk and milk products within their state boundaries. There have been few times when so many from all sectors of the public, whether producer, consumer or professionally oriented, have realized the necessity to take action to protect the public health. The great majority of those in the dairy industry realize that protection of the public, health is and must continue to be our most important consideration. At a time when so much public attention is focused on the need to protect the public health and provide a safe and wholesome food supply, it is unconscouncable that we continue to delay action to provide protection for the public against sale of unpasteurized milk or milk products in interstate commerce for direct beverage consumption. John B. Adams, Director' Milk Regulatory And Animal Health Affairs PAGENO="0151" Unpasteurized Milk R~pdsttndfros,JAMAtt R.Jecoulof9.A,,,s,ks, MedioulMzocluM, OOebut 19. 1984, Moss 252 Cop~vçh1 1984. M,edco, MOOaIM,oclcts,, The Hazards of a Health Fetish Morris E. Potter, DVM; Arnold F. Kaufmann, DVM; Paul A. Blake, MD; Roger A. Feldman, MD AS THE dairy industry began to industrialize in the ISOOs, the mass production and distribution of milk and dairy products led to widespread outbreaks of milkborne disease. The greatest perceived milkborne hazards of the time were poor sanitation and handling procedures, as well as dis- eased dairy cows. Repeated outbreaks of typhoid, scarlet fever, diphtheria, diarrheal disease, and septic sore throat were caused by milk that was produced, transported, and sold under unhygienic conditions. Nationwide problems with contam- inated milk led to two public health movements that attacked the pur- veyors of bad milk and each other with equal alacrity. The certified milk movement promoted sanitation in all phases of milk production and mar- keting under the oversight of medical milk commissions but denounced pas- Fto,t, Ito Oioiuion of Buotetiul Disnssss, Contst fotIstuctioc~ Ossases, C.etsss lot PnnussCocttot. Musts. Rsptkttesqeoststoflloiaios ot8actetiotDisensos Costs, tot kstestioss Oseusos, 1800 Clifton Rd NE. Atlasta, GA 30333 (St Potts,). 2048 JAMA, Oct 19, 1984-Vol 252, No. 15 teuri;Ation, claiming that it caused nutritional deficiencies, allowed the marketing of sterilized filth, and destroyed the natural flavor of milk. Conversely, the pasteurized milk movement denounced certified milk as unsafe despite the sanitary precau- tions.' Ultimately, the best of both movements became public policy. Pasteurization was accepted as the primary safeguard for the nation's milk supply after several epidemics were traced to certified raw milk, while the sanitary concepts of the certified milk movement were incor- porated into milk hygiene codes as important adjunctive safeguards. The apparent public health impact of safe milk was substantial; for example, the number of infant deaths due to diarrhea in Washington, DC, dropped from 477 in 1894, the year before sanitary requirements for milk were strengthened, to 72 in 1909.' Although there is no objective evi- dence that milk pasteurization has an adverse effect on human nutrition or health, the sale of raw milk (certified and uncertified) has persisted and even increased in recent years under intensive promotion by "health food" enthusiasts using arguments similar to those advanced in the 1890s. In this review, we discuss the has- ardn and purported benefits of raw milk consumption to help the practic- ing physician and other health pro. fessionals more fully appreciate the risk posed to human health by raw milk and to enable them to under- stand and rebut arguments advanced in support of consumption of raw milk. DefinitIons Milk, as discussed in this review, is cow milk unless otherwise specified. Coat milk is increasingly promoted as a health food, but constitutes less than 1% of total milk consumption in the United States. Raw (unpasteurized) milk may be certified or uncertified. Certified raw milk is produced in accordance with methods and standards established by the American Association of Medi- cal Milk Commissions, Inc (an indus- try-supported organization). This milk is produced by a few large dairies and is often sold, where state laws allow, in retail food stores. Uncertified raw milk is typically pro- duced in small volumes by individual dairy farmers and sold on the prem- ises of the producing farm or by home delivery. Pasteurized milk is milk heated for specified time and temperature com- binations designed to kill all micro- 145 State of the Art M. Therese Southgate, MD, Section Coordinator * Meaningful differences in nutritional value between pasteurized and unpasteurized milk have not been demonstrated, and other purported benefits of raw milk consumption have not been substantiated. Conversely, the role of unpasteurized dairy products In the transmission of infectious diseases has been established repeatedly. To effectively counsel patients attracted by the health claims made for raw milk, practicing physicians must understand both the rationale used by proponents of raw milk and the magnitude of the risk involved in drinking raw milk. (JAMA 1984;252:2050-2054) Unpasieseized Milk-Potter ci ci PAGENO="0152" Comparison of Nutritional Values published a report about his observa- In Raw and Pasteurized Milk lions on cats fed varying combina- tions of raw and heat-treated milk Pasteurization causes minor and raw and cooked meat. In his first changes in milk, and advocates of raw and largest series of experiments, milk have at one time or another Pottenger observed many diseases in claimed that virtually every detect- cats fed raw milk and cooked meat, able change has profound health but essentially no disease in those fed implications. Pasteurization affects raw milk and raw meat. Raw milk six milk constituents with known advocates have erroneously cited this nutritional benefits: three vitamins article as having reported that din- for which milk is a minor source ease occurred in cats fed pasteurized (thiamine, B,, and C), calcium, pro- milk (eg, Llyod F. Smith, MD's article tom, and fat. Thiamine is reduced Why Certified Raw Milk, Let's Live from approximately 0.45 to 0.42 mg/ Magazine). Smaller experiments re- I; vitamin B, is reduced at a maxi- ported in the same article showed mum from 3 to 2.7 pg/Is; and vitamin that a diet of one-third raw meat and C is reducc(f from 2.0 to 1.8 mg/L. two.thirdn milk (pasteurized or not) None of these losses exceeds 10%, and (lid not provide adequate nutrition for none can be considered important, cats. About 6% of calcium is rendered The major health benefits claimed insoluble, and about i/o of milk pro- for raw milk are summarized in Table tein is coagulated. The major etTect 1. These claims, except for a few on fat is a slight disaggregation of fat recent variants, were rebutted more glubules, resulting in a reduced cream than 40 years ago by Wilson in his line in whole milk. The observed monograph Tue Pasteurization of changes have no effect on the bio- Milk. This book is required reading availability of these three nutrients.' for anyone interested in the topic. Raw milk has also been said to con- tain untlefined and un,letectal,le Infectious Disease Hazards health promoters, such as an anti- of Raw Milk stilTness factor invaluable for treat- Abundant evidence has shown that ment of arthritis, hut ouch claims raw milk serves as the oource of have not been substantiated in the bacteria that cause outbreaks of din- mc,lical literature, ease in humans: in recent years, most Numerous studies of the relative frequently salmonellonin and campy- nutritional merits of raw and pus- lobacteriosis. In the investigations of teurized milk have been conducted in such outbreaks, the epidemiologic evi- animals and humans, and us differ- dence, combined with knowledge t'nces were detectable. One animal abost the occurrence of specific path- study deserves particular attention ogens in cattle and the isolation of because a misrepresentation of the some of these pathogens from raw results has become prominent in the milk, leaves no doubt that rasv milk is raw milk folklitre. In 1916, Pottenger' a vehicle for disease in humans. 146 Table 1-Purported Health Benefits Derioed From Drinking Raw Milk' ~ nobnnqiientiy pnxdoeod tsr thin sxxtzrtisr, Eyhucorsrrnittarsu to disnuro Us esidoxso eristo is xsppsit of this shim is, us milk; ox the soirtinry, rnilkbomn dinrunu ann 0 probtom is nsisiit stodiux soorpn,ieu mu zed poxteaszod milk Erhursur fortuity Thin ooeoopt en bunod ox reisreprosnrtutisn of nxirmnt funding ntoduno that ousisud dutioioirt duoto Contuirs ksrotisiut nxzyrrzs. Some enzymes urn ieactiuutod by puntosmiuutisx. bst thrnr errzymrn urn pu'obnbty ,szotisntrd by pxpnirr hornixeon. ned zotikodius nodior guntrio uviduiy; hsoesyn oootnxt of cow milk ixoesurtoufi. uxd hsrresmn urn rot ,ynotuuuted by punteorizutise tnmpnmntoron; rho nmuii qouxtity of uxtibody ix esrmui milk, nhitn rot ,ruohsztrd by pun. in rot sbno,bzd in thu humor intuxtirni frost Csntnien sidelined nsbntoesnn iosh Thnnu oiai,rn weouerrt to (trIo morn thnr ureodotrs CocOs's iustobuciiii Luotskusiih urn ssets,vi,rnetn rutherthuri eutorut loin of milk; puntrorinud daoy prolostS coetu500n zdded iaOobnoitii urn as~lbto organisms that transmit disease to humans through milk. Currently ac- cepted time-temperature combina- tions ioclnde 63 °C for 30 minutes, 71.6 °C for 15 s, and 89 e~ or higher for 1 s. Pasteurization does not steri- lize milk, but doe~ make the milk safe to drink. Pasteurization should be distinguished from homogenization (emulsification of milk fat) and for- tification (addition of vitamins A and/or D). In the health food litera- ture, commentaries about the pur- ported nutritional hazards of pasteur- ized milk tend to blend the three processes into one. Like pasteurized milk, raw milk may be sold homoge- nized and with vitamins A and 1) added. The regulatory standards for pas- teurized milk vary by state, hut these standards all meet or exceed those in the Grade A Pasteurized Milk Ordi- nance recommended by the Food and Drug Administration. Individual state regulations on the sale of raw milk also vary, with some prohibiting such sales, ethers allowing sales only on the premises of the proilocer, and others setting up stanilards jtaral- leling their pasteurized milk ordi- nance. All milk ordinances set mini- mum standards for dairy animal health, personnel health, environ- mental hygiene, and milk quality. Quality control programs supple- menting the official regulatory pro- grams are commonplace in the dairy industry. The standards for hygiene of certified feaw milk that are estab- lished by the American Association of Medical Milk Commissions, bc, rep- resent only one of many such pro- grams. JAMA, Oct 19, loud-Vol 252, No. t5 Unpasteurized Milk-Potter of at 2049 PAGENO="0153" 147 Modern sanitary and health stan- dards observed by the dairy industry have made contamination from envi- ronmental sources, including humans, an infrequent problem. In contrast, programs relying solely on sanitary and health standards have not suc- ceeded in eliminating contamination caused by symptomatic or asympto- matic infection in the milk-producing animal. Contamination from animals with organisms such as Salmonella and Campylobacter has thus become the primary hazard for raw milk consumers. Salmoneliosts Many outbreaks of oalmonellosis due to consumption of raw or improp- erly pasteurized milk, nonfat dry milk, and cheese have been de- scribed." Salmonellae have been iso- lated from raw milk repeatedly during investigations of such out- breaks." Milk is an ideal growth medium for Salmonella, and some strains of Salmonella can even sur- vive in cultured milk products, such as yogurt, for as long as two weeks. Surveillance of human salmonello- sis in the United States is based primarily on reports of isolates iden- tified at state public health laborato- ries, and these isolates are believed to represent only a small percentage of the cases that occur. Most isolates belong to a few common serotypes, so epidemiologic investigations are usu- ally not initiated unless there is an unusual incidence of a relatively rare serotype or a serotype that is a mark- er for a particular problem. There- fore, the relationship of sporadic cases to a common source is usually not detected when they are caused by a common serotype. Isolates of Sal- monella dublin, a relatively rare sero~ type known to be host adapted to cattle, are more likely to be investi- gated and identified as being derived from raw milk than are the corn- manly isolated serotypes. Numerous studies in multiple locations have confirmed the role of raw milk in the transmission of S dublin to hu- mans."' Based on their 1982 data, California health authorities calcu- lated that the risk of S dublin infec- tion was 84 times higher in persons who consumed raw milk than in per. sons who did not (S. B. Werner, MD, oral communication, October 1983). Salmonella dublin infections are of particular concern because the associ- ated illness tends to be severe. The relative virulence of S dublin is illus- trated by its ability to invade the bloodstream' and the rates of hospi- talization and mortality for infected individuals."' Salmonella dublin is 13 times more likely to be isolated from blood than are other Salmonella nero- types, and more than half of the patients with S dublin infection are hospitalized. In two reports, 10% to 20% of the cases of S dublin infection were fatal." Risk of S dublin infec- tion is significantly higher in persons over the age of 40 years and in persons with underlying chronic ill- nesses or taking antacids." The problem of raw milk-associated salmonellosis is not restricted to S dublin. From a baseline of three Sat. monella typhimurium isolates in four years, the number of isolates of S typhimurium from persons in a three-county area of Oregon in- creased to 27 in three months in early 1983.' Epidemiologic investigation in- criminated raw milk and cream from a single dairy, and S typhimurium with the same plasmid profile was isolated from milk, milk filters at the dairy, the dairy cows, and the ill Re,cently, in Vermont, eight persons (aged 10 months to 60 years) in four families had diarrhea, abdominal cramps, and fever." All had drunk raw milk from a single dairy. Salmo- nella det'by was isolated from the patients and the milk. In 1980, a multiresiotant S typhimurium was isolated from patients and milk (lur- ing an outbreak of enteritis involving 105 persons who had drunk raw milk from a single source in Montana." Campylobacteriosis Since culture of diarrheal stools for Campylobacter jejuni became com- mon, many milkborne outbreaks of campylobacteriosis have been de- tected. Fourteen (61%) of 23 Campy. lobacter outbreaks reported to the Centers for Disease Control (CDC) from 1980 through 1982 were traced to consumption of raw milk (Mark Finch, MD, unpublished data, Decem- ber 1983). In a detailed one-year study of sporadic campylobacteriosis con- ducted in Iowa in 1982 and 1983, 35'S of the ill persons had drsink raw milk during the week before onset of ill- ness; drinking raw milk was the only significant difference between cases and controls (P<.05; relative risk, 9.3)." In the United States, outbreaks of campylobacteriosis associated with drinking unpasteurized milk have recently been reported in Arizona, California, Colorado, Georgia, Kan- sas, Maine, Oregon, and Pennsylva- nia." In the outbreak of campylo- bacteriosis in Arizona," two cohort studies showed that households with members who drank raw milk re- ported diarrheal disease significantly more frequently than those in which no one drank raw milk, with relative risks of 4.7 and 3.4. In the Georgia outbreak, illness due to campylobac- teriosis in 30 households was strongly associated with consumption of raw milk (odds ratio, 29.5), while contacts with pets, livestock, or well water were not associated with illness." As in Arizona and Georgia, only con- sumption of raw milk was signifi- cantly associated with enteritis in the other outbreaks. Other Diseases Other bacterial diseases associated with drinking unpasteurized milk from cows include brucellosis, coli- bacillosis, listeriosis, tuberculosis, corynehacteriosis, staphylococcosis, streptococcosis, streptobacillosis, and yersiniosis (Table 2). These diseases are now infrequently reported as milkborne diseases in the United Slates, hut they illustrate the wide range of potential hazards. Milk other than cow's milk has also been associated with diseaoe in hu- mans. Toxoplasmosis has been associ- ated with raw goat milk," and bru- cellosis and campylobacteriosis have followed consumption of raw goat's milk cheese." The virus of tickborne encephalitis is shed in milk, and fresh cheese made from unpasteurized sheep milk has been associated with this disease." Toxin-producing staph- ylococci have been isolated from cheese made from raw sheep's milk.0 Comment The relative merits of raw and pasteurized milk have been debated for at least 90 years. In this period, the theoretic health benefits of raw milk have never withstood careful Uspatteurized Milk-Poller et at 2050 JAMA. Oct 19. 1984-Vol 282, No. 15 PAGENO="0154" scientific scrutiny. Epidemic rickets and scurvy and the other dire con- sequences of milk pasteurization prophesized by early raw milk advo- cates have not occurred. Conversely the fact that raw milk presents a substantially greater inherent risk of infectious disease has been demon- strated repeatedly. Surprisingly, the controversy continues. Regulation of the sale of raw milk often inyolves discussion of freedom of choice. A major feature of the individual's right to free choice, how- ever, is informed consent, and incor- rect information on the purported benefits of drinking raw milk is so widespread that truly informed con- sent is difficult to achieve. Also, in matters of foodstuffs, parents make choices for their children. Therefore, the children of advocates of raw milk are exposed to the risks of infectious diseases without a full understanding of the danger.'~" Children also tend to drink what is given to them in school without questioning its safety. There have been numerous outbreaks of enteric diseases in schoolchildren giv- en raw milk while on field trips to dairies in the United States," and a large outbreak of campylobacteriosis traced to the consumption of free raw milk at school was reported in England.' Observations in England and Wales, where an estimated 3.5% of the milk is consumed without pas- teurization. support the contention that raw silk is an unsafe food product. In the period 1951 through 1980, these two countries reported 233 outbreaks of communicable disease attributed to milk or dairy products, with approximately 9,400 cases and four deaths." Seventy-five percent of the outbreaks and about 40% of the cases were associated with raw milk; most of the remaining cases involved faulty pasteurization or obvious post- pasteurization contamination. Con- tamination by Salmonella caused 74% of the outbreaks in this period. A detailed cost-benefit analysis per- formed to determine the value of a ban on the commercial sale of raw milk in Scotland clearly demon- strated a favorable ratio on the basis of the costs of milkhorne nalmonello- sis alone." The role of raw milk as a vehicle of C jejuni infection, however, was not tlemonstrated until 1978, when many laboratories began to look for the organisms in diarrheal stools. Since then, many raw milk-associ- ated Cttmpylobacter outbreaks involv- ing thousands of cases have been reported by English investigators."' When one considers the known health risks, it is apparent that raw milk is not being singled out for unwarranted attention by public health authorities. Other ready-to- consume foods of domestic animal origin are subjected to processing procedures rendering them safe for consumption and are microbiological- ly monitored for adequacy of process- ing. Raw foods of animal origin, such as chicken, may be contaminated with Salmosella and Campylobacter, but routine bacteriologic monitoring of these foods is nut done because these raw foods are normally cooked before consumption. Furthermore, extensive efforts are made to inform the public of the hazards and the proper cooking procedures for these products, and practical measures to eliminate the contamination are not available. In food hygiene, as in the operating room, clean is not synonymous with safe. The raw milk industry points to standards such as total bacterial counts as proof of safety, hut the high incidence of disease associated with raw milk is strong evidence that these standards are unreliable indexes of safety. Milk is an excellent vehicle of infection because its fat content pro- tects pathogeno from gastric acid, and, being fluid, it has a relatively short gastric transit time. Thus, low- level contamination, which would be readily controlled by pasteurization, Unpasleurized Milk-Putter et at 2051 148 Table 2 -Milkbonne Bacteniat Diseases at Less Frequent Occurrence ,n the Uutted Staten becceltunis to humans: in ha united States. appraaiotately 0th at ha reported cases urn attcbutmttocOnsonrptOn at cepastruriend daile ptodoctn; products or anu third at thesa canen era do,nnst~caty produend" Eechenchia cull Outbreaks at diarrhea haoa bean reported in persons otto mnssenad anpanteueend cnaam" and Bce ctrnesa". plan' ,nid-nrediatad entitnicroblal-rasistant £colihaon also bean molded rant ndb° Listen-is rnooaeytogenau Lintuod ot000tlytOOerrea hen been isolated ton, unpenteotiend cue ued aheep rvtk"": sheddtng of L,etenu ,n ens, persists to, lung periods at lIen alter the nOb passes thu oisuat eaaminution tullouing t,star,os;n": autdonce ut mOb- buena liateriosia a tttooans has tuna nntabkstrad" Mycubactehats tubzrculoaie, sutticienttuttarctn bacilli ore aactetad by a single cue tnith tuberculoas manttttn tn teaks thu rnttb at 100 clean cues MycabaCterluot bocia lntectisaa tat duets"; in 000. tubaruatosis ces diagnosed in 3 dairy herds tn Attune: 1302 at 3,760 cartln tastad tar tuhetoulosin aura positiua" Cot-ytrebacrztiute pseudo- A cusa at acudatioa tonnititis and cenoicat lynrphadenitis that tesultad ,n prolonged honptralteum;un aas dencobed tn tubeecutoaie 30-mar-old eon ahosa closest rennet dsrtestio anircal euponore ann dcebtng rea coca and neat's etik" Staptrylocaoccs cutout Staphylococci in etilk. either true ntastitio milk ne borneo centurciuatiau. cause gustranntanhs tn nonsttrners etren they ingest the treat-stable entnrotoeie peuduced be the staphyt0000sl5t Stt'epteoaocus sp gtteptocucni cause auatiety at diseasas in hunters end load animals and era rnportant saprophytns m rr,tk and nib products: like the staphylococci, they nay be present in milk in alga combats ctten they cause tnastttts n the nslk- ptodusinuaeirnal: StneptoeoocoO eoocpidootiousis a common cease at tnaslittn in nattla. and m,lkhornn uotbneaks in humans tolteeed by acute poststteptocoocal glonrerolonephrttts hace bean reported": a reonet cut- bnoak has be en associuted cith consueption ut cheese made toot tao ntlk'° Steeptobaeillus ,noetilitot'nris In the 10205, there cern some uaty large nutbreaks at strnptobauilosis teased a cursunrptton at rec mtlk". ctsen S trreoilitourris Is saluted rem milk, the presumption of sontamiration by tuts In made: tie cnltkaly that thu dsnesa ooutd ptessnt a nrilkhoeee problent na dairy pracccieg sceantly accepted ntaedatds at deny heutene Vm'eieia eotet'oeelileca Yet-oieia etmlz,-oeo!itica is trequently bond in animal nruironnrnnla, cay be present n unpustnunted milk at h~h con- centrations, end gtoas at teltiserator tamperatu'es"t in u study 0 Ontutta. Setonmune" toond Yeneerte te 105.01 the tea milk senrples. 9'S, 01 the cheese curd nuerples, none ot the cheddar cheese semplen, and I at 265 pasteut- mend milk samples; Yzr-000ic ente,'ooetimica aen isolated Item rac milk met scspnctnd toctttorne autbreak et unnstnto- sisinMonttaal'5 JAMA, Oct 19, 1984-Vat 252, No. 15 PAGENO="0155" presents an important hazard to the raw-milk consumer. This hazard is magnified when the consumer has less resistance to infection because of age or underlying disease. The promotion of raw milk as pro. 1. Magruder GL: Further oboervatiuon on the milk supply of Washington, DC. JAMA 1910; 55501-509. 2. Kelley ER, Oshorn SH: Further euidero'eax to the relative importuner of milk infection in the t,-annmisoion of eertain communicable dis- of man, Am JPohlie Health 1930l1866-73. 3. Kon SE: Nutritional effeetn on milk of chemical additices and proeenoin~ is F~19h International Conojroaa on Natritiow Washing- too, D.C. Washington, DC, Food and Agriculture Organinalion, 1960, ppl-8. 4. Kon SK: Milbond Milk P,-odaetein llamas Nutrition, FAD Nutritional Studies 27. Rome, Food and Agriculture Organization, United Nations, 1972 5. Graham tIM: Alteration of nutritice value rcnalting from processing and fortification of milk and milk products. J Dairy Sci 1974; 57:738-745. 6. Pottenger FM Jr ElTect.af heat-processed fonda and melubuliaed vitamin D milk on dento- facial slractures of experimental animals. Am J 1)rthcul l946318467.485. 7. Wiloun CS: The Panteat-i:ulion of Milk London, Butler & Tanner Ltd. 1942. 8. Taylor DN, Bird JM, Mover JS, et a!: Sol,noxrlla dahlin infections in the United Slates, 1979-1980. Jlnfecl Die 1982A4h322-327. 9. Small RG, Sharp 2CM: A milk-home out- break due to Salmonella dublin, J Hyg Cam- bridge 1979:8595-100. 10. Schroeder SA: What the sanitarian should know ahout aalmonellae and staphylococci in milk and milk products. J Milk Food Tech l967;315376-380. II. Krogh BP: The survival of paihogeon in chceae and milk powder. J Dairy Rca 1971; 3091-Ill. 12. Collins RN, Teegec MD, Goldsby JR. et al: lnlerntateoolbreakafSalmonellansewbnoneuiek infection traced to powdered milk. J.4MA 1969; 21131138-044. 13. Fonlaire RE, Cohen ML. Martin WT, et al: Epidrmie aolmonelloniu from cheddar ohncac: Sureeillunrc and prevention. Am J Npidcmiol 188l;lll:247-253. 14. Marlh EH: Sulmonellae and salmonellonis usaoeiated with milk and milk productn.JDai,-y Sei l969;52283-315. 15. Gibnun EA: An outbreak of &nlnsono'lla dublin infection in goats. Vet lIce l957;691026- 1020. 16. Bulgin MS. Anderson BC: Salmonellools in gusts. JAm Vel Med Assoe l98l;l7&729.723. 17. Werner SB, Humphrey CL, Kamei 1: Anuo- eioliun between raw milk and human Salmonella duhlio infcotian. RrMedJ 19752238.241. 10- lOoser MJ, Feldman RA: Solnsono-lla basIc- ren,iu: Reporlu to the Centers far Dincaae Con- trol, 1968-1979. J Infect Die 1981:1421743-741. 19. Salmonella dablin associated with raw milk: Washington State. MMWR. lOOl;318373- 374. 20. Ficrer 2: lnvusiocSalmanu-lla dublin infer- tiannauooeiated with drinking raw milk. WualJ Med l983;l38:665-669. 21. Oct-gun l)ivinion of Health: Row milk aoau-iat,-,l oalmonella outbreak in northeouters Oregon. Communicable Die Summary 1183; :121-2. 211. Vogt RL, Hakey A, Allen 2: Salmonella ,-ntt-n-ttidio nerotype derby and connomption of viding major health benefits beyond those of pasteurized milk han not been supported by tho evidence. In contrast, the hazards of raw milk have beon proved. Sale of raw milk, however, in still permitted. Phyui- References raw milk. J 1st/i-cl Iba 1981:1441158. 23. Salmonelloois associated with run milk: Montana. MMWR 1981:318211-212. 24. Sebmid OP. Schaefer R, Sehucfcr J, et at: human campylobacterioois in a medium-aincd lana city, ahotracted, in lIed Islenaeicxo-e (`on- feresce oxAntimicrohialAgu-ntn ondC#cmotta-n-- apy. Wanhingtan, DC, American Society for Microbiology, 1983, p160. 25. Taylor ON, Porter BW, WilliamnCA, rtal: Campglohaeter enteritin: A large aothrcah traced to commercial raw milk. Weal J Med 1035,137:365-369. 26. Taylor RP, Weinstein WM~ Bryner ill: Campylahas-ler fetus infection in human sub- jects. Anoocialion with raw milk. Am J Med 1979:66:779-783. 27. Blaser MJ, C ravens J, Powers BW, et at: Campylahacbm enteritin usnociated with anpas- lcarined milk. Am JMed l975;67:7l5-718. 28. Patter ME, RInser Mi, Sikcn BK, rt ol: lloman Campyluhorlo-s- infection unsorioted with errlified raw milk. Am J Epidemiol 1903;h17:475- 483. 29. Outbreak of Campylohaelum entecitis oust- rialed with raw milk: Cannon. MMWR 1181; 318210-228. 30. Maine Dept of Damon Serviecu: Raw milk and human gastrointestinal dinense: Problems implicated with the legalioed sale of rectified ran milk. EpiGram, December 1981, pp 1-2. 31. Raa-milk associated illness: Oregon. MMWR 198L,31h90-57. 32. C~mpylohacteriasis annacialed with raw milk e~nnamption: Pennsylvania. MMWII 1983; 35337-344. 33. Ricmann lIP, Meyer ME, Theis ill, st a!: Tonoplasmosiu in en infant fed unpuoteurined gout milk. J Pcdialr 1975:87:573-576. 34. Sucks JJ, Roberto RR, Brookn NF: Tuna- plunmosin infection aaaocialed with raw goat's milk. JAMA 19852401728-1732. 35. Fan MD. Itasfmann AF Bracclloais in the United Slates, 1965-1974. J Infect Din 1077; 136:312-310. 36. Young 163. Suuannapsrrat U: Bcuecllonis oatkrcok attributed to ingestion of aspastcor. iced goat chrese. Arch Isis-n-n Med 1975:135:240- 243. 37. Eekmon M8. Brucellosia linked to Mnnieao checse. JAMA 1975;232.636-637. 38. Gilbert CL, Dsvoren RA, Cole ME, ct oh Midtrimrntmr abortins associated with neptico- mia mooned by Campnjloboeterjs-juos. l0-d JAuot 1981:1:505-506. 39. Crcnibana M, Scks'yaoa M, Slapalaoa 5, et al: Sheep milk-boron cpidcmic of lit-b-borne encephalitis in Slovahin. Intervin-okvjy 1971:5:57- 61. 49. H sjek V: ldontificotion of cnterolanigcnio staphylococci from sheep and sheep cheese. Apgd I/ntis-on Microbial 1978:35:264-260- 41. Ootaria Ministry of llealth: Suspected raw m:lk-as.naeiated eampylahacterionis. Brilish Cu- lamhia. Cost Din Wet-hip Rep 1983:9-19:73-75. 42 White FMM, McCarthy ME: Row milk and health in humans. Can Med Arson, J 1982; 126:1268-1262. 43. Jones I'll, Willis AT, Robinson DA, ct at: Compylokacter cntecitin anaooiatcd with theecs- oomptios of free school milk. J Ilyg (`amt,-i:loe 1981;07:l55-162. 44. Gathraith NO, Forbes P. Cliffortl C: Cnm- municulsle diseanc associated with milk and dairy products in England and Walns 1951-80. Bc- Med J1985240176l-l765. 45. Cohen DR. Porter IA, Reid TMS, et a!: A cost benefit ntody of milk-ho roe nolmonclbasin. J Ilyg Cambridge 1583;9l:l7-23. 46. Jones DM, Rohisnon DA, Eldridgc J: Sero- logical stadirs in two natbmcahn of Campylahac- icr jejani infection. J Hyg Cacshridgc 1981; 117:163-170. 47. Robinson nA Jones DM: Milk-borne Cam- psdttao-t,-c infection. tIc Med J 198l;2821374- 1376. 40. llobbs hOC, Rowe B, Kendall M, et al: Escken-ichia coti 027 in adult diarrhea. J Hyg Cambridge 1976:77:393-400. 49. Marier R,WelloJG,Swusssn RC,ntal:As wathmcak of enleropathogesic Eoebcmichia cxli foadkornc disease traced to importrd French rhenur. Lancet 197551376-1370. 56. Johnston OW, Bruce 2,111112: hvcidcvcc uf antibiotic-resistant Enehen-iehia coliin milk pro- duecd in the went of Ss,stland. J Apyl Ilaeleriol 198ljit:77-83. 51. Dijkslra SC: Inocotigutiwnu on the surviv- al timco of Lislen'ia bacteria in nanpnnsion of brain tissue, silage and feces and is milk. Zentlrothl Rabteriol 1971;2l6:52-95. 52. tlull RF: fnfevtisan abortions in owes. Compcsd Constin Ed l982;4:2l6-22l. 53. Gray ML, Killinger AH: Lialcria mosoenj- togeses and liateric infections. Buclen-iol Rev 1966;31b309-382 54. Kalis P, LeFruch JL, Smith W, et a!: Listerosis. Am JMed Sci l976;27l:159-l69. 55. Kleehamg 1111: Tuhereol:,siu and other myeuhaettrisuiu, in llohhcrt WT, McCullsek WI, Schnsrresberger PR lcdu): Di.ncaaco Tcosmnilh-d From Animula to Man, ed 6. Springfield. Ill, Charles C Thomas Publisher, 1975, p315. 56. Mathis BM. LanglcyJ: Bovine tuberculosis inns Arinona dairy herd.JAm Vel MedAaaoc 1901:178.141-142. 57. Goldhcmger AC, Lipsky BA, Plorde 22: Soppsrutivn geeoolomataan lympkadooitia caused by Corsjnehucleriam ovia(pneadotohcrco- lasts). Am JClin Palhol 1981;76:406-490. 58. Parry WH: Milk-borne diseases. Loscet l966;211l6-219. 59. Bamnham N, Thumntos TJ, Lange K: Nephritiu caused by Streptococcus oooepidessi- s-sun (Lsncefield group C). Lancel 1983:1:945-940. 60. Group (7 strrptocuvcal infections anssci~ ated with eating humcmado chneno: Ncw Mcsics. MMWII l903;35510~516. 61. Place ElI, Sutton 1K: Erythema arthrit- icum epidemicom )hluorrkill fever). Arch Isles's Msd l934;M:659-(84. 62 vantrappn (7, A60 110, Gekocs K, 01 at: Yeroinia csteritis. Mcd Clix North Am 1985 66:639-653. 63. Black RE Yerninimis, in l.ast 3M led): Maony-Roncnau Public lleallh and Preventive Mrdicino-, ed 11. New York, Appleton-Century. Crofta, 1980, chaps, pp456-457. 64. Sohiemasos DA: Association of Yerainia snte,-ocalilica with the manufacture of cheese anslorearrmnreinpastrurioedmilk.ApplEnvi- ran Microbial 1978;36:274-277. 65. Ilcalth and Welfare Canada: Yernisia ,-nlrroeolilicu gantroentorilis uatbccuk: Mon- treal. Can Din Weekly Rep 1976;573-74. linpaalesrized Milk-Potter el al 149 cians and other health professionals muut be aware of the facts concerning risks and benefits from raw milk to better advise patients who have ques- tions about the safety and benefits of raw milk consumption. 2052 JAMA, OcI 19, 1984-Vol 252. No. 15 Pcioteol and Published in the United Staten of ,flmecica PAGENO="0156" 150 Mr. WAXMAN. Thank you, Mr. Adams. In the opinion of the Milk Producers Federation, is it scientifical- ly and commercially feasible to produce and market raw milk that is safe for human consumption? Mr. ADAMS. No, it is not. We take great pride today, as has been pointed out earlier this morning, in maintaining a high level of sanitation, environmental hygiene and veterinary practice. But the overwhelming consensus within the National Conference on Inter- state Milk Shipments, which represents all State governments and the Federal Government on this issue, has been since 1950 that pasteurization was absolutely essential; that it was essential as a part of a total package of sanitation and public health in terms of providing the best protection that we could provide for all the people. So pasteurization is a very inherent and important part of providing overall assurance to the American people. We support the position of NCIMS which recognizes the impor- tance of requiring raw milk to be produced under sanitary condi- tions and pasteurized. This is a position supported by many public health agencies and associations that you have cited earlier. Mr. WAXMAN. Thank you. Mr. Dannemeyer, do you have any questions for Mr. Adams? Mr. DANNEMEYER. Yes, I do. Thank you, Mr. Chairman. Mr. Adams, are you familiar with the publications by physicians and others that attribute the loss of nutritional value as a result of heat process, known as pasteurization, to milk? Mr. ADAMS. I am not intimately familiar with all of them. I have read some of them and I have known of them in the past involving this issue for several years. Yes, I am familiar with the fact that those publications exist. Mr. DANNEMEYER. And people who produce them and some of whom testified today, claim that there is a nutritional loss from the heat process known as pasteurization. Are you familiar with those claims? Mr. ADAMS. I am familiar with their claims, but in our opinion, they are unsubstantiated claims and we have supplied for your record a paper from the National Dairy Council that reviews such claims. It is part of the references we have provided today for the record. In the two references provided, the science of statistical sig- nificance is reviewed. What is significant-and that is the key question here-what is the significant nutritional difference statis- tically? I don't believe the evidence, the overall evidence, supports the claim that there is a subtantial difference. Mr. DANNEMEYER. Are you familiar with the work of a physician by the name of Annand in England? Mr. ADAMS. No, I am not. Mr. DANNEMEYER. Dr. Annand is a physician who traced the in- crease in incidence of arterialschlerosis of patients that began con- suming pasteurized milk. In other words, 2 or 3 years after the group who normally used and consumed raw milk, they then began using pasteurized milk, there was a significant, marked increase in the incidence of arterialschlerosis in those population groups that made that change. Are you familiar with that work? PAGENO="0157" 151 Mr. ADAMS. I am familiar with the basic theory that is known- we refer to it as the Oster theory. That theory has been greatly studied. There is no basic scientific evidence to justify that theory. Mr. DANNEMEYER. Pardon me, I am not talking about Dr. Oster. Dr. Oster's claim is that the process known as homogenization is approximately related to increase of arterioschlerosis. Dr. Annand claims that the consumption of pasteurized milk is responsible for the increased incidence of arteriosclerosis. Are you familiar with the claim of Dr. Annand? Mr. ADAMS. I am not particularly familiar with that claim, but we will be glad to supply for the record, I believe, other informa- tion which would not support it, and that will come from the Na- tional Dairy Council. Mr. WAXMAN. I think the next panel would be better equipped to discuss this. Mr. DANNEMEYER. Are you familiar with the case in Arizona of the 66 people who evidenced symptoms of salmonella from con- sumption of pasteurized milk? Mr. ADAMS. I am not particularly familiar with that, but we do have a situation where you can have postpasteurization contamina- tion. That is probably the situation in most cases where we have had problems with pasteurized milk. It has come from contamina- tion, people contamination, following pasteurization and that is due to a breakdown in the system, and that is something that we always face, something we try to eliminate. But again, we are deal- ing with human beings in the work chain, and distribution prob- lems, so those kinds of problems are always going to have a poten- tial for occurring. Mr. DANNEMEYER. There were 1,004 cases in 1982 in Memphis, TN from Yersinia enterocolitica from pasteurized milk, was there not? Mr. ADAMS. Yes, and if you will go back and look at the epidemi- ology behind those cases, for the most part, I think, it was attrib- uted to postpasteurization contamination. So you cannot attribute them necessarily to a breakdown in the pasteurization itself. Mr. DANNEMEYER. In the perfect world, if that is what we are seeing, cause us to conclude that in order to avoid any of these ill- nesses, we should just say to the people of America, we can't drink milk at all? Mr. ADAMS. What we should say is that the milk industry is most seriously interested in minimizing the overall risk and pasteuriza- tion is absolutely critical to minimizing that overall risk. It is like an added insurance policy and if we can provide that added insur- ance, then we want to do it, and we want to do it in the spirit of protecting the overall public health. Mr. DANNEMEYER. But there are hundreds of thousands of people in the State of California and in America who claim that they want to drink certified raw milk because it is nutritionally superi- or, and they also claim that there is an increased incidence of arte- riosclerosis from consumption of pasteurized milk. Shouldn't these people who want to consume certified raw milk be able to do that? Mr. AD~s. That should be an issue that the State of California has to deal with, but in terms of interstate commerce, what we are dealing with in terms of this particular hearing, as far as its appli- PAGENO="0158" 152 cation right now at the Federal level, is do we ban interstate ship- ment? Mr. DANNEMEYER. It is the same issue, isn't it? Mr. ADAMS. Well, it is the same issue in terms of the potential public health threat, but it is a different issue in terms of the me- chanics of how you get to the solution to the problem. Mr. DANNEMEYER. To me it is a question of balancing of risks and I think that the evidence has disclosed that very well. Thank you, Mr. Chairman. Mr. WAXMAN. Thank you, Mr. Dannemeyer. Mr. Adams, thank you for being with us. We appreciate your tes- timony. Dr. Chin, why don't we start with you? Let me indicate to all the gentlemen here, as we indicated to you in advance, your prepared statements will be made part of the record in full. We would like to limit you to no more than b min- utes in your summary of that statement. We need to do that in order to get the full opportunity for all the witnesses to be heard and to have questions and answers as well. STATEMENTS OF JAMES CHIN, M.D., CHIEF INFECTIOUS DISEASE SECTION, CALIFORNIA DEPARTMENT OF HEALTH SERVICES; MORRIS E. POTTER, DVM, VETERINARY EPIDEMIOLOGIST, CENTER FOR INFECTIOUS DISEASES, CENTERS FOR DISEASE CONTROL; R. DEAN THOMAS, PRESIDENT, DELST CHEMICAL & RESEARCH, INC.; AND PATTON SMITH, DVM, ASSISTANT DIREC- TOR, CALIFORNIA DEPARTMENT OF FOOD AND AGRICULTURE, ACCOMPANIED BY JOHN ORSBORN, DVM, CHIEF, VETERINARI- AN LABORATORY SERVICES Dr. CHIN. Thank you. I won't take the full 5 minutes. I am Dr. James Chin. I am chief of infectious disease section for the California Department of Health Services. This is a position I have held since 1970, and I am also a lecturer in epidemiology in the UC School of Public Health in Berkeley, associate editor of one of the other leading infectious disease text books used in this coun- try. I would say at the very beginning to Mr. Dannemeyer, I am not here to declare war on salmonella. However, I think a lot of my remarks will not be interpreted as friendly to raw milk. I would summarize my testimony that basically is an update of the testimony that our infectious disease section submitted to the FDA hearing. Data collected and analyzed by our infectious disease section have very clearly documented over the past decade the con- tinuing association of certified raw milk with human infectious dis- ease problems. Our findings linking human disease to raw milk are not unique and have been reported from other States and other nations, and in recurring fashion, as variations on a theme. The locales change, the names of the dairies change and numbers of cases change, but the end result is raw milk has regularly caused human disease. While raw milk represents less than 10 percent of all milk pro- duction in both this country and in the United Kingdom, more than 90 percent-we are not talking about a perfect world, we are PAGENO="0159" 153 talking about more than 90 percent of all milk-borne disease is re- lated to raw milk use. Given the existence of salmonella and cam- pylobacter in cattle, cow's milk if consumed raw is clearly poten- tially hazardous. As indicated in prior testimony, there is no way that present technology can prevent the pathogens from entering the milk by occasional fecal contamination during the milking process or by direct innoculation from mammary shedding through an infected udder. People from our California State Food and Agriculture De- partment can comment more on such findings. Review of the risks associated with the use of raw milk in Cali- fornia for 1980 to 1983 was made by a group at UCLA supported by a grant from the American Association of Milk Commissions. These investigators concluded, after extensive examination of available data on human disease associated with use of raw milk, and certi- fied raw milk, that, first, there appeared to be a residual causal as- sociation of certified raw milk with salmonella dublin infection, such that in California in 1980-83, raw milk use elevated the aver- age risk of reported salmonella dublin infection by a factor of any- where from 14 to 180 times with possibly a stronger effect in 1983. Second, up to a third or a half of the reported salmonella dublin caseload in California could be attributed to certified raw milk. Third, for the 4-year period 1980-83, there appeared to have been between 23 and 25 deaths attributable to salmonella dublin infec- tions acquired from raw milk, with perhaps half of these deaths oc- curring in 1983. Fourth, certified raw milk users with compromized health status had far higher rates of salmonella dublin and far higher mortality rates than certified milk users in good health or noncertified milk users in compromized health. This study, like virtually all other studies published in the medi- cal and scientific literature, finds the association of raw milk with some human infectious disease problems to be indisputable, to be large, and to be causal. I will be happy to answer any questions later. [Dr. Chin's prepared statement follows:] PAGENO="0160" 154 Disease in California Associated with Certified Raw Milk from Infectious Disease Section California Department of Health Services 2151 Berkeley Way * Berkeley, California 94704 I. Introduction There are presently in California 15 raw milk dairies - 6 goat dairies and 9 cow dairies. Togetherthey produce less than 1% of all the market milk distributed in the State. P4iiong them are two certified * raw milk dairies; one is a certified raw goat milk dairy that produces 400 gallons/day and the other is a certified raw cow milk dairy, (Alta Dena Dairy) that produces 10,000-12,000 gallons/day. The Alta Dena volume represents 80 to 85% of all raw milk produced in California. Some of that certified raw milk (CRM) is distributed, through middlemen, in interstate commerce. Over the last 15 years our *surveillance of milkborne disease in California has shown that virtually all of it has been associated with Alta Dana's CRM. During this period, two bacterial diseases have occurred in users of this milk: salmonellosis (particularly Salmonella dublin) and campylobacteriOsis. Each is discussed below. II. SalmonellOsjl A. History - Unlike the experience reported by other states and nations, raw_milk-associated salmonellosis in California has not occurred in outbreak form but rather _~p~~dicai]1 in time and place. This pattern of disease occurrence suggests that the contamination (discussed below.) of certified raw milk is intermit- tent and low grade. However, the problem is increasing, despite the fact that the surveillance of salmonellosis in California has not changed in decades. (State law requires-that all specimens from which salmonella are isolated be submitted to the State laboratory for typing. Virtually all salmonella cases are thus identified by laboratories; public health follow-up is often carried out locally before serotyping results are available.) - In 1981 there were 46 S. dublin cases; in 1982 there were 70 cases; in 1983 there were 123; and in 1984, .141-cases were identified. Undoubtedly, many more cases of S. dublin occur than are iden- tified .since only a part of those ill will visit a doctor for an illness, and an even smaller part will have a specimen taken for laboratory analysis. Estimates of the number of actual cases for every identified case range from 10 to 100: the commonest sal- monella serotypes are thought to have the greatest number of unreported cases. Furthermore, many other salmonella serotypes -- of the 2100 serotypeS known -- have been recovered from CRM in California, so probably many more salmonella cases (in addition to those due to S. dublin) are related to CRM use. However, S. dublin provides a convenient epidemiologic marker for investiga- tion since it is specifically host-adapted to cattle, much as S. typhi is adapted to humans, S. putiorum and S. gallinarum to chickens, and S. choierae-sui8 to swine. PAGENO="0161" 155 B. Character of S. dublin disease - The demographic characteristics of S. dublin cases consistently differed from cases infected with other serotypes. S. dublin patients tend to be older and their health is often further compromised by one or more chronic conditions. It may he that persons with compromised health status are at much greater risk of infection and disease from low levels *of salmonella contamination in food than is the population at large. In California, about 20% of.the population would he clas- sified as having compromised health status with regard to S. dublin infection, if we include in the group: (1) those under 1 or 75 and over; (2) those who are pregnant; (3) those with cancer, diabetes, hematologic disorders, liver disease or alcoholism, arthritis, collagen, vascular or renal disease; (4) those receiv- ing chemo-, radiation or corticosteroid therapy; and (5) those with gastrointestinal, neurological and post-traumatic conditions. A large proportion of the S. dublin cases had cancer, particularly lymphoma and leukemia, or were taking systemic corticosteroids and/or c `icr imrnunosuppressants for a large variety of disorders. At least 7 had AIDS. Through the years, more than 80% of cases consist~itly had S. dublin recovered from blood and other extra- intestinal sites such as cerebrospinal fluid, lung, abdominal cavity, etc. This finding is not simply a reflection of the older age of the i~ypical S. dublin host: when age-~sex matched controls infected with other salmonella serotypes were compared for source of positive specimen, less than 15% were identified by cultures of blood and other extra-intestinal sites (i.e., 85% of cases with other salmonella infections were identified by stool culture). Another indication of the severity of S. dublin infection is the fact that 75% of S. dublin patients required hospitalization compared with only 35% of matched cpntrols. Finally, deaths among S. dublin patients have run between 20 to 25% for the last 15 years. Death in one out of every 4 or 5 patients must be regarded as due to a very severe disease. For 1981-1983, we identified 63 deaths among 239 patients with S. dublin infection. C. Association with CRM - In both 1981 and 1982, 24% of S. dublin cases reported use of CRM. Not only was 1983 a record year for cases (123) hut there was also an increased association of cases with CR11 use (44%) (Reference B. Data for 1984 are not yet complete, hut among those cases for whom data are available, 36% reported use of CR11. No other risk factor has been as prevalent among cases, and even though S. dublin is host-adapted to cattle, only a small percent (15% or less) of cases through the years reported use of either lightly cooked ("rare") or uncooked beef or beef liver. The risk of contracting 9. dublin in California from use of CR11 has been estimated to he 458 per million population (based on the assumption that each user drinks one pint daily). This is 158 52-266 0-85-6 PAGENO="0162" 156 Disease in California Associated with Certified Raw Milk times the risk of the population-at-large who do not drink raw milk (Reference 1). When cases were compared with age, sex and residence matcl~ed controls who were infected about the same time with other salmonella serotypes, a chi square test gave a value of 41, a value which would be expected to occur by chance alone, less than once in 100,000,000 times (Reference 2). The relative risk is among the highest values reported in epidemiologic studies. Just as the majority of smokers do not develop lung cancer, so, too, the majority of CRM users apparently do not develop S. dublin disease. That there are not more reported S. dublin cases is likely due to the fact that the population that drinks CRM is small and the contamination is low grade and probably intermittent. D. Isolations from Milk - Since 1977, a total of 191 sal monel 1 a isolations have been made from CRM by 14 different laboratories (local, state, and federal), including the FDA's laboratories in both San Francisco and Los Angeles. Other laboratories typically sample only 1 or 2 containers of milk, but on each of the 3 or 4 times that FDA sampled CRM it tested 20-40 containers of one day's production: on each of those occasions FDA found at least several containers positive for S. dublin. Such results for a single production lot suggest either unequal distribution of contamina- tion in the milk so that some containers are contaminated and others are not, or that contamination is routinely present (perhaps at very low levels) but is missed in some containers because present technology is not sufficiently sensitive to detect it. The dairy's own quality control laboratory cannot be relied upon to identify salmonella in CRM (see discussion in attached Reference 3, a sworn declaration entered into evidence by Richard M. Ruby of the FDA's Los Angeles Laboratory). The only State agency that tests CRM (and other raw milk) on a routine basis is the California Department of Food & Agriculture which tests 2 containers of milk from each dairy herd only once/month in dry months and twice/month during wet months. E. Antibiograms - Antibiogram tests of human S. dublin isolates demonstrated a statistically significant association between antibiogram patterns of isolates recovered from CRM users and the antibiograms patterns recovered from CRM itself (References 4 - 6). Those who did not drink CRM had a variety of otTi~F antibiogram patterns. The epidemiologic and antibiogram links between 5. dublin and raw milk make biologic sense in view of S. dublin's recognized adaptation to cattle. F. Summary - California has clearly documented the association of S. dubiin disease with raw milk use (specifically CRM). Our findings also show that S. dublin has greater virulence than most other salmonella serotypes (more hospitalizations and more frequent PAGENO="0163" 157 isolations from blood and other deep body sites). A study con- ducted by the Centers for Disease Control in 1979 and 1980 of sporadic S. dublin cases that occurred elsewhere in the nation, ~femonstrated these same points (Reference 7). III. Carupylobacteriosis A. Serologic Study - In the investigation (Reference 8) of a cluster 61' 4 cases of Campylobacter infection in Los AngeTes, 3 reported use of the same brand of CRM (as reported above involving S. dublin infection) whereas only 3 of 49 control subjects reported raw milk use (p = 0.0003). The investigation was followed up by a serologic survey conducted among a pediatric outpatient group. Four of 23 (17%) of raw milk drinkers had demonstrable antibody titer to carnpyiobacter jejuni whereas none of 13 non-drinkers of raw milk had a titer. 8. Outbreak, 1984 - An outbreak of Cainpylobacter jejuni occurred in !l':.:i 1984 among 12 of a class of 28 kindergarteners and their chaperones who were provided CRM at. the dairy's bottling plant (Reference 9). It was the same CRM implicated in the ongoing Salmonella dubl.in problem. C. jejuni was confirmed in stools of 9 of the 12 ill people: the pathogen was not recovered from school- mates who had not made the field trip. IV. Corroboration by Other Studies The findings linking human disease to raw milk are not unique to California but have been reported from other States an~ other nations in recurring fashion, -as variations on a theee. -The locales change, the names of the dairies change, and the numbers of cases change but the end result is that raw milk has regularly caused human disease. While raw milk represents less than 10% of all milk production in both this country and the United Kingdom, more than 90% of all milkborne disease is related to raw milk use. Given the existing prevalence of salmonellosis and campylobacteriosis in cattle (which ray or may not appear ill due to those infections), bovine milk, consumed raw, is clearly hazardous: there is no way that present technology can prevent the pathogens from entering the milk' by occasional fecal contamination during the milking process (salmonella and campylobacter) or by direct inoculation via mammary shedding through an infected udder (salmonella). Only- pasteurization can he relied upon to destroy these pathogens in raw milk. The Federal Register of August 3, 1984, beginning on page 31,067, provided a useful bibliog- raphy, but it is far from complete. For example, in May of 1983 the Director of the Centers for Disease Control (Dr. Foege) responded to an important list of questions (References 10-14) posed by the California Chapter of the American Academy of Pediatrics (Dr. Bolton); Foege concluded in a covering letter that `Because the accumulated PAGENO="0164" 158 evidence indicates that unpasteurized (raw) milk is inherently unsafe, the Centers for Disease Control supports pasteurization of milk and milk products (Reference 12). Foege extensively documented the association between raw milk and human disease in this country and abroad, both from raw milk and certified raw milk. Foege's detailed and well-referenced responses to many other questions in *his brief paper merit careful review by all who want or need to be versed in the current state of knowledge. Though S. dublin is relatively rare among the 2100 salmonella serotypes, it is one of the common causes of milkborne outbreaks. Further, an important national study conducted by COG in 1979 and 1980 showed raw milk to be the mqst important risk factor for sporadic cases as well (Reference 7). As Foege put it, raw milk is `an important source of S. dubTin infections outside of California, as well as within California" (Reference 13). Moreover, the COG stidy (Reference 7) corroborated California's findings that S. dublin was particularly invasive, that it resulted in serious mor- bidity and high mortality, and that the infected hosts often were compromised by underlying health problems. The same clinical findings on the invasiveness of S. dublin were independently reported in a later publication (Reference 15) from San Diego which, like COG, also reported a case-control study that impli- cated raw milk (the same brand of CRM as discussed earlier). As mentioned earlier, California published a review of its 1983 S. dublin cases (Reference 1); this was followed by COG's publication of the matter in Morbidity & Mortality Weekly Report (Reference 16). In their editorf~i note, COG reported how widespread was milkborne salmonellosis; and that in recognition of `the economic burden of railkborne salmoneliosis, Scotland banned the sale and distribution of raw milk in 1983. The tremendous success that Scotland has had in eliminating community outbreaks of milkborne disease since compulsory pasteurization was introduced August 1, 1983, is. reported in attached Reference 17. A review of the risks associated with use of raw milk in California for 1980-1983 was made by a group at UCLA supported by a grant from the American Association of Medical Milk Commissions (References 18). These investigators concluded after their extensive examination of available data on human disease associated with the use of raw milk and certified raw milk, that: (1) there appeared to he a residual causal association of certified raw milk with S. dubtin infection, such that in California during 1980-1983 raw milk use elevated the average risk of reported S. dublin infection by a factor of 14-180 times, with possibly a stronger effect in 1983; (2) between a third and a half of the reported S. dublin case load in California could be attributed to certified raw milk; (3) over the four-year period 1980- 1983, there appeared to have been between 23 and 25 deaths attributable to S. dublin infection acquired from raw milk, with perhaps half of those deaths occurring in 1983; and (4) CRM users with PAGENO="0165" 159 compromised health status had far higher rates of reported S. dublin infection and far higher mortality rates than CRM users in good health or than non CRM users in compromised health. Essentially then, this study like the others cited found that the association of certified raw milk with S. dublin infection is indisputable, large and causal. REFERENCES~ 1. Infectious Disease Section: California Morbidity /fl2, March 30, 1984. Salmonella dublin in California: Increasing incidence and increasing association with certified raw milk exposure. 2. Infectious Disease Section: (Unpublished) Case/control study of 1983 Salmonella data establishes certified raw milk as the most important risk factor for S. dublin infection. 3. Declaration of R. M. Ruby of Food & Drug Administration, January 23, 1983. 4. Antibiogram study of S. dublin isolates from humans and certified raw milk, California, January 1, 1977-April 20, 1978. 5. Further statistical tests on the antibiogram patterns of S. dublin recovered from humans and certified raw milk between January 1, 1977- April 20, 1978. 6. Statistical study of antibiogram patterns of S. dublin isolates recovered from humans and certified raw milk in California in calendar year 1982. 7. D. N. Taylor, et al.: Salmonella dublin infections in the United States, 1979-1980. J Inf Dis 146:322-327, 1982. 8. Taylor PR, Weinstein NM, Bryner JH. Ccvnpylobacter fetus infection in human subjects: association with raw milk. Amer J Med 66:779-782, May 1979. 9. Infectious Disease Section: California Morbidity /~23, June 15, 1984. Campylobacter outbreak associated with certified raw milk products, Los Angeles County. 10. Memo by S. B. Werner on the Centers for Disease Control `s position regarding raw milk, June 2, 1983. 11. Letter to James Chin from John Bolton, May 28, 1983. PAGENO="0166" 160 12. Covering letter by William H. Foege (Director, Centers for Disease Control) to Dr. Bolton, May 27, 1983. 13. Seven. page statement by William H. Foege (Director, Centers for Disease Control) entitled Questions and Answers on Safety of Raw Milk". . -. 14. Letter to William H. Foege by John Bolton, May 4, 1983. 15. J. Fierer: Invasive S~zimoneiia dubiin infections associated with drinking raw milk. West J Med 138:665-669, May 1983. 16. Centers for Disease Control: Saimonel~a dubiin and raw milk consumption. Morbidity & Mortality Weekly R~port 33(14):196-198, A~'ril 13, 1984. 17. Latter to Morris E. Potter from J. C. M. Sharp, May 29, 1984. 18. Richwald GR, Greenland S. An assessment of risks associated with raw mi~k consumption in California. (Unpublished) 1984. All references are available upon request from: Infectious Disease Section 2151 Berkeley Way Berkeley, CA 94704-9980 PAGENO="0167" 161 Mr. WAXMAN. Thank you. Dr. Potter. STATEMENT OF MORRIS POTTER, DVM Dr. P0TrER.Thank you, Mr. Chairman. The division of bacterial diseases of CDC is responsible for con- ducting surveillance programs, reference activities, epidemiological investigations, and field and laboratory studies of bacterial dis- eases. By these activities the division has accumulated and ana- lyzed information on infectious diseases that have been transmitted to humans by consuming raw milk and raw milk products. Medical history is replete with evidence of the risks of drinking unpasteurized milk. Despite this knowledge, unpasteurized milk continues to be an important source of human disease. The most frequently documented associations between unpasteurized milk and illness are the numerous outbreaks and sporadic cases of bacte- rial infections, primarily campylobacter and salmonella species that have occurred in the United States in the last 20 years. To best understand this association with illness, it is useful to examine the data in greater detail. From 1980 to 1983, 53 percent of the food-borne outbreaks of campylobacteriosis reported to CDC from many States were associ- ated with drinking unpasteurized milk. In a detailed 1-year study of sporadic cases of campylobacteriosis conducted in Iowa, in 1982 and 1983, 35 percent of all of the ill persons had drunk unpasteur- ized milk during the week before onset of illness and drinking un- pasteurized milk was the only significant difference between cases and controls. In a study we conducted in Georgia, campylobacter jejuni was found in the feces of 40 percent of 193 healthy cows. All these data lead us to conclude that consumption of unpas- teurized milk carries an unavoidable risk of campylobacter infec- tions. Salmonellosis also frequently causes a diarrheal illness. Howev- er, the very young, older individuals, and persons with compro- mised host defenses are more likely to develop systemic, or blood and organ system infections with potentially fatal outcomes. This latter group of patients with underlying disease are persons to whom foods with purported special health value may have particu- lar appeal. Individual salmonella strains belong to one of 2,100 different groups called serotypes. Certain salmonella serotypes are most fre- quently isolated from specific animals. For example, salmonella cholerae-suis from hogs and Salmonella dublin from cattle. These two serotypes can also infect humans. When they do, they can cause a range of illness from mild to fatal. Over 40,000 salmonella isolates are reported in the United States each year and many more are unreported. In outbreaks in which the vehicle of transmission is identified, meat and poultry are the most common sources of salmonella infections. Dairy products, in- cluding raw milk, are associated with a small proportion of out- breaks. The evidence from outbreak investigations that unpasteurized milk is the vehicle for many salmonella infections in humans clear- PAGENO="0168" 162 ly is supported by a review of the CDC national salmonella surveil- lance activity data. In the period 1965-83, 11 outbreaks of salmo- nellosis associated with drinking unpasteurized milk involving more than 300 persons were reported. In addition, sporadic cases of Salmonella dublin infection in California and in other States have been associated with drinking unpasteurized milk. Information derived from two recent surveys indicate that the commercial sale of unpasteurized milk to the final consumer is pro- hibited in 20 States, and permitted in 24 States. Six States restrict the sale of unpasteurized milk to direct farm sales to the final con- sumer. During the 4-year period 1980-83, 515 isolations of salmo- nella dublin were reported to the National salmonella Surveillance Activity. Ninety-four percent of the isolates were reported from the 24 States permitting the commercial sale of unpasteurized milk, whereas only 5 percent occurred in the 20 States not allowing Un- pasteurized milk sales. Although this observed relationship alone does not prove causa- tion, when the numbers of isolates are adjusted by the 1981 popula- tion statistics, the reported rate of isolation of salmonella dublin is 10 times greater in those States permitting commercial sale of un- pasteurized milk than in States that do not. A nationwide case control study-excluding California and Oregon-in 1979 and 1980, revealed that the risk of salmonella dublin infection was 18 times higher in persons who drank unpas- teurized milk than in those who did not. Isolates of salmonella dublin, a relatively rare serotype known to be host-adapted to cattle, are more likely to be investigated and found to be derived from unpasteurized milk than those types more commonly isolated from humans and animals. Thus, salmonella dublin infections transmitted by unpasteurized milk represent only the tip of the ice- berg of salmonella infections transmitted by unpasteurized milk. Unpasteurized dairy products also have been repeatedly shown to be the vehicles for a variety of other human pathogens. In addi- tion to the risk from known pathogens, consumption of unpasteur- ized milk has also been responsible for a prolonged disease of un- known etiology for which no effective treatment has been found de- spite intensive efforts. Consumption of unpasteurized milk was linked to an outbreak of chronic diarrhea involving 122 persons in Minnesota in 1984. The illness was characterized by acute onset of diarrhea with marked urgency, and between 6 and 25 episodes of diarrhea per day, and lasted more than nine months for most cases. Approximately 8 percent of the long-term consumers of un- pasteurized milk from the implicated dairy have had onset of diar- rhea since the outbreak began. When last contacted in November, 88 percent of the patients were still ill. From the early 1900's until the end of World War II, prior to widespread pasteurization, outbreaks of human illness, including diarrhea, TB and brucellosis, were frequently caused by drinking unpasteurized milk. Since 1952, 49 of the 53 milk-borne disease out- breaks reported in the CDC's morbidity and mortality weekly report were associated with unpasteurized milk. The evidence available to us today is sufficient to show that unpasteurized milk is a vehicle for salmonella dublin, other salmonella serotypes, and campylobacter jejuni infections in humans in the United States. PAGENO="0169" 163 Pasteurization is a safe and effective method for drastically re- ducing the risk to health from milk and milk products. [Dr. Potter's prepared statement follows:] PAGENO="0170" 164 MORRIS E. POTTER, D.V.M. VETERINARY EPIDEMIOLOGIST, CENTER FOR INFECTIOUS DISEASES, CENTERS FOR DISEASE CONTROL I am Morris Potter, Veterinary Epidemiologist, Division of Bacterial Diseases, Center for Infectious Diseases, Centers for Disease Control. I am pleased to respond to the committee's invitation to discuss the adverse health effects of consuming raw or unpasteurized milk. The Division of Bacterial Diseases is responsible for conduct of surveillance programs, reference activities, epidemic investigations, and field and laboratory studies of bacterial diseases. By these activities the Division has accumulated and analyzed information on infectious diseases that have been transmitted to humans by consuming raw milk and raw milk products. Medical history is replete with evidence of the risks of drinking unpasteurized milk. Despite this knowledge, unpasteurized milk continues to be an important source of human disease. The most frequently documented associations between unpasteurized milk and illness are the numerous outbreaks and sporadic cases of bacterial infections, primarily Campylobacter and Salmonella species, that have occurred in the United States in the last 20 years. To best understand this association with illness it is useful to examine the data in greater detail. In 1980 - 1983, 18 (53%) of the 34 foodborne outbreaks of campylobacteriosis reported to CDC were associated with drinking unpasteurized milk'. In the United States since 1980, outbreaks of campylobacteriosis associated with drinking unpasteurized milk have been reported in several States from all parts of the country210. An outbreak of campylobacteriosis in Arizona2 invoived approximately 190 cases of illness in persons from 88 families who drank one brand of unpasteurized milk. In another outbreak, SO cases of campylobacteriosis in 30 households were compared with well persons, PAGENO="0171" 165 and disease was strongly associated with having drunk unpasteurized milk4. In addition, within households with at least one ill person, those who were ill had drunk larger amounts of unpasteurized milk than had well persons. In a detailed I-year study of sporadic cases of campylobacteriosis conducted in Iowa in 1982-1983, 35% of all ill persons had drunk unpasteurized milk during the week before onset of illness, and drinking unpasteurized milk was the only significant difference between cases and controls (p ~ 3 3 ~ ~ <~actly the complexity of milk composition. This complexity reflects the intricacy of the physiological effects of milk on newborn of the same species of mammals - Mi 1 k is responsible for the mai r~tenance of the 1 ink betwoen mother and offspring suddenly broken by the act of birth (S.K. kon, 1972. °) - The young thrives on the mother's milk until it begins taking other foods. The value of milk of certain species is restricted when used by grown up mammals of the same species and by PAGENO="0251" 245 newborns of another species. Nevertheless, milk, according to Kon (i.e. p. 11) `is almost unique as a balanced source of most of man's dietary needs" of importance here especially is the effect of cow milk on the immune response of newborn. To show the intricacy of the problem let's look at the lipid composition of milk (2,3) Table I, and specifically fatty acid composition of milkf at (4), Table II. Table I is based on milk average composition containing 4.Ol~ total milk lipid. Table II (taken from article of Brunner , 5) is a set of results obtained from the cream portion of composite Ayrshire milk. These tables show how unusually complex is milk composition. Brunner notices that "in opposition to the crystallization habit of the mixed triglycerides of total milkf at, this high-melting glyceride fraction exhibits distinct polymorphic phase transitions, viz gamma--> alpha--> beta'--> beta--> when a rapidly chilled specimen is slowly warmed'. Protein fractions of milk show also a very high degree of hetergeneity. Table III presents distribution and properties of principal milk proteins. This table is taken from Brunner's article (5) and presents data obtained by Jennes (6), Rose (7) and Swaisgood (B). Caseins for instance, known to laypeople as ~casein, a milk protein, are a highly heterogeneous group of phosphoproteins consisting of three principal components (alpha s,-casein.beta-casein and kappa-casein and several minor components (among them gamma- casein) Very important parts of milk proteins (qualitatively and not quantitatively) are milk enzymes. Twenty five different milk enzymes have been described (5, p. 632 and 633). Their location in milk PAGENO="0252" 246 differ. Some of them are in micellar casein, some in serum, some in fat globule membranes, some in Golgi membranes, some in plasma membrane and some in endoplasmic reticulum. Description of these enzymes requires special biochemical glossary not easily available to non-professionals. It should be said here, however, that enzymes, which chemically are proteins, form a network of biological catalysts, modifiers of biological reactions. in living systems. All the reactions catalyzed ( modified) by enzymes form what we call metabolism. Enzymes recognize chemicals in living systems and transform the recognized chemicals ( substrates) into products. The enzymes of milk are very important for an infant using this milk. They are also important for proper utilization of milk components by other groups of users of milk. The proper activity of milk enzymes depends on the intactness of their microenvironment: on the lack of destruction of their localization structures within milk itself. Even salts of milk present a high degree of complexity. First, it is necessary to state that milk ash and milk salts are no synonymous terms (Brunner, 5, l.c., p 634). Ash is the residue remaining after the incineration of milk at 600 degrees Celcius. It has no biological structure. It consists of the oxides of sodium, potassium, calcium, magnesium, iron, phosphorus and sulfur and chlorides. The salts of milk show variety, often colloidal structures in a highly labile equilibrium with milk proteins (compare Brunner, 5, l.c., p635). High temperatures, as Brunner remarks, l.c., "shift the equilibrium in favor of the complexed form of calcium reducing the concentration of the ionized calcium". The complexity of the milk structure which we tried to present in PAGENO="0253" 247 a simplified form here is very strongly affected by processing of milk. Heat Treatment of Milk The development of pasteurization (e.g. 61.8 degress Celcius for 30 minutes or 71.8 degrees Celcius for 15 seconds or ultrahigh temperature pasteurization: 93.4 degrees C for 3 seconds to 149.5 degrees C for 1 second; Brunner 1.c.) has had a very important effect on the epidemiology of human populations which have been using milk during the last hundred or so years. The process has been invented to destroy pathogenic organisms in milk (it has been standardized on destruction of Mycobacterium tuberculosis). At the times when the infectious diseases were a invincible threat to human societies pasteurization was a big step forwards. Today! at the age of antibiotics! the environmental presence of factors which decrease our immune response and induce chronic metabolic diseases is a much bigger threat. The progress of food technology and the industrialization of our dairy industry introduce new forms of foods which did not pass the scrutiny of human evolution. This should always convince us to allow these groups of our society which are poorly adapted to new forms of foods to use the old forms of foods when other dangers of these old forms of foods are under control. Specifically I think about the effects of heat treatment on milk. Heat-induced protein-protein interacting are according to Brunner, l.c. p. 646 `extensive and complex. We know for instance that milk processed at high temperature does not form a proper curd when treated with rennin (or rennet enzyme, a pepsin-like proteinase used as a milk-coagulating enzyme of young mammals and requiring calcium ions for it effect), therefore such milk! by this procedure, cannot be used to produce cheese. This is an excellent example of the changes of PAGENO="0254" 248 biological properties of milk as a result of the heat treatment. The detailed discussion of such effects would be too professional: good for physiologists and clinicians and not for the general public. The generalization is clear: many properties of milk are lost or modified by processing, especially by the heat processing. To name a few more examples, we quote after Brunner further: (5, p. 647) `aside from the partial destruction of vitamin C and portions of the B vitamins, high temprature processes induce the so called "browning" reaction (of milk) which progresses during storage until the products are no longer acceptable'. As the principal participant of this reaction is the epsilon amino group of lysine-- the "browning' decreases the availability of this essential amino acid from milk. Relatively more recent treatment of milk, introduced after pasteLlrization. is homogenization of milk. The main reason homoc~enization was introduced was not a health reason: it was an industrial reason. Homogenization attempts to secure stabilization of the lipids of milk against the density separation. What is still not fully appreciated is the fact the homogenization alters the protein systems of milk. Aqain the details should be left to scientific discussions. For a very good summary we refer the readers to the sub-chapter on homogenization in the excellent book edited by Fennema (l.c. 5, p 64B). Formation for instance 1gM-kappa casein complex induced by homogenization stabilizes the fat emulsion but modifies the immune properties of milk. There are scientific studies on the negative effects of this phenomenon in the children, the main users of milk. PAGENO="0255" 249 We know today that several recently discovered milk components (immunoglobulin A, immunoglubulin M, immunoglobulin F, lactoferrin, C3 and C4 of the complement system, to name the few) show susceptibility to damage caused by pasteurization (10). All the data presented in this discussion and taken from the scientific literature refer to raw milk unless specifically stated otherwise. The scientists studying physiology of milk, always base their finding on raw milk as a reference situation. Why do they do it? They study an unmodified biological phenomenon and not an artifact distorted by human technology unless the effect of this technology is to be investigated (11). Table IV present localizations of milk enzymes in the intact (raw) milk structures. The processing e.g. homogenization by destroying the structures modifies and abolishes the activities of milk enzymes. The new knowledge about mi 1 k should al low us to reexamine our approach to raw milk as a marketable food product and object of food processing. PAGENO="0256" 250 Conclusions Attention of nutritionists and food technologists has been focused on the nutritive value of gross components of milk, a set of data available to them since the turn of the century. This attitude led to simplified views on the role of milk in nutrition, especially in the nutrition of infants and children. Milk was considered as a sr~ of protein, lactose, fat, certain vitamins and some minerals. This attitude also put no restriction on many technological procedures in milk processing. The progress of nutritional biochemistry and biochemical analytical methodology as applied to milk revealed not only new milk components and details of milk structure but also led to the discovery of new nutritional effects of milk (e.g in the maintenance of the immune response of an infant) available in raw milk and less detectable in processed forms of milk. We all agree today that the raw milk supply should be derived from healthy cows with healthy udders and be produced under sanitary conditions. When such conditions are fullfilled, the market availability of raw milk should be maintained next to other forms of milk. More and more scientific data indicate today that the users of raw milk, especially the inf ant users of it. in our industralized and polluted environment do benefit from the effects of newly discovered milk ingredients. PAGENO="0257" 251 k~gr~'pt)y 1. W.6. Gordon and E.O. Whittier. `Fundamentals of Dairy Chemistry" (B.H. Webb and A.H. Johnson, eds) AVI Pubi. Westport, Conn. 1965, pp 1-36. 2. F.E. Kurtz. "Fundamentals of Dairy Chemistry" l.c. pp 91-169. 3. R. Jenness and S. Patton. "Principles of Dairy Chemistry" Wiley, N.Y. 1958. 4. S.F. Herb, P. Magidman, F.E. Luddy and R.W. Riemenschneider. 3 Amer Oil Chem Soc 39, 142, 1962. 5. J.R. Brunner, Chapter 14 of "Principles of Food Science part I". Ed. O.R. Fennema, Marcel Dekker Inc. N. Y. 1976, p. 619. 6. R. Jenness in "Milk Proteins, Chemistry and Molecular Biology" (H.A. McKenzie, ed) vol 1. Academic Press, N.Y. 1970, pp 17-40. 7. D. Rose, J.R. Brunner, E.B. Kalan, B.L. Larson, P. Melnychyn, H.E. Swarsgood and D.F. Waugh. 1970. J. Dairy Sci. 53 , 1, 1970. 8. H.E. Swaisgood. Crit. Rev. Food Technol. 4, 375 (1973). 9. S.K. Kon "Milk and Milk Products in Human NLtrition" 2nd ed. Food and Agriculture Org. of the U.N. Rome 1972. 10. G.J. Reynolds, 0.1. Lewis Jones, D.M. Isherwood et al "A Simplified System of Human Milk Banking" 1982, Early Hum. Dcv. (Netherlands) vol 7 no. 3 pp 281-292. 11. J.W. Meduski, M.D., Ph.D., USC School of Medicine, Personal Communi cation. 52-266 0-85-9 PAGENO="0258" 9~-9S 39.0 0.25-0.48 0.14 0.016-0.038 0.01 0.85-1.28 0.4 0.011-0.015 0.00~ 0.011-0.023 0.007 0;10~0.44 0.1 0.2-1.0 0.3 0.013-0.068 0.02 0.22~0.41 0.1 0.007 0.003 0.0007-0.009 0.0C2 252 TABLE I. Lipid Compositiob of MIII A1~roxltnate concentritioo Perc~itage of lipid of gfliter Lipid class (range values) Triglycerides DiglycerideS MonoglyCeIide$ Ketcmcid glt~cerldes AldehydogeftiC glycerides Glyceryl ethers Free fatty acids PbospbolipMIS Cerebrosides Sterols Squalene Carotenoidi Fat-soluble vitamins PAGENO="0259" 253 £AbL.&. LI. Fatty ACId Composition of Milkfat Acldb - Acidb Iaturatnd acids 40 279 50 001 6:0 2.34 7:0 0.02 8:0 1.06 9:0 0.03 10:0 3.04 110 0.03 12:0 2.87 13:~ 0.06 14:0 8.94 15:0 0.79 16:0 23.8 17:0 0.70 18:0 13.2 19:0 0.27 20:0 0.28 21:0 0.04 22:0 0.11 23:0 0.03 240 0.07 25:0 0.01 26:0 0.07 - - Branched-chain acldt 14:Obr 0.10 13:Obr 0.04 16:Obr . 0.17 15:ObTAC 0.24 18:Obr Trace 15:ObTBC 0.38 20:Obr Trace 17:0 brA0 0.35 - - 17:0 brBC 0.25 Monounsaturatid acids 0.27 15:1 0.07 0.14 .17:1 0.27 l4:IC 0.76 19:1 0.06 * 1.79 21:1 0.02 29.6 23:1 0.03 20:1 0.22 22:1 0.03 24:1 0.01 Polyimaturated acids D1~ TrIenes 18:2 2.11 18:3 0.50 0.63 18:3C01ü1 0.01 0.09 20:3 0.11 20:2 0.05 22:3 0.02 22:2 0.01 T.tsa~S 30:4 0.14 *0:5 0.04 22:4 0.05 22:5 0.06 ~?IpTSS prec.dI~ tb Colon designate the ewnber ot carbon atoms ~prIaI~ ~ acid *harnas boss foUowir~ tha colon ds.ig'te tha mnaber 01 ~ bond. In ~ narbon chain. -* CA and B dssignat. Isomers. ?er~1 d~lo bmsl. bclnd.s cia, trana, and iar~I1 Iu~l,-bond Isomers. 1~claiaa cia and trina Isomers. - ci. ,trme; t,t - t a ,nas;~ ec*J * PAGENO="0260" TABLE Ill Distribution and Properties of the Principal Milk Proteinsa A~rozimate concentraUon . Approximate koe%ectrtc Percentage of total protein * . molecular point Component (range of values) g/liter Polymorphe P -811 -8-8- weight p14 Caseina 75-85 (250)b . 46 ~51-Casein 45-55 13.7 A, B, C, D 8 0 0 23,500 5.0 ~-Caaein 26-35 6.2 A1,A2,A3,B,C,D 5 0 0 24,000 4.5 k-Caasin 6-15 3.7 A, B 1 2 0 19,0000 3.7-4.2 y-Ca.ein 3-7 1.2 `A1,A2,A3,B 1 0 0 20,000 5.8 Whey proteins 15-25 (5,2)b . ` . . fl-Laotoglobulin "7-12 3.0 A, B, C, B A, B 0 1 2 lM,000 ~ 5.3 ~-1aotaalbumln 2-5 0.7 0 0 4 14,200 5.1 ImmunoglobullS 1.5-2.5 0.6 - 0 0 VsrlabLs~ l60,000~ 5.6-6.0 erum albumin 0.74.3 0.3 0 1 17 69,000 4.7 Minor proteins 2,0-4.0. 0.6 . . aCompilad partially from data presentad by Jannese Rose at ii. , and Swaisgood *bAssumed average composition: 2.50% casein, 0.52% whey protein. CMOIecular wstght of osrbohydrat.-(rss species; species containing up to I 1~ carbohydrate moicileR (.1)00 daltons psr `~ moiety) exist. mixture o(glycoprotein.. 5Primary structure Is irKilviduelly variable. *tFour chain molecules, coneistir~g of two light and two heavy chains lotermolecularily bound through -8-8- groups. Light sal heavy chains contain intramolecular -8-8- loops. ~Approxft~te molecular weight of monomers IgGl and lgG2; 1gM is a pentamer (..1,000,000) and IgA is a dimer (.400.000). PAGENO="0261" 255 Table IV c~ -Mannos idase Lipase Protease Esterase - Lactoperoxidase Lysozyme a-Atnylase 8-Anmlase Riboriuclease Sulfhydryi oxidase Catalase Alkaline phosphatase Acid phosphatase Aldolase Xanthine oxidase Phosphcxiiesterase NADH-cytochrome c reductase Acetylcholinesterase Mg2~-activated ATPase Glucose-6 -phosphat.ase 5 `-Nucleotldase UDP-Galactose hydrolase UDP-Glucose hydrolase UDP-Cmiactosyl transferase Triglyceride synthetase E. C.3.2.1.24 E. C. 3. 1. 1.3 E.C.3.4.4. - E.C.3. 1. 1.1 E. C. 1.11.1.7 E. C. 3.2.1.17 E.C.3.2. 1.1 E.C.3.2. 1.2 E. C.2. 7. 7. 16 E.C. 1.8.3.- E. C. 1. 11. 1.6 E.C.3. 1.3.1 E.C.3.1.3.2 E. C.4. 1.2.7 E.C. 1.2.3.2 E.C.3.1.4.1 E.C. 1.6.2.1 E.C.3.1.1.7 E. C. 3. 6. 1.4 E. C. 3. 1. 3. 9 E.C.3.1.3.5 Enzymes Identified in Milk Enzyme (trivial name) * Class ificationa number - Distributionb MC MC MC S S S S S S S FGM, MC, S FGM, S FGM, S FGM, S FGM FGM FGM, ER FGM FGM FGM FGM, PMC FGM, PMC FGM, PMC E.C.2.4. 1.22 GM, S ER *Ac(,~Jing to Committee on Enzymes of the International Union of Biochemists L2J. bDesjg~ates location in milk; viz., MC, rnicellar casein; 5, serum (whey); FGM, fat globule membrane; GM, Golgi membrane; PM, plasma membrane; aed ER, endoplastnic reticulum. CServe as marker enzymes for PM a~ FGM. PAGENO="0262" 256 Mr. WAXMAN. Thank you very much, Mrs. Gooch. In your testi- mony you acknowledge the fact that there are high risk individuals and you think perhaps a warning to them so they could make an informed decision would be a reasOnable course to take, certainly far preferable, if I understand what you are saying, to banning it competely. Is that a fair statement? Mrs. GoocH. I personally am not sure there would be a need for a warning, but certainly if given the alternative I would prefer a warning over the banning of the milk. Mr. WAXMAN. We have had some people tell us that with infants it would be less than advisable to give them raw milk, with people who have been ill and whose immune system might be less than fully active that they ought to refrain from raw milk. Don't you think those people ought to be informed of that? Mrs. GoocH. I heard that testimony, yes. However, in the paper I present to you, you will find other testi- mony that states that immune factors in certified raw milk are far greater and may have potential benefits that regular pasturized milk does not have. Mr. WAXMAN. So, you dispute the statement that infants ought to avoid using raw milk? Mrs. GoocH. Certainly most of the customers that come in and purchase raw milk do give the raw milk to infants after they have been removed from breast feeding, and they choose the raw milk for their children over pasteurized milk because of the research they have indeed done about the benefits. But getting back to the labeling situation, I would far prefer a label, a warning label, in relation to the choice of not having that product at all. Mr. WAXMAN. Thank you. Mrs. GoocH. Let people make up their own minds through the process of education as to what they want to do. Mr. WAXMAN. Mr. Stueve, what do you think of the idea of high risk groups? Do you think there are high risk groups that ought to refrain from use of raw milk for that high risk group? Mr. STUEVE. Babies. Mr. WAXMAN. Yes, and invalids? Mr. STUEVE. If a mother can't nurse a small baby, and a pediatri- cian gives them a formula-you can't give the whole cows milk to a baby-but you have a formula, then you boil the water but not the milk. With a small baby like that-I will call it the formula milk- if baby is fussing and crying and you put it on raw milk formula, in 24 hours the baby sleeps like it should be sleeping. It gets all the food value which it cannot get from the others. It is impossible. Mr. WAXMAN. So, you would subscribe to the statement that raw milk's easy digestibility makes it the ideal formula milk for babies? Mr. STUEVE. Right; the same with people that are not well, there is far more of a factor there in the food value that they receive than what you are talking about, because I maintain nobody gets salmonella from my milk. We haven't had any contaminated produce nor do we intend to have any. PAGENO="0263" 257 Mr. WAXMAN. Over the years we have heard that mothers have been advised that milk for formula should be heated to enhance di- gestibility. Do you think the generations of mothers were wrongly informed by their pediatricians? Mr. STUEVE. Yes, absolutely. Mr. WAXMAN. You do? Mr. STUEVE. Absolutely. Mr. WAXMAN. Now, you do not consider unmodified cows milk unsuitable for newborns, you consider it desirable for newborns, is that your testimony? Mr. STUEVE. I think the best thing for a baby is for the mother to nurse it. If she can't, the next best thing is certified raw milk with a formula. You boil the water, but not the milk. Mr. WAXMAN. Then you dispute there are any high-risk catego- ries of individuals? Mr. STUEVE. No; high risk, none. Mr. WAXMAN. It is the ideal thing for everybody? Mr. STUEVE. I think the best thing a baby can get, like I men- tioned, again, is the mother's nursing, but if she can't the next best thing is to be fed raw milk, not soya milk or pasteurized formula milk, because you have a processed food and the baby is starving from it. I maintain where a mother doesn't nurse a child and it's been on the pasteurized formula milk, it will have some kind of problem before it is 21 years old. Mr. WAXMAN. There is a group called the American Association of Medical Milk Commissions-this is a group that does the certifi- cation for milk products. Mr. STUEVE. Right. Mr. WAXMAN. They recently revised their quality control proce- dures and as I understand it, in their new revision they deleted the requirement that certified raw milk be free from salmonella orga- n~sms. Are you familiar with that deletion? Mr. STUEVE. First of all, can I go back a little bit? The health department put this into effect in 1969 in a bill. They start picking up my milk every Monday morning for the milk commission lab, as well as our own lab. So, it ~as written in, but it had meant nothing, absolutely meant nothing. All this checking for salmonella has been a waste of time and money for the State as well as ourselves. Mr. WAXMAN. The State doesn't? This commission sets standards for it? Mr. STUEVE. Right. Mr. WAXMAN. This is a trademark used, and they certify milk. Mr. STUEVE. Because it was the way it was written, sort of writ- ten that all cows had to be free from salmonella and, you know, that is almost an impossibility because a cow can have salmonella in her stool feces but passes through, it is gone and it does not shed in the milk. It is very rare, it is as rare as hen's teeth almost for a cow to shed salmonella through her milk because this cow would be sick if she had it in her blood and chances are she will die and she wouldn't be producing milk. PAGENO="0264" 258 Mr. WAXMAN. With all the controversy about salmonella being in milk, why suddenly does this commission decide that one of its standards would no longer be to check for salmonella? Mr. STUEVE. We still do it. We check our milk every day, every day, for salmonella. Mr. WAXMAN. You say "we," are you-- Mr. STUEVE. Alta-Dena Dairy. Mr. WAXMAN. How about the milk commission? Mr. STUEVE. The commission gets it at least once a week or twice a week. Mr. WAXMAN. But they changed their rules. They said they are no longer going to check to see whether there is-no longer require that certified raw milk be free from salmonella. Mr. STUEVE. That is correct. It is a waste of money. It is not necessary because salmonella has been no problem. If you have an outbreak of salmonella in a res- taurant, sure you go in and find where it is. We never had an out- break. Look at our record. None. Mr. WAXMAN. I have heard about recalls. Who ordered them? Mr. STUEVE. We didn't. We never recalled our milk. We say there is nothing wrong with the milk-use it. Mr. NOVELL. May I address that, Mr. Chairman? Mr. WAXMAN. Yes. Mr. NOVELL. Thank you. The recalls are the basis for isolation for the salmonella. One thing you have to understand is in our society where salmonella can be found in McDonald's hamburgers-it has been, frequently- and can be found in other areas there is no other product checked for salmonella on a routine basis. Mr. WAXMAN. That can be found in-- Mr. NOVELL. It is ubiquitous. Mr. WAXMAN. Has it been found in raw milk? Mr. NOVELL. Sure it has been found in raw milk. Mr. STUEVE. And in our-- Mr. WAXMAN. Who ordered the recalls? Mr. NOVELL. The State of California ordered the recalls. Those recalls are not based on any illness. They are based on an attempt at isolation. Mr. WAXMAN. They are based on trying to prevent illness, aren't they? Mr. NOVELL. I don't believe so. If they were, they would be more concerned about the outbreak of yersinia entercoutia bacteria from pasteurized milk in a state that doesn't allow raw milk. If they were more concerned about it they would have investigated the 115 salmonella dublin cases that came from cooked roast beef. Mr. WAXMAN. When they recalled the milk that had salmonella in it, the purpose of that was not to prevent illness, but to do what? Mr. NOVELL. To eliminate the product over a period of years to the consuming public that wanted it. You see they can-- Mr. WAXMAN. And you say that recalls are part of a conspiracy to remove raw milk from the consuming public? Mr. NOVELL. I will not use the word conspiracy. I believe there are some people that feel raw milk shouldn't be available and that is the issue. PAGENO="0265" 259 Mr. WAXMAN. What about recalling just a few items? Mr. NOVELL. Pardon me? Mr. WAXMAN. We had testimony from a woman this morning who said that she found later that the milk had been recalled, that it had salmonella in it, and that had caused medical problems, caused her, in fact, to lose her children; but now when she found out that milk was recalled-what did that mean? Mr. NOVELL. I don't know what it means, but you are misstating the facts of the matter, and that is in litigation, and I am sure like the rest of the litigation that occurs in the matter of Alta-Dena Dairy it will be completely vindicated. But if I can answer your ini- tial question, the isolations are for routine testing. If it was done in supermarkets and restaurants and hospitals we would isolate sal- monella. The interesting thing is that from 192 isolations of salmo- nella in California there should be thousands and thousands of ill- nesses but there are not any. The people claim there are allegedly 600 cases of illness from raw milk throughout the United States, yet twice that many cases occurred on just two occasions in two States where raw milk is banned. It was from pasteurized milk. So what is everybody saying, that we should have a zero-risk? We won't have any pasteurized milk either. Mr. WAXMAN. I appreciate what you had to say. Just to clarify where we have differences of testimony. One place, by the way, Mr. Stueve, where there is no difference in the testimony, everybody claims that your dairy is quite sanitary and you take a great deal of precautions. Mr. STUEVE. I invite you to come and see it. I would like for you come and see it. Mr. WAXMAN. I will see if we can do it one of these days. You are certainly to be congratulated because you are trying to do the best you can in sanitation. But where we have differences of opinion in testimony today is, that there are some who say that there are individuals who are high risk for infection from various pathogens including salmonel- la, and some people have said the high risks are infants, invalids, elderly. This has been disputed. The witnesses before me right now have-you, Mr. Stueve, and Mrs. Gooch have disputed that. Second, is-whether salmonella and other pathogens can or are more likely to be in raw milk. You say no. Others say yes. So, these are the differences we have. The third area of difference in the testimony is whether with all the sanitation measures you take, whether that, in fact, will elimi- nate the pathogens in the milk, and there is a question of whether that is accurate or not. Some people claim that pasteurization on top of everything else, would, as a heating process, destroy those pathogens. I gather what you are saying to us in your testimony is that raw milk need not be pasteurized at all because there are no pathogens anywhere. Have I accurately stated that? Mr. STUEVE. I didn't say there would be no pathogens. I say our certified raw milk is the safest milk in the world, bar none. But when you want to do that kind of testing like-- PAGENO="0266" 260 Mr. WAXMAN. But it's not safe if you have pathogens in it. Mr. STUEVE. Well-- Mr. NOVELL. That is not true. If it is in the environment, Mr. Chairman, in the food environment, and it is throughout our food environment-you are talking about salmonella-of course, there are problems from time to time. Mr. WAXMAN. Any product-let me-- Mr. STUEVE. If you have a food item with salmonella in it-sal- monella is really not a pathogen, because if I have salmonella, I can't give it to you unless I am unclean and I give you some food to eat. Otherwise I can't give it to you. Mr. WAXMAN. If I have a food item with salmonella or other pathogens in it, that is not the healthiest item in the world to eat. Mr. STUEVE. I guarantee you, you eat salmonella weekly, if not daily, because in such a minute quantity that doesn't bother you. Because when we took a sampling by the Moore swab system, we took sandwichs from five different restaurants and we brought them in and we find one out of four with salmonella. Mr. WAXMAN. That is another dispute we have had this morning and into this afternoon, whether salmonella makes any difference or not. We had testimony from Mr. Thomas, and he didn't think it made a lot of difference, and others thought it did. You would subscribe to Mr. Thomas' point of view, that it doesn't make a lot of difference if you are exposed to it? Mr. STUEVE. If we had a salmonella in milk-first of all, if we take a plate test, the plate would be brown, and then you would have a contaminated product, and we would have it off the market ourselves, real fast. But the way we produce our milk-and when you are trying to isolate this with a Moore swab system, we take that again and check it and it is not there, so that is why I ques- tion it. The milk was not refrigerated. So, I say it had been there for days and had a salmonella in it. I don't believe that. I want to see who tested it because it is not easy to check and see if you have a salmonella to start with, and say it is a salmonella dublin. It has to be sent out to Ames, IA, or the Centers for Disease Control in Atlanta, to really type it. Mr. WAXMAN. Thank you very much. Mr. Dannemeyer. Mr. DANNEMEYER. Thank you, Mr. Chairman. Mr. Stueve, there was testimony earlier by one of the witnesses about campylobacter involving the products of Alta-Dena Dairy. Do you have comments about that? Mr. STUEVE. That is an odd deal, too, because we were in Sacra- mento, and I didn't find out until we were in Sacramento, when it was brought up. This group had their own symposium and brought in campylobacter from my milk. When we find out about it-this particular group said kids came to the dairy, the health officer came out and the tour guide showed how they got certified or kefir milk or ice cream. Then it was shown that the kids from there, when they saw the plant-they come out and they love the calves, because at the county fair all the kids come out and pet the calves. So, we have a couple of calves out there-so they petted the calves, and there is a water trough half underneath the fence, and PAGENO="0267" 261 they splashed around the water. If they got it from raw milk-for gosh sakes, there was thousands and thousands of gallons out there, they would all have gotten it. So, it didn't come from the milk, it came from the outside, from petting calves or water splashing. I think Dr. Orsborn can verify this also. This is where you get campylobacter, but not from ingestion of raw certified milk the way we handle our milk, because we produce our milk with one coliform, sometimes zero coliform, and the plates are low. How can you get campylobacter out of it? It is impossible. First of all Dr. Winn says it is impossible and evidence from the Centers for Disease Control-- Mr. DANNEMEYER. OK. Mr. STUEVE. But again you see what happened, what I am talk- ing about, conspiracy, organized crime. This was picked up and brought up to Sacramento to bring out, and put out in the news media that campylobacter was in our milk before we even found out ourselves about it. I am telling you we are up against a conspiracy, organized crime here. Mr. DANNEMEYER. Thank you very much. I think that record would be deficient on this issue unless we state a little bit briefly of one of the problems, as I see it, in this entire controversy. This producer of certified raw milk has brought a product to the people of California. There is a need for it. But this producer has been, and still is, under the jurisdiction of the following public enti- ties, the State Department Public Health, the State Department of Agriculture, the County of Los Angeles Public Health, and the Los Angeles County Medical Milk Commission. Each of those public entities has their own particular bias to pursue. And that abundance of governmental regulations of this producer of certified raw milk is partly responsible for this entire controversy. The Department of Agriculture of the State of California has kind of been in the middle of this controversy, but there are two or three individuals in the State Department of Public Health who, when they went through medical school years ago, were taught by their professors that all milk should be pasteurized, and they still believe that, and they are sincere in that belief. But they have adopted as a cause for the achievement of their career in public health in California, that they want to be known in the anals of public health as the people who are responsible for eradicating from the consumers of our state the menace known as certified raw milk. And they have almost limitless resources. They have lawyers, they have statisticians, they have biologists, they have cohorts working from the Centers for Disease Control in Atlanta, GA, and around the country, and they have just circled the wagons in a circle, and their view is getting a little smaller. As the data from Mr. Thomas points out, you have to shake your head. There is a existing standard for E. coli, a pathogen in milk. For that pathogen, not more than 10 colonies per milliliter pro- duced more deaths than salmonella in 1979. PAGENO="0268" 262 Yet, we are not doing anything, we are not hearing anything from the public health world about proceeding against food prod- ucts that contain E. coliform bacteria, which produces more deaths than salmonella. Yet, we hear all this effort about eliminating certified raw milk from the consumers choice, a product which is healthful and needed, and nutritious, at a time when they are doing nothing about these 11,255 cases of salmonella food poisoning. I am disappointed, Mr. Chairman, in Dr. Chin-who is a nice gentleman-that he didn't come in with his flag declaring war on salmonella in California, because logically he should be doing that. We know why-he will be laughed from his office as a public offi- cial if he proposed we eliminate hospitals and water and beef and turkey. Why? Because the producers of those products are so basic to our culture that we couldn't really function without them. So, they have zeroed in on this producer of certified raw milk and brought the whole resources of the State to bear on them, all flying under the flag of public health. I think it is a tragedy. It is a perversion of what public activities and laws are all about. I think the correct course we should take with our colleagues is just let people make a choice as to what products they choose to. pursue. Thank you very much. Mr. WAXMAN. Thank you, Mr. Dannemeyer. You just heard my colleague, Mr. Dannemeyer's, description of the people in the public health world who think there is a problem with salmonella. He said he thinks they are well-meaning but mis- taken. They have some notion that pasteurization was an advance that killed these pathogens in salmonella, but in fact, they are wrong. That is his description. Your description is they are part of organized crime. What do you mean by that? Mr. STUEVE. Because as I give you my-what I read for you-we started taking them on. Humphrey is the one that carried the ball all the time. He is the one that came-if you recall now Dr. Werner, Dr. Bolton, and Dr. Fierer are also involved in this. I was told these three were in school together, so, you see the circum- stances on that. But everything points right down. This is an organized crime to knock Alta-Dena out of certified raw milk, and probably, if they could, they would probably have no more raw milk in these United States of America. That would be one of the biggest objects they would try to create. But the biggest thing is it is a conspiracy on us because we took on, one, the health department and beat them in court. That is the biggest point. I was told at that time-in fact, in 1969 I was the mayor of Mon- rovia, and before served on the city council-you can't fight city hall, I felt when you are right you have to stand up for it. You can't lay down. Mr. WAXMAN. Let's hold back the audience response so we can finish up the meeting. I want to explore this one issue with you because it seems to me you are saying because some people disagree with you and would PAGENO="0269" 263 reach the conclusion that raw milk, because they believe it is un- healthy for the American public, should be banned-even though you strongly disagree, to say they are part of organized crime is a pretty extreme statement. Do you stand by that statement? Mr. STEVVE. Yes, I am. Mr. NOVELL. May I respond to that, Harold? Mr. WAXMAN. I want to hear Mr. Stueve's statement, because he made the comment on it. If you make extreme statements like that, I must tell you, that sounds so extreme to me that it chal- lenges your credibility in other statements you make, if this is not one you can stand on. Mr. STUEVE. When Louis Pasteur brought in pasteurization it was used for wines, and the beer producers picked it up-not in Germany where they drink it so fast, but for bottled beer. But draft beer is still raw here. But the wine people turned back-they are making it. Gallo and Wenty, they are making it all raw again be- cause they found out they have more flavor and better tasting wines with it. The milk people picked it up to "kill all evil." I still predict to you by the year a little over 2000, over half the people in Califor- nia will be back to raw milk again because they will find out how much more they are missing over this time, like growing heart dis- ease. Mr. WAXMAN. I understand, but why did you say, "organized crime." It is a point you assert and I respect that fact. Mr. STUEVE. How can any-- Mr. WAXMAN. Why do you say the people you disagree with, who may be well intentioned, are part of organized crime? Mr. STUEVE. Why did they put into the bill that time and stick salmonella in it, into the bill in 1969? At that time they couldn't find it with that technique. So later on they put in a Moore swab system, and going that way I think you can find anything you want to. So, it was on purpose put in there. So, right away in 1970 why did they come in full force and pick on our milk all the time? Even Dr. Chin came and said, yes, there still could have been a Q-fever in milk, and they had a test made up for our younger herd and made a testing and they became a laugh. Because Q-fever is air- borne and you cannot get it from ingesting. The same with this other here, with salmonella. Why didn't we have an outbreak? Look around. We had no breakout. You find this one case, and the biggest case, of salmonella dublin, which was Vandenburg Air Force Base from cooked roast beef, and everybody eats meat, so why show the other, why does it come to us only one case at a time? It is ridiculous. Mr. WAXMAN. I understand. Thank you very much. Mr. DANNEMEYER. Do you have anything? Mr. Novell wanted to respond. Mr. NOVELL. Specifically, when you look at statistics that is where it becomes suspicious and that is where this "conspiracy" arises that Mr. Stueve talks about. For example, there was a study published in 1979 by Dr. Werner and Dr. Humphrey about 113 PAGENO="0270" 264 cases over a 5-year period in California, and they said 35 of the people were associated with raw milk. That particular study left out the 115 from cooked roast beef. Mr. WAXMAN. Do you believe the people who wanted to ban raw milk are part of organized crime. Mr. NOVELL. I wouldn't use the words organized crime. I don't think that he is using that by intending to refer to what you-it is a colloquialism. I don't think Mr. Stueve means to infer-that there is Mafia involved. Mr. WAXMAN. I wanted that explained. You think it is a colloqui- alism? Mr. NOVELL. Yes. But when you refer to the studies that Mr. Potter referred to by Dr. Taylor-Dr. Taylor in 1979 and 1980 it was-finds that in 18 States there are 57 cases of salmonella dublin, other than California and Oregon, and 12 people contracted it from raw milk-but what he put in his study, but buried, that 8 people drank milk not intended for commercial use and one person was from India. When you compare that with the control, which is 5 out of 62, you have 3 of 57. So, there was lower risk for raw milk users. When you take Dr. Potter's study, I respect his view, but he said in his study the people that drank most of the milk got sick. That is not true. Mr. Thorn was one of the persons in his study. He drank most of the milk and he didn't get sick. His child who didn't drink the milk got sick. So, there was no explanation for that particular one. That study even admitted they did not isolate the organism in the milk. They also didn't know of seasonal variations. Nor could they say it was related to the milk. I could go on and on and on. I have submitted this in writing, but every study we look at has this in it. Everytime somebody says the statistics are unassailable it is simply false. The statistics are there. There is twice as much illness from pasteurized milk and only two occasions from two nonraw-milk States than from all the raw milk alleged illness in all the United States. So, if you want to get back to "where is the risk?", I submit to you that the risk is in the areas where people are not paying atten- tion to sanitation, and that to reduce the risk we have to do that as has been suggested earlier. Thank you. Mr. WAXMAN. Thank you very much. I want to thank the three of you very much for your testimony. There are people in the audience who feel strongly and want to add to this record. We will be pleased to receive any written comments that any of you want to make and put it in the record with the transcript that we will share with our colleagues in Washington. Mr. WAXMAN. I thank everybody who participated in this hear- ing we appreciate your activity and assistance. We stand ad- journed. [Whereupon, at 1:40 p.m., the hearing adjourned.] [The following letters were received for the record:] PAGENO="0271" 265 February 20, 1985 Honorable Henry A. Waxman Chairman, Subcommittee on Health and the Environment 2415 Rayburn House Office Building Washington, D. C. 20515 Dear Hr. Waxman: I attended the hearing on The Health Risks and Benefits of Unpasteurized Milk held February 13, 1985, at the University of California, Los Angeles. This same type question arose last fall in the California legislature. At that time officers of all the Cooperatives who operate processing facilities in the state visited the Governor's office and, in unison, opposed a relaxation of the present law. This group represents aboUt 70% of the milk producers and about 80% of the milk produced in Cali- fornia. This group opposed the legislation because every reported case of milk borne Salmonella dublin gives the entire Dairy Industry a bad reputation. This group is unanimous in its opposition to the sale and distribution of raw milk. I hope your Subcommittee will recommend the Food and Drug Administration enforce the present law banning raw milk sales. Very truly yours, DY'~NISH CREAMERY ASSOCIATION Galen W. Brunner President and General Manager GWB: 1 f cc: John Adams, NMPF P.O. BOX 11865. FRESNO, CAIJFORNIA 93775 / PHONE (209) 233-5154 / GALEN W. BRUNNER, GENERAL MANAGER PAGENO="0272" 266 AMERICAN MEDICAL ASSOCIATION / 535 NORTH DEARBORN STREET CHICAGO, ILLINOIS 60610 PHONE(312)645-5000 . TWX 910-221-0300 .IAMESH. SAMMONS, M.D. Executive Vice President (645-4300) February 28, 1985 The Honorable Henry A. Waxman U.S. House of Representatives Washington, D.C. 20515 Re: Milk Pasteurization Dear Chairman Waxman: On February 13, 1985, the House Energy and Commerce Committee held a field hearing concerning the risks and benefits of pasteurized milk. The American Medical Association believes that all milk sold for human consumption should be required to be pasteurized because convincing scientific evidence exists that raw milk poses a significant public health threat. We recently expressed our view on this issue to the Food and Drug Administration. A copy of our statement along with an article published in the Journal of the American Medical Association concerning the health hazards of drinking unpasteurized milk is enclosed. We hope this information proves useful to you. Sincerely, James H. ammons, M.D. JHS/hf l758p PAGENO="0273" 267 `3 AMERICAN MEDICAL ASSOCIATION 3, f 53SNORTH DEARBORN STREET * CHICAGO, ILLINOIS 60610 . PHONE(312) 645-5000 TWX 910-221-0300 JAMESH.SAMMONS, M.D. Ezeculwe Vice President (645-43501 October 29, 1984 Frank Young, M.D., Ph.D. Commissioner do Dockets Management Branch (HFA-305) Food. and Drug Administration Room 4-62 5600 Fishers Lane - Rockville, Maryland 20857 Re: Docket No. 81 N-0204C Milk Pasteurization as published in tha Federal Register of August 3, 1984, (49 F.R. 31065) Dear Dr. Young: In the Federal Register of August 3, 1984, the Food end Drug Administration (FDA) published a notice requesting inforration as to whether there is a public health concern regardiog the marketing and human consumption of raw milk, including certified raw milk, and raw milk products. The FDA also requested comments concerning whether it is the most reasonable regulatory option to require that all raw silk and rca milk products sold for huaan consumption should be pasteurized. There ia convincing scientific evidence that raw milk poses a significant public health risk. Raw silk has been identified as the source of bacteria that have caused outbreaks of ualmonellos~s and carspylobacterlosis. Other serious bacterial diseases linked to the drinking of unpasteurized tailk include tuberculosis, staphylococcocic, brucellosis, listeriosis, colibaciliosis and corynehacteriosis. Because milk has a fat content that protects pathe3ens from gastric acid acid Ii~ a a relatively short gcistric transit time, unpasteurized milk can be a ~o~d vehicle for the transmisciou of infectious diseases. The Al-IA believes that all silk sold for hucoac consusrption should 3-a required to be pasteurized. Pasteurization kills the bacteria that transmit disease to humans. In addition, pasteurization has not baen found to have any adverse health effects. Finally, studies have found teat rcw nile provides no significant health benefits over those ~iOV1~i.d by pasteurized milk. We have included a copy of an article publ~mhed in the October 19, 1984 Journal of the_A~erican Medical Associntion that discusses the health hazards of drinking unpasteurizeci milk. We appreciate the opportunity to express our view. Sincerely, /~ /1 ,,/f~ L_~.~af~3 fc~'~ 4 ~ * James H. ~sIsiflaicsu M.D. INS/hf Enclosure l6llp PAGENO="0274" 268 Cupyught 1084, Aco,iuo, Mrdie&Az,ouietiec State of the Art M. Therese Southgate, MD, Section Coordinator Unpasteurized Milk The Hazards of a Health Fetish Morris B. Potter, DVM; Arnold F. Kaufmann, DVM; Paul A. Blake, MD; Roger A. Feldman, MD AS THE dairy industry began to industrialize in the 1800s, the mass production and distribution of milk and dairy products led to svidespread outbreaks of milkborne disease. The greatest perceived milkborne hazardo of the time were psor sanitation and handling procedures, as svell as dis- eased dairy cows. Repeated outbreaks of typhoid, `scarlet fever, diphtheria, diarrheal disease, and septic sore throat were caused by milk that svas produced, transported, and sold under unhygienic conditions. Nationsvide problems with contam- inated milk led to two public health movements that attacked the pur- veyors of bad milk and each other ovith equal alacrity. The certified milk movement promoted sanitation in all phases of milk production and mar- keting under the oversight of medical milk commissions but denounced pas- teurization, claiming that it caused nutritional deficiencies, allowed the marketing of sterilized filth, and destroyed the natural flavor of milk. Conversely, the pasteurized milk movement denounced certified milk as unsafe despite the sanitary precau- tions.' Ultimately, the best of both movements became public policy. Pasteurization was accepted as the primary safeguard for the nation's milk supply after several epidemics overe traced to certified raw milk, while the sanitary concepts of the certified milk movement svere incor- porated into milk hygiene codes as important adjunctive safeguards. The apparent public health impact of safe milk ovas substantial; for example, the number of infant deaths due to diarrhea in Washington, DC, dropped from 477 in 1894, the year before sanitary requirements for milk were strengthened, to 72 in 1909. Although there io no objective evi- dence that milk pasteurization has an adverse effect on human nutrition or health, the sale of rasv milk (certified and uncertified) has persisted and even increased in recent years under intensive promotion by "health food" enthusiasts using arguments similar to those advanced in the 1890s. In this review, we discuos the haz- ards and purported benefits of raw milk consumption to help the practic- ing physician and other health pro- fessionals more fully appreciate the risk posed to human health by raw milk and to enable them to under- stand and rebut arguments advanced in support of consumption of raw milk. Definitions Milk, as discussed in this reviesv, is cow milk unless otherwise specified. Goat milk is increasingly promoted as a health food, but constitutes less than 1% of total milk consumption in the United States. Raw (unpasteurized) milk may be certified or uncertified. Certified rasv milk is produced in accordance with methods and standards established by the American Association of Medi- cal Milk Commissions, Inc (an indus- try-supported organization). This milk is produced by a fesv large dairies and is often sold, where state laws allosv, in retail food stores. Uncertified raw milk is typically pro- duced in small volumes by individual dairy farmers and sold on the prem- ises of the producing farm or by home delivery. Pasteurized milk is milk heated for specified time and temperature com- binations designed to kill all micro- * Meaningful differences in nutritional value between pasteurized and unpasteurized milk have not been demonstrated, and other purported benefits of raw milk consumption have not been substantiated. Conversely, the role of unpasteurized dairy products in the transmission of Infectious diseases has been established repeatedly. To effectively counsel patients attracted by the health claims made for raw milk, practicing physicians must understand both the rationale used by proponents of raw milk and the magnitude of the risk involved in drinking raw milk. (JAMA 1984;252,2050-2054) F,sx 1hz Di,uisc of Bsctz,ie! Diszzszs, Cello lcfeufious Diszmo~, Cmtn,sfo, Diszosn Coct,cf, Rop0lt1oquzstltu Diui9c,, cfSsetn,iulDuzzlzl. Czutz, to, Icf~otio~s Disnusm, 1600 Cuff 0, Rd NE. Allude. 58 3033319' Poftz,l. 2048 JAMA, Oul 19, 1984-Vol 252, No. it Unpasleurized Milk-Potter el al PAGENO="0275" organisms that transmit disease ts humans through milk. Currently ac- cepted time-temperature csmbina- tisns include 63 °C fur 30 minutes, 71.6 `C for 15 s, and 89 °C or higher for 1 s. Pasteurization does not steri- lize milk, but doe~ make the milk safe to drink. Pasteurization should be distinguished from homogenization (emulsification of milk fat) and for- tification (addition of vitamins A and/sr D). In the health food litera- ture, commentaries about the pur- ported nutritional hazards of pasteur- ized milk tend to blend the three processes into one. Like pasteurized milk, raw milk may be sold homoge- nized and svith vitamins A and D added. The regulatory standards for pas- teurized milk vary by state, but these standards all meet or exceed those in the Grade A Pasteurized Milk Ordi- nance recommended by the Food and Drug Administration. Individual state regulations on the sale of raw milk also vary, with some prohibiting such sales, others allowing sales only on the premises of the producer, and others setting up standards paral- leling their pasteurized milk ordi- nance. All milk ordinances set mini- mum standards for dairy animal health, personnel health, environ- mental hygiene, and milk quality. Quality contrsl programs supple- menting the official regulatory pro- grams are commonplace in the dairy industry. The standards for hygiene of certified rasv milk that are estab- lished by the American Associatisn of Medical Milk Commissions, Inc, rep- resent only one of many such pro- JAMA, Out 10, 1984-Vsf 252, No. 15 Comparison of Nutritional Values in Raw and Pasteurized Milk Pasteurization causes minor changes in milk, and advocates of raw milk have at one time or another claimed that virtually every detect- able change has profound health implications. Pasteurization affects six milk constituents with known nutritional benefits: three vitamins for which milk is a minor source (thiamine, B,, and C), calcium, pro- tein, and fat.' Thiamine is reduced from approximately 0.45 to 0.42 mg/ L; vitamin B,, is reduced at a maxi- mum from 3 to 2.7 pzg/L; and vitamin C is reduced from 2.0 to 1.8 mg/L. None of these losses exceeds 10%, and none can be considered important. About 6% of calcium is rendered insoluble, and about 1% of milk pro- tein is coagulated. The major effect on fat is a slight disaggregation of fat globulou, resulting in a reduced cream line in whole milk. The observed changes have no effect on the his- availability of these three nutrients.' Raw milk has also been said to con- tain undefined and undetectable health promoters, such as an anti- stiffness factor invaluable for treat- ment of arthritis, but such claims have not been substantiated in the medical literature. Numerous studies of the relative nutritional merits of rasv and pas- teurized milk have been conducted in animals and humans, and no differ- ences were detectable. One animal study deserves particular attention because a misrepresentation of the results has become prominent in the raw milk folklore. In 1946, Pottenger' published a report about his observa- tions so cats fed varying combina- tions of raw and heat-treated milk and raw and cooked meat. In his first and largest series of experiments, Pottenger observed many diseases in cats fed raw milk and cooked meat, but essentially no disease in those fed raw milk and raw meat. Raw milk advocates have erroneously cited this article as having reported that dis- ease occurred in cats fed pasteul-ized milk (eg, Llyod F. Smith, MD's article Why Certified Rasv Milk, Let~s Live Magazine). Smaller experiments re- ported in the same article showed that a diet of one-third raw meat and two-thirds milk (pasteurized or not) did not provide adequate nutrition for cats. The major health benefits claimed for raw milk are summarized in Table 1. These claims, except for a few recent variants, were rebutted more than 40 years ago by Wilson in his monograph The Pasteurization of Milk. This book is required reading for anyone interested in the topic. Infectious Disease Hazards of Raw Milk Abundant evidence has shown that raw milk serves as the source of bacteria that cause outbreaks of dis- ease in humans: in recent years, most frequently salmonellosis and campy- lobacteriosis. In the investigations of such outbreaks, the epidemiologic evi- dence, combined ovith knowledge about the occurrence of specific path- ogens in cattle and the isolation of some of these pathogens from raw milk, leaves no doubt that rasv milk is a vehicle for disease in humans. 269 Table f.-Parported Health Benefits Derived From Drinking Raw Milk' Promotes proper development of tooth This claim in primarily dnri,ed from a stady of boys ohs drank raz milk end bud a lao incidence of caries; and nedaees,ns,do,oo of carrot no comparisons ooro made oilh persons ohs drunk pasroarlood milk; no neiontitis evidence has boon Enhances ms/stance tsd;soaso No eoderco eo;srs nsappso of this claim ton tao milk; on the cart,ary, mi/kborno disease oas a problem Enhances tert,l;ty Th,s concept is based on misrepresentation of animal foadirg sfader fhaf involsed denciort diets Connors bonor;c;al oroymos, Some oroymes are `nacrisafod by pasloariaation, bar hose enaymos are probably inavli,alod by popsin hnrmoros. and arl~brd~os and/or gasrr;v acidify; hormone csnlonf of coo milk isancenfain. and hormones aronof inacri,ared by pasreavzar,sr fomperafaros; rho smull qaanriry of antibody in normal mi/k. ohio nsf inaclisalod by pus- is not absorbod in ho haman inresrinal tract Csnfalrscndetyned sabtransossa5, Those claims amoant to littlo more than anecdoles Contort lactsbac,/l, Lacrobac,//, are contaminants rather than natural flora of n/k; panteariozd dairy prodayts sontaining added lantsbayill arc asailablo Unpastesrized Milk-Potter ml of 2049 PAGENO="0276" Modern sanitary.and health stan- dards observed by the dairy industry have made contamination from envi- ronmental sources, including humans, an infrequent problem. In contrast, programs relying solely on sanitary and health standards have not suc- ceeded in eliminating contamination caused by symptomatic or asympto- matic infection in the milk-producing animal. Contamination from animals with organisms such as Salmonella and Campylobacler has thus become the primary hazard for raw milk consumers. Salmonellosis Many outbreaks of salmonellosis due to consumption of raw or improp- erly pasteurized milk, nonfat dry milk, and cheese have been de- scribed.'' Salmonellae have been iso- lated from raw milk repeatedly during investigations of such out- breaks.' Milk is an ideal growth medium for Salmonella, and some strains of Salmonella can even sur- vive in cultured milk products, such as yogurt, for as long as two weeks. Surveillance of human salmonello- sb in the United States is based primarily on reports of isolates iden- tifIed at state public health laborato- ries, and these isolates are believed to represent only a small percentage of the cases that occur. Most isolates belong to a few common serotypes, so epidemiologic investigations are usu- ally not initiated unless there is an unusual incidence of a relatively rare serotype or a serotype that is a mark- er for a particular problem. There- fore, the relationship of sporadic cases to a common source is usually not detected when they are caused by a common serotype. Isolates of Sal- monella dublin, a relatively rare sero- type known to he host adapted to cattle, are more likely to be investi- gated and identified as being derived from raw milk than are the com- monly isolated serotypes. Numerous studies in multiple locations have confirmed the role of rasv milk in the transmission of S dublin to hu- mans." Based on their 1982 data, California health authorities calcu- lated that the risk of S dublin infec- tion was 84 times higher in persons who consumed raw milk than in per- sons who did not (S. B. Werner, MD, oral communication, October 1983). Salmonella dublin infections are of particular concern because the associ- ated illness tends to be severe. The relative virulence of S dublin is illus- trated by its ability to invade the bloodstream' and the rates of hospi- talization and mortality for infected individuals."' Salmonella dublin is 13 times more likely to be isolated from blood than are other Salmonella nero- types, and more than half of the patients with S dublin infection are hospitalized. In two reports, 10% to 20% of tlse cases of S dublin infection were fatal.' Risk of S dublin infec- tion is significantly higher in persons over the age of 40 years and in persons with underlying chronic ill- nesses or taking antacids.'' The problem of raw milk-associated salmonellosis is not restricted to S dublin. From a baseline of three Sal- monella lyphimurium isolates in four years, the number of isolates of S lyphimurium from persons in a three-county area of Oregon in- creased to 27 in three months in early 1983.' Epidemiologic investigation in- criminated raw milk and cream from a single dairy, and S typhsmu'tum with the same plasmid profile was isolated from milk, milk filters at the dairy, the dairy cows, and the ill persons. Recently, in Vermont, eight persons (aged 10 months to 60 years) in four families had diarrhea, abdominal cramps, and fever." All had drunk raw milk from a single dairy. Salmo- nella derby was isolated from the patients and the milk. In 1980, a multiresistant S typhimursum was isolated from patients and milk dur- ing an outbreak of enteritis involving 105 persons who had drunk raw milk from a single source in Montana." Campylobacteriosis Since culture of diarrheal stools for Campylobacter jejuni became com- mon, many milkbsrne outbreaks of campylobacteriosis have been de- tected. Fourteen (61%) of 23 Campy- lobacter outbreaks reported to the Centers for Disease Control (CDC) from 1980 through 1982 were traced to consumption of raw milk (Mark Finch, MD, unpublished data, Decem- ber 1983). In a detailed one-year study of sporadic campylobacteriosis con- ducted in Iowa in 1982 and 1983, 35% of the ill persons had drunk raw milk during the week before onset of ill- ness; drinking raw milk was the only significant difference between cases and controls (P'z.OS; relative risk, 9.3)." In the United States, outbreaks of campylobacteriosis associated with drinking unpasteurized milk have recently been reported in Arizona, California, Colorado, Georgia, Kan- sas, Maine, Oregon, and Pennsylva- nia." In the outbreak of campylo- bacteriosis in Arizona," two cohort studies showed that households with members who drank raw milk re- ported diarrheal disease significantly more frequently than those in which no one drank raw milk, with relative risks of 4.7 and 3.4. In the Georgia outbreak, illness due to campylobac- teriosis in 30 households was strongly associated with consumption of rasv milk (odds ratio, 29.5), svhile contacts with pets, livestock, or well ovater were not associated with illness." As in Arizona and Georgia, only con- sumption of raw milk was signifi- cantly associated with enteritis in the other outbreaks. Other Diseases Other bacterial diseases associated with drinking unpasteurized milk from cows include brucellosis, coli- bacillosis, listeriosis, tuberculosis, corynebacteriosis, staphylococcosis, streptococcosis, streptobacillosio, and yersiniosis (Table 2). These diseases are now infrequently reported as milkborne diseases in the United States, but they illustrate the wide range of potential hazards. Milk other than cow's milk has also been associated with disease in hu- mans. Toxoplasmosis has been associ- ated with raw goat milk,"' and bru- cellosis and campylobacteriosis have followed consumption of raw goat's milk cheese.'" The virus of tickborne encephalitis is shed in milk, and fresh cheese made from unpasteurized sheep milk has been associated with thin disease." Toxin-producing staph- ylococci have been isolated from cheese made from raw sheep's milk." Comment The relative merits of raw and pasteurized milk have been debated for at least 90 years. In this period, the theoretic health benefits of raw milk have never withstood careful Unpasteurized Milk-Potter ci at 270 2050 JAMA. Oct 19, 1984--Vol 282, No. 15 PAGENO="0277" scientific scrutiny. Epidemic rickets and scurvy and the other dire con- sequences of milk pasteurization prophesized by early raw milk advo- cates have not occurred. Conversely, the fact that raw milk presents a substantially greater inherent risk of infectious disease has been demon- strated repeatedly. Surprisingly, the controversy continues. Regulation of the sale of raw milk often involves discussion of freedom of choice. A major feature of the individual's right to free choice, how- ever, is informed consent, and incor- rect information en the purpsrted benefits of drinking raw milk is so widespread that truly informed con- sent is difficult to achieve. Also, in matters of foodstuffs, parents make choices for their children. Therefore, the children of advocates of raw milk are exposed to the risks of infectious diseases without a full understanding of the danger.'" Children also tend to drink what is given to them in school without questioning its safety. There have been numerous outbreaks of enteric diseases in schoolchildren giv- en raw milk while on field trips to dairies in the United States," and a large outbreak of campylobacteriosis traced to the consumption of free raw milk at school svas reported in England." JAMA, Oct 19, 1984-Vet 252, No. 15 Observations in England and Wales, where an estimated 3.5% of the milk is consumed without pas- teurization, support the contention that raw milk is an unsafe food product. In the period 1951 through 1980, these two countries reported 233 outbreaks of communicable disease attributed to milk or dairy products, with approximately 9,400 cases and four deaths." Seventy-five percent of the outbreaks and about 40% of the cases were associated with raw milk; most of the remaining cases involved faulty pasteurioation or obvious post- pasteurization contamination. Con- tamination by Salmonella caused 74% of the outbreaks in this period. A detailed cost-benefit analysis per- formed to determine the value of a ban on the commercial sole of raw milk in Scotland clearly demon- strated a favorable ratio on the basis of the costs of milkborne salmonello- sin alone." The role of raw milk as a vehicle of C jejuni infection, however, was not demonstrated until 1978, when many laboratories began to look for the organisms in diarrheal stools. Since then, many raw milk-associ- ated Campylobacten- outbreaks involv- ing thousands of cases have been reported by English investigators." When one considers the known health risks, it is apparent that raw milk is not being singled out for unwarranted attention by public health authorities. Other ready-to- consume foods of domestic animal origin are subjected to processing procedures rendering them safe for consumption and are microbiological. ly monitored for adequacy of process- ing. Raw foods of animal origin, ouch as chicken, may be contaminated with Salmonella and Campylobacteo', but routine bacteriologic monitoring of these foods is not done because these raw foods are normally cooked before consumption. Furthermore, extensive efforts are mode to inform the public of the hazards and the proper cooking procedures for these products, and practical measures to eliminate the contamination are not available. In food hygiene, as in the operating room, clean is not synonymous with safe. The raw milk industry points to standards suds as total bacterial counts as proof of safety, but the high incidence of disease associated with raw milk is strong evidence that these standards are unreliable indexes of safety. Milk is an excellent vehicle of infection because its fat content pro- tects pathogens from gastric acid, and, being fluid, it has a relatively short gastric transit time. Thus, loss-- level contamination, which would be readily controlled by pasteurization, 271 Table 2.-Mo/kborne Bacterial Diseases of Less Frequest Occurrence in the United States Agent Ces,mests Bsiee/ia sp Wo,/donde, es/k and other deity p,sduxts sortooniruted cith Brace//asp ore the p/n/ny uehis/,s of breoel/osis to hotness; in the Onited States, epprooi~nutc/y 10% of the reported eases are anniboted tosonserrption otanpasteunzeddairyproduots; prodaststoronettnirdotthesesase,are dxnnstisa/lyprodusnd" Eeeheoehoz coO Outbreaks of diarrhea hues been reported in persons cho 000sun,ed unpasteu,ized croon" asd eticehooso"; plan. rsd'r,edigted untin/icrobia/-r,sigtant Eeo/ihaee also bees isolated true ni/h'0 Los/zoo tn0000ytogzreo Looter/a ,n000rytogznec has been isolated turn unpasteurized soc and shoop ni/k"; shedding of Linteria in ni/k persots for lonu periods or torrn attor the r,ilk posses the aisuu/ noarninction to/toeing lisneriosis"; saidoosc ct ni/k- borne 5ster/onis is hunnans has been cstobtshed°' Myrobaytznoo,n tobnee/os,o, Ouft,s,ent tobenale bcsi/5 are excreted by a s/nub soc cith tubersu/sos nnastitio to rake then//hot too clean Myeoboenenann beau ontzot;oas ton intarts"; in 1900. tuberculosis eas diagnosod in 3 dairy herds in Anizonu; 302 013,760 cattle tested or tuberculosis zone position" Cooyoebuetenen pnexde- A sase ot noudatoac tonso//itis and cerxiool lynphgdenitis hot tesa/ted in prolonged hospitaszutisn ous desedbed in a tabz,-ya/oocou 35'yearo/d non ct/os, clesest resent donestis urinal eoposore cas drinking toe soc's end goon's nt/k" Staphyloyoeoonaooreuu Stuphylosocci in ni/k, zither non nasnitis ni/her honor ocrtaninution, 000sc oustroentedtis in consuners chen they ingest the houtstable enterotooin prodused by the staphylocooci" Sn'epnootoeeausp Stnepronsesisooseaaoniety of diseases in hananu and bc,, Oninu/s and one innponann suprophylos in nilk and ni/k produsts; lobe hr staphy/ocosci, boy nay be pncsent in ni/k in large nunbnrs eher thry cause nun/i/is in the ni/k' prod using anina/; Sto'cptcyoeeaocoocpideniyeo is usonnen cause ot nosti/is incur/c. end n/kbonne oanbreaks on bongos to//seed by anato poststneptososy~/ g/onnra/onephritis huan boon reported"; a bnnok has boon essosiuted cith sonsionpnion otchonsu nude tnon rue ni/k" Strzptobaeo//au ncno5/onnoo In the t920s, them core sons sery Igru, outbreaks ot strep/obaci//osis traced to oonsunpnon et roe ni/k"; chen S nooo/ilornoo os isolated non ni/k, the pnesonption of conteninution by tar, is nude; it/s on/ike/y that this disease could present a nilkbsrnu problem in a doiry prustising canently u500pred standards etduiny hyginne Yzrn,nooznnayoyoayya Vzrnonoa zotzroao/ohya is t~zqoent/y t500d in urinal eneironnorts, noy be present in onpusteunioed ni/k at high con cennratoons, and uroes at reftogenuror tenpenatotes"; in a study in Ontario, Oshienunn" sand Yzruioio in 0% of the nau no/k sunpbes, 0%ot the shoosu curd sanp/os, nOmO 0/the sheddor cheese sunpbes, and 1 at 265 paslea,. oed n/k sunpins; Yeo'c,oio zonyo-oeo/i/iaa egs iss/uted coo toe ni/k inasospesled tosdbsroo oonbruuk or ycrsinio. Unposteuriznd Milk-Po9er ef 0/ 2051 PAGENO="0278" presents an important hazard to the raw-milk consumer. This hazard is magnified when the consumer has less resistance to infection because of age or underlying disease. The promotion of raw milk as pro- viding major health benefits beyond those of pasteurized milk has not been supported by the evidence. In contrast, the hazards of raw milk have been proved. Sale of raw milk, however, is still permitted. Physi- clans and other health professionals must be aware of the facts concerning risks and benefits from raw milk to better advise patients who have ques- tions about the safety and benefits of raw milk consumption. 1. Mograde,- GL: Faethze obseeo'atiooccn the milk mpply of Washington, DC. JA.'cIA 1910; 55:501-509. 2. Kelley ER, Osboen OH: Faether zoidenceos to the eclotice impoelasce of milk infection in the tranomissios of cortais commocicooble dis- easescf not. Am JPsblic Hmolth 1920;1O:O6-73. 3. Kon OK: Noteitianal effects on milk of chemical additions atd peocesning, in Fcflh Iolcc-notionool Coegn-coo on A'atvilimc. Wonhiocg. Ion, D.C Washington, DC, Food and Agcicaltore Orgotizalio,c, 1960, PP1.0 4. Koo SE: Milk ond Milk Pc'odscl, in Hsmonc N,alc'itimo, FAD Noteitionol Stodie, 27. Rome, Food otd Agc-icaltac'e Oegasicatiso, United Nations, 1972. 5. Graham 051: Alteeotios of cotnitine colon rzsolting from peoceosing and fortitcalios off milk ttd milk pc-odacts. J Doic'y Sci 1974; 57:739-745. 6. Poltesgee PSI Je: Effect of heat-peoceosed foods and metakoliced nitamin D milk on de,ctn- facial steoctaees of enpceimeotol animal,. Am J Oc'lhod l946;30467-405. 7. Wilson GO: The Paclcsc-iaolionc of Milk. London, Batlee & Tassee LId, 1942. 0. Tayloe DN, Bizd JM, Macno JO, zt al: Salmonella dcaklis itfectiost in the United Slates, 1979-1980. J Infccl Dio 1902;140:322-327. 9. Small RD. Sharp JCM: A milk-hoenc not- heeak doe to Salmonella doblino. J Hog Cam- hnidgc 1979;82:95.lOO. IS. Schrcedce SA: \Vhat the canitaniaco ,koold ksna: aboat salmonella, end staphylococci it milk and milk peodacls. J Milk Fond Tech 1907;3l:370-300. 11. Keogh BP: The seminal nf pathogens in cheese and milk ponnd,c'. J Dairy Rca 1971; 30:91-111. 12. Collins RN, Teegee MD, Galdsby JB, ct al: Interstate nolbezok nf Salmonella ncnaln'nnma'ick infection traced to ponndcred milk. JAMA 1968; 203:839-844. 13. Fn,ctaine RE, Cohen ML, Mactic \VT, ct oh Epidemic salnonneIlasis from cheddar cheese: Sac'neillance and peenention. Am J Epidcmiol 1980;lll:247-253. 14. Marth EH: Salmonellac and salmoncllonis asnociatedocithmilkandmilkpeodacts.JDoic'y Sci 1969;52:283-315. 15. Gibson EA: An natkeeak nf So.lmnnclla dnklin infeetinn in goat,. Vet Roe 1957;69:102l- 1028. 16. Balgis MO, Andee,oc, BC: Salmnnellonio in goatn. JAm Vol McdAccoc 1981;178:720-723. 17. werner on, Homphrey GL, Kamci 1: A,en- ciatios betoneen eon milk and haman Salmonella dshlinc infection. Be' MedJ 1979;2:238-241. 10. Blaner MA, Feldman BA: Salmonella bade- remia: Repents to the C,ntees fne Disease Con- trnl, 1968-1979. J Infect Din 1901;l43:743-746. 19. Salmonella dnblin associated oith moon milk: Wa,hingtcn Stat,. MMWR 1901;30:373- 374. 20. Fierce J: Innasine Salmonella dcahlio infec- tiaccostoeioted nilh deinking ran milk. Weal J Med 1983;138:665-609. 21. Oregon Diaioion of Health: Rose milk associated ,almonella catbeeak in noetheonteen Oeegnn. Cmnmnnicable Dis Sammac-y 1903; 301-2. 22. Vcgt RL, Hokey A, Allen J: Solmasello cnlccitidio sceotype decOy and consamptins nO References roan milk. J Infect Dia 1981;l44:608. 23. Salmanellnois associated nnith ran milk: Montana. MAfWR l981;30:2ll-2l2. 24. Sebmid GP, Schaefsr R, Ochaefee J, at al: Haman canopylabacteriasis in a mediam-ai,ed lona city, abstracted, in S3cd Intccscicnec Con- fcccnec moAntimicc'obialAgcntc and Chcmoihcc- a~. Woshicgtnn, DC, American Society fne Miceohiology, 1903, p 160. 25. Taylor DN, Porter BW, Williams CA, sI al: Campylobaclcc esteritis: A large oothecak traced In commercial cane milk. Wool J Med 1182;137:36l-369. 26. Taylor RP, Weinstein WM, Bryser JH: Campyloboetce felon isfzction is hamas oak' jectn Association milk eon' milk. Am J Med 1979;66:779-783. 27. Blasee MJ, Crao-ecn J, Poe-set BW, cI al: Campyiaboclcc enteritis aasnciated milk ocpas- tcaeined milk. Am JMcd 1979;67:715-7l8. 20. Pntler ME, Blasce MA, likes RK, cl ci: Homan Compylaboctce- infection asoocioted milk ccelified man milk. Am JEpida'miall9O3;117:475- 403. 29. Onthecak nf Compylahoclce enteeltis ciated milk ran' milk: Kastan. MMWR 1981; 35:218-225. 30. Maine Dept nf Haman Sernicet: Boos' milk and hamas gaotrointeotinal disease: Petblemo implicated onith lbs lcgalincd cole nf eeetified ram milk. Epi-Gcam, December 1981, pp 1-2. 31. Baa-milk atsociated illneno: Oeegos. MMWR 1901;30:90-97. 32. Campylobacteriotio associated onith ran' milk conoamptias: Pennsylnasia. MMWR 1903; 35337-344. 33. Riemann HP, Mcycc ME, Theio JH, et al: Tonnplssmnois in an infant fed aspotteac-ised gtat milk. JPcdiolc 1975;87:573-576. 34. Sacks JJ, Rnbeeln RB, Bennks NP: Toon- planmtoio infectio,c annaciated a-ilk ran' goat's milk. JAMA 1902;248:1728-1732. 35. Pane OlD, Kaofma,cn AP: Bmocellaoio in 1hz United Staten, 1965-1974. J Infect Din 1977; 136:312-316. 36. Ynong EJ, Oanacnnpacest U: Beacellaoio aatbreak attriboted Is ingestiaso of onpootear- med goat cheese. Aech 184cc-n Med 1975;135:240- 243. 37. Echman MR: Broecllosio linked In Mesican cheene. JAMA 1975;232:636-637. 30. Gilbert DL, Dannrcn RA, Cale ME, et ol: Midleimeoter aboelios assnciated milk septice. mia canoed by Compylabactccjcjsni. McdJAsnt 1981;t:585-586. 39. Geesikona M, Sckeyona M, Stopalona 5, et al: Sheep milk-koenc epidemic of tick-bores znecphalilio in Slanakia. Intcs'nicalogy 1975;5:57- 61. 40.HajekV:IdentiScationtfsnteeatotigettic otaphylacncci fcnm oheep and theep ehecoz. Appl Entcicccn Mieecbial 1978;35:264-26S. 41. Ontarit Mini,tey of Heallb: Snspccted eon milk-aotaciated eampylnbacterioois: Beitish Co- lombia. Coo Din Wcckly Rep 5903;9-1h73-75. 42. While FMM, SleCarthy ME: Race milk asd health in hama,on. Con Mcd Aaam 1 1982; 120:1260-1262. 43. Jnnes PH, Willis AT, Robinntn DA, c-I al: Campylnbactee enteeitis ansacialed cnilh thecon- samplino nf fete schtol milk. 1 Hyg Combn-idgc 1981;87:I55-162. 44. Galbraith NO, Focbco P. Cliffnrd C: Cam- monicable dioeasc aottciatcd n'ith milk and dairy prndacln ist England and Wales 1951.80. Bc Med 1 1982;248:1761.1765. 45, Cnhcn DR. Fcc-tee IA, Reid TMO, c-I al: A cost benefit tlady nf milk-b orne salmonelltsil. 1 Hyg Camhcidge 1983;9l:t7-23. 46. Janet DM, Rnbinlnn DA, Eldridgn J: Ocea- Ingical stadien in too aatbreako of Campylakae- lee jejsni infection. 1 Hog Csmbcidge 1981; 07:163-170. 47. Rabinoos DA, Jones DM: Milk-banne Com- pyloboetce infectios. Bc Med 1 1981;28S:1374- 1376. 48. Hobbs BC, Roan B, Kendall M, c-I al: Eachecichia coli 027 in adolt diaeehea. 1 Mpg Combcidgc 1976;77:393-400. 49. Marier R, Wells AG, On-anson BC, c-I at: An natbreah nf enteenpalbogenic Eaehcciehia cali foodbaenn disease teaced to inpoeted Fmesch cheete. Lanect 1973;21376-S378. 50. Johnnttn DW, Ssoee A, Hill A: Incidence nf antibintic-ceointanl Eochceichia cali in milk pcI- daced in the osest of Scatland.JApplBoclcn-ial 19S3;54:77-83. 51. Dijkotra RG: Isnestigatians as the name-in- times nO Listecio baclceia in soopcntion nf beam tissac, silage and feces and in milk. Zestcolbl Bahtcciol 197S;21O:02-95. 52. Hall RP: Infectioos aboetiono in Campend Ccntio Ed 1902;4:216-221. 53. Gray ML, Killinger AH: Listecio ctanmy- ago-coca and litlec-ic isfentinns. Rcelcnal Ret, 1966;3h309-382. 54. Kalio F, LcPmoeh JL, Smith W, et al: Liotcmoois. Am J Med Sci 1976;271:159-169. 51. Klncbaeg HH: Tobarcolonis and nther snycnbacoeeinoio, in Habbeet WT, MeCollack VIP, Ochnorresberger PR lcds): Diacasco Tconnmitted Fcam Animoln to Man, ed 6. SpeingOnld, Ill, Chaeleo C Thamaa Pablinher, 1975, p 315. 56. Malhin BM, Langley J: Banine toheecolonin in an Ariznna daiey bend. JAm Vet Med Ascae t981;175:141-142. 57. Goldbeeger AC, Liptky BA, Plnrdc JJ: Sappaeatine grostolomatoat lymphodenitis caaned by Cacysebactecitam ania(pseadalabec-eo. loom). Am 1 Clin Pathal 198t;76:486-490. 58. Pac-ry WH: Milk-boene diseasen. Laneet 1960;0216-219. 59. Baenham M, Thtmnton TJ, Lnnge K: Nephritit eaoncd by Slceptmneeon eonepidecni- (Loncefield genap C). Lnncct 1903;1:945-948. 60. Gmoop C olreplncoccal infectians assnci- sled ocith eating homemade cheese: Neon' Menien. MMWR 1983;3051O-51f. 61. Place EH, Sottts LE: Erythema aelbeit- icaco epidemicam (Heneehill fener). Acch Intone Mcd 5934;54:659.604. 62. Vanteappen G, Agg HO, Geboes K, et al: Yeccinia estnritis. Med Clis Nocth Am 1902; 66:639-653. 63. Blank RE: Yeeoiniosis, in LasI JM (ed): Mancy-Roocnos Public Health and Pcecenolinc Medicine, ad 11. Neon Ynek, Appletto-Ccnlas-y- Ceofto, 1980, chap 9, pp456-457. 64. Schinmann DA: Association nf Yecoistia entcn-ocolitieo ns'ith Ike manofactsee tf cheese and nceaec-aneeinpanleocincdmilk.ApplEnci- con Miccoleicl 197S;3k274-277. 65. Health and Welfaec Canada: Yeccinia enlecocolitica gassecentemitis natbmeah: Mtn- Ic-cal. Con Din Weekly Rep 1970,073-74. 2052 JAMA, Ont 19, 1984-Vol 252, No. 15 Unpastnamiznd Milk-Patter cot at 272 Peiteled and Published in he United States a! dmee:ca PAGENO="0279" 273 STATEMENT OF EVELYN B. BINZ The following is an answer to the article in the summer 1984 Public Citi- zen criticizing the U.S. Dept of Health and Human Services for stalling on a proposal to ban the Bale of raw milk. j There has been a decline in the consumption of milk in recent decades, but raw milk use increased for a time. Government health officials favor the large dairies which sell only pasteurized and homogenized milk, bought from many different farms. They are overly strict in inspecting raw milk, a con- venient object of official zeal,-getting rid of all that disease caused by raw milk, they tell us. But there are few if any really verified serious or fatal cases of illness from raw milk sanitarily- produced. - 2 Raw milk is more digestible than pasteurized bebause the nutrients are unchanged by heat. Vitamin C is retained and milk sugar is not carmelized,etc. Homogenization changes the milk physically and chemically. The fat globulem are fractionalized to distribute the cream evenly through the milk and an en- zyme is produced, xanthine oxidase. Some scientists think that these changes may irritate the lining of the blood vessels and cause the deposit of a pro- tective layer of cholesterol plaque. 3 Many users of raw milk choose it for health reasons. 4 Some doctors are ignorant of the value of raw milk nutrionally, and some may find it convenient to blame its use for-their treatment failures, ~ Pasteurization does lessen the danger of disease from unclean practices when milk is collected from many sources, but Alta Dena uses the milk only from their own healthy, tested cows. Milk from the family cow, the world over, is not boiled or even parboiled. It is known to be unharmful even though raw. Animals given a choice between raw and pasteurized milk select the raw. Boiled milk because it is considered constipating Is sometimes used as a cure for diarrhea. ~ The organism Salmonella dublin occui~s commonly in air and can easily be passed to unprotected milk by a cough or'~ven rubbing the hands over the speci- men being analyzed and allowing time for i~ncubation. A health food such as raw, natural milk, produced under the standards of Alta Dena Dairies should not be banned except on incontrovertible evidence of serious illness caused by it and this has not occurred. Raw milk sours naturally and is a healthful food; it does not putrefy as heated milk does. Only in raw milk does milk's lactic acid have bacteriostatic powers; it kills bacteria if 2~~ive~ ~ . - PAGENO="0280" PAGENO="0281" EMERGENCY REYE'S SYNDROME PREVENTION ACT OF 1985 FRIDAY, MARCH 15, 1985 HOUSE OF REPRESENTATIVES, COMMITTEE ON ENERGY AND COMMERCE, SUBCOMMITTEE ON HEALTH AND THE ENVIRONMENT, Washington, DC. The subcommittee met, pursuant to notice, at 10 a.m., in room 2322, Rayburn House Office Building, Hon. Henry A. Waxman (chairman) presiding. Mr. WAXMAN. Today we are considering the "Emergency Reye's Syndrome Prevention Act of 1985." We are also examining the ade- quacy of steps taken by the Department of Health and Human Services and the aspirin industry in the past few months to alert the public to the possible dangers associated with the use of aspirin during certain childhood diseases. This hearing deals with a very serious disease-a deadly illness that strikes down hundreds of perfectly healthy children each year. This tragedy is made all the worse by the fact that this disease might be preventable. The public needs to know whether every pos- sible precaution is being taken to spare families the agony of need- lessly losing a child. Reye's Syndrome mainly strikes children up to 19 years of age. It is often fatal and may produce brain damage when the victim lives. It typically follows chickenpox or influenza, both of which increase during the winter months. Just when children seem to be recover- ing from those illnesses, they may suddenly get desperately ill and lapse into a coma with Reye s Syndrome. For several years, a growing body of scientific evidence has sug- gested that the use of aspirin is associated with Reye's Syndrome. Nearly 3 years ago the evidence was strong enough to lead a tech- nical committee of the American Academy of Pediatrics to con- clude that there is a high probability that the administration of as- pirin contributes to the causation of Reye's Syndrome. That committee recommended that aspirin not be prescribed for children with influenza or chickenpox and called on the govern- ment and aspirin manufacturers to inform the public of the rela- tionship with Reye's Syndrome. Earlier this year, the Institute of Medicine reviewed new data from a Public Health Service pilot study and once again found a strong association between Reye's Syndrome and the use of aspirin. They recommended that steps be taken to protect the public health even before the full study is completed. (275) PAGENO="0282" 276 Shortly thereafter, Secretary Heckler announced that the De- partment would pursue a voluntary approach. She asked the aspi- rin industry to put warning labels on aspirin products. She raised high hopes that industry compliance would be rapid and effective. When the Secretary announced the voluntary program, we ex- pressed the concern that unnecessary delays or noncompliance could be fatal to many children and young adults. On January 11, we requested that the Secretary report back to the subcommittee by today on specific aspects of the voluntary program. From information that has been made available to the subcom- mittee thus far it appears that this voluntary effort is failing on four counts: 1. The labels that have been negotiated are inadequate and vague. They do not mention Reye's Syndrome and only suggest that parents consult a physician before using aspirin for children with chickenpox or flu; 2. Little consideration was given to assuring that the label was displayed in a prominent format clearly visible to consumers; 3. With the possible exception of one manufacturer, the labels will not appear on aspirin bottles until after the current flu season; and 4. Not all of the industry is even represented in the negotiations on voluntary labeling. The scientific evidence for the link between aspirin and Reye's Syndrome is strong and consistent. But we are all aware that all studies have their limitations. The recently released pilot study is just that, a pilot study for a larger study that should proceed. The scientific evidence, however, is not at issue here. The Secretary of Health and Human Services has determined that the scientific evi- dence calls for protective action now. She has announced that pre- ventive action should not be delayed until the larger study is com- pleted. More and more studies may lead to better decisions. But some scientific questions may never be resolved to everyone's satisfac- tion. We know there are still people who are willing to dispute the link between cigarettes and lung cancer. When a threat to the pub- lic's health might exist, public officials must decide when to act. The Secretary has made that decision. What is of concern to this subcommittee is whether the Depart- ment and the aspirin industry have done enough to protect the public from this fearsome disease. If the problem is Reye's Syn- drome, why not say so on the label? If the problem is aspirin, why not require the warning on all aspirin products? If the problem is influenza, why ignore the current flu season? The Emergency Reye's Syndrome Prevention Act would take steps that might well have been ordered by the Department of Health and Human Services in January, or perhaps even years ago. A clear warning would be required on all aspirin products, along with an eye-catching logo that will attract people to actually read the label. All advertisements would have to contain the same warning. Fortunately, this terrible s~yndrome is rare. But that is no conso- lation to parents who didn t know that giving aspirin to their young child could be deadly. Nor is it any consolation to families PAGENO="0283" 277 with a teenager who dIed or suffered brain damage because there was no obvious warning on the aspirin bottle. The National Reye's Syndrome Foundation tells us that six chil- dren died of Reye's Syndrome in the first 2 months of this year. Even one unnecessary death is too many. Children cannot protect themselves. Parents cannot protect their children from dangers they know nothing about. If the Department of Health and Human Services can identify risks but then is unwilling or unable to take strong enough measures, the Congress must act. We look forward to discussing these questions with our witnesses today. [The text of H.R. 1381 follows:] PAGENO="0284" 278 99TH CONGRESS 1ST SESSION * * To amend the Federal Food, Drug, and Cosmetic Act to provide for warnings concerning the use by children of drugs containing aspirin, and for other purposes. IN TIlE HOUSE OF REPRESENTATIVES FEBRUARY 28, 1985 Mr. WAXMAN introduced the following bill; which was referred to the Committee on Energy and Commerce ABILL To amend the Federal Food, Drug, and Cosmetic Act to pro- vide for warnings concerning the use by children of drugs containing aspirin, and for other purposes. 1 Be it enacted b?J the Senate and House of Representa- 2 tives of the United States of America in Congress assembled, 3 SECTION 1. SHORT TITLES 4 This Act may be cited as the "Emergency Reye's Syn- 5 drome Prevention Act of 1985". 6 SEC. 2. ASPIRIN WARNING. 7 Section 502 of the Federal Food, Drug, and Cosmetic 8 Act is amended by adding at the end thereof the following: 9 "(u) During the period beginning upon the expiration of 10 30 days after the date of the enactment of this paragraph and PAGENO="0285" 279 2 1 ending on the date the requirements of paragraph (v) take 2 effect, if it is a drug which contains a salicylate unless the 3 container in which it is sold at retail bears the statement 4 prescribed by paragraph (v)(1)(A) and unless each retail es- 5 tablishment at which it is offered for sale displays prominent- 6 ly, where the drug is held for sale, a notice containing such 7 statement. 8. "(v)(1) If it is a drug which contains a salicylate unless 9 in accordance with paragraph (2)- 10 "(A) its labeling contains the following statement: 11 `WARNING: This product should not be given to indi- 12 viduals under the age of 21 years who have chicken 13 pox, influenza, or flu symptoms. This product contains 14 aspirin or another salicylate which has been strongly 15 associated with the development of Reye's Syndrome, 16 a serious and often fatal childhood disease.'; and 17 "(B) the manufacturer, packer, or distributor (in- 18 cluding all retail establishments) thereof includes in all 19 advertisements and other printed and descriptive 20 matter issued or caused to be issued by the manufac- 21 turer, packer, or distributor with respect to any drug 22 which contains a salicylate the statement required by 23 clause (A). PAGENO="0286" 280 3 1 "(2)(A) The statement required by subparagraph (1)(A) 2 shall be in the following form: WARNING: This product should not be given to individuals under the age of 21 years who have chicken pox, influenza, or flu symptoms. This product contains aspirin or another salicylate which has been strongly associated with the development of Reye's Syndrome, a serious and often fatal childhood disease. 3 "(B) In the label required by clause (A), the arrow shall 4 be printed in yellow and the circle shall be printed in red. 5 "(3) The Secretary shall promulgate such regulations as 6 may be necessary to implement the requirements of subpara- 7 graphs (1) and (2).". 8 SEC. 3. REGULATION DATE. 9 The Secretary of Health and Human Services shall pro- 10 mulgate the regulations required by section 502(v)(3) of the 11 Federal Food, Drug, and Cosmetic Act not later than 180 12 days after the date of the enactment of this Act. PAGENO="0287" 281 Mr. WAXMAN. Before I call on our very distinguished first wit- ness, a Member of the U.S. Senate, I want to recognize Congress- man Wyden for any opening comments he wishes to make. Mr. WYDEN. Thank you very much, Mr. Chairman. I want to commend you for your outstanding work in this area, particularly in protecting the young people of this country. It seems to me what we face here is a very clear case of foot-dragging on the part of Public Health Service and the Food and Drug Ad- ministration. It seems to me that they have essentially written off the current flu season that is just ending. The reason these hearings are so important is that we need to make sure that steps are taken so we don't miss the boat on yet another flu season. There is no question about the scientific evi- dence in this area. The evidence is crystal clear that there is a link between Reye's Syndrome and aspirin and that the public needs to be protected. During the course of this hearing we need to identify the bottlenecks within the Department, within the Public Health Service, and the Food and Drug Administration that are prevent- ing critical information about the health risks from aspirin from actually reaching the public. So I am very appreciative of Chair- man Waxman's leadership in this area, and look forward to our im- portant hearings. Thank you, Mr. Chairman. Mr. WAXMAN. Thank you, Mr. Wyden. We are pleased to recognize a new member of our subcommittee. We are delighted that he is a member of the subcommittee and with us today, Congressman Bates. If you have an opening state- ment, you may present it now. If not, we are just pleased to have you with us. Mr. BATES. No, Mr. Chairman. I am just here to gain some in- sight into this problem. Thank you. Mr. WAXMAN. Not a new member but a distinguished and long- term member of the subcommittee, the gentleman from New York, Mr. Scheuer. I recognize him at this time. Mr. SCHEURER. No statement, Mr. Chairman. Mr. WAXMAN. Thank you very much. Senator Metzenbaum is the author of the Emergency Reye's Syn- drome Act of 1985 in the Senate. Senator, we are delighted you have come to our subcommittee to present testimony in support of this legislation. This is another example of your leadership in the area of consumer protection and recognition of the need for govern- ment to intervene to protect the public health. We are pleased to welcome you at this time. STATEMENT OF HON. HOWARD H. METZENBAUM, A U.S. SENATOR FROM THE STATE OF OHIO Senator METZENBAUM. I am very delighted to appear before your committee and I am frank to admit to you that each morning before I drink my orange juice I say: Isn't the country fortunate that Henry Waxman is the chairman of the Subcommittee on Health and Environment. I do that each morning. Mr. WAXMAN. What is in that orange juice? PAGENO="0288" 282 Mr. WYDEN. And your other meals as well, right? Senator METZENBAUM. That is right. And of course it's a fact, and of course I say it first facetiously but it is a fact that I think the country is fortunate. Mr. WAXMAN. It isn't true? Senator METZENBAUM. The country is fortunate that you have stepped forward on so many health issues and been willing to pro- vide the leadership that is needed in order to legislatively act when so many others would be willing to drag their feet, and to think about it, appoint commissions or committees to make further stud- ies. Here we have a situation where we know the problem. Reye's Syndrome is linked with aspirin as far as children are concerned, if they take it when they have chickenpox or influenza. It is indispu- table. The facts are there. Now, in connection with some health matters, we don't know the answer, and if we knew the answer, it would be such a bonanza as far as the health aspects of this country are concerned, of cancer, heart ailments that occur. We don't always have the answer. It is a high percentage. What we would give to find an answer for that at the present time. But in connection with Reye's Syndrome, we know that the ingestion of aspirin by children when they have chickenpox or in- fluenza does have the potential to harm the children. That is irrefutable, and we can prevent it, so why not. We are not saying ban the sale of aspirin. We are saying make the parent aware of the risk. Tell the parent with a label that highlights it in color, and says what the problem is. Now, the Secretary and the industry have worked out a volun- tary kind of agreement, but that is not good enough. The child is ill. The child is crying. The bottle of aspirin is there, and the parent sees on the bottle "Consult your physician first." The parent says: "I can't reach the doctor. It is two o'clock in the morn- ing. He doesn't want me to call. And besides, this afternoon I un- derstand he plays golf, and that is his privilege." But the fact is the baby is hurting. So the parent says: "Well, it won't hurt that much. I'll just give him or her two aspirins." That is not an adequate answer. That is begging the question, be- cause if the doctor says what the doctor should say, the doctor is going to say "don't give the child the aspirin." So why not put it on the label? We have got to make the warning strong. We have got to make it specific, and if I am not mistaken, Mr. Chairman, this may be the first instance in which legislators, you, I and the others who have joined with us, have ever proposed in legislation that you even have to have the color on the label indicating so that it is not just lost in the black and white, but it has the yellow and the red to highlight it, so that the parent won't miss it. We have seen that voluntary cooperation doesn't work. They tried it with infant formula, legislation that I was involved in and you supported, and it didn't work there. We have seen it with re- spect to food labeling, and it hasn't worked. You buy almost any product today and you can't find out what you are getting in that product. PAGENO="0289" 283 Knowing what we know, how can we be satisfied until we are sure that we are doing everything possible to protect the children? Now, the FDA will say, as I understand it, the evidence is not complete. They want to see what the results are with respect to voluntary participation. I would say as the grandparent of two little children that I love very dearly, or as the parent of any other child, why expose that child to any risk at all, if there is no need to do so? Children of America are exposed to enough risks at the present time without exposing them to something that we know is danger- ous. Some risks we can't do anything about. This is something we can do something about, and I believe, Mr. Chairman, that the speed with which you have moved forward in connection with this hearing indicates that you are not going to do wnat so many others would like us in the Congress to do, and that is to dance around the issue, to play the music, to orchestrate the issue, but not to act decisively. And I say to you that I will use every ounce of strength and pressure and persuasiveness that I have as far as moving this matter forward in the U.S. Senate, and I feel confident that you are going to be successful in your endeavor in the House. I congratulate you upon it, and pledge you my total cooperation. Thank you, Mr. Chairman. Mr. WAXMAN. Thank you very much, Senator Metzenbaum. I ap- preciate the testimony you have given, because I was astounded at this voluntary agreement that the Secretary negotiated. First of all, not all the aspirin companies were even part of the negotia- tions, so some may not even go along with what she worked out. She decided there is a public health threat and the public should be informed about this connection between aspirin and Reye's Syn- drome. But then she wants to have on the labels-and probably not even until next year-just call your doctor when you are about to use the aspirin for flu. That is what most people think aspirin is for, relief of symptoms of flu. And then think of children who will self-medicate-they don't re- alize we are talking about up to 19 years of age-that seems to me about the most inadequate kind of warning label possible. Volun- tary efforts aren't bad, but it looks like the voluntary effort here was one where they agreed to put this label on, and not give her trouble, because the industry seems to know how ineffective that label would be. Then, of course, what disturbs me is this is March. The flu season, December, January, February, March, maybe into April, we have so little time to warn people for this year, and already a handful of children who otherwise should have been able to have this illness prevented have already died. Maybe this hearing will reach some families, because I don't think the warning label the Secretary negotiated will, but we have got to move legislation. Voluntary efforts are fine if they work, but voluntary efforts that don't have the chance of really reaching the public are meaning- less. Therefore I think as you do, I know, that Congress must pass a law stating the logo, the warning, the kind of campaign that has a chance to inform the public about the danger of a disease that might be prevented if parents would know not to use aspirin for their children for those symptoms. 52-266 0-85--b PAGENO="0290" 284 Senator METZENBAUM. Mr. Chairman, the evidence is so over- whelming that it shouldn't be done, and yet I know that you will have appearing before you this morning representatives of the in- dustry and other spokespersons who will come forward to indicate that we should not act, and that we ought to let the voluntary pro- cedures prevail. I would hope that you would ask-if not on your own behalf on my behalf-if you had a child or you have a child, `r a grandchild, would you be willing to give that child or grandchild aspirin at the time of influenza or chickenpox. And if you wouldn't be willing to do that, how can you as an industry representative or public offi- cial not do everything possible to see that no other child or grand- child takes aspirin into their stomachs at the time they have chick- enpox or influenza. What bothers me is why the industry isn't here saying you don't need legislation; we will do it. You are right. Why they are using that kind of political maneuvering to do it on a voluntary basis, are we going to affect their sales-yeah-much? So what? So what? Maybe if we had some malpractice suits or lawsuits that frightened them as happened in so many other arenas, maybe that would be a deterrent. But what bothers me is that here is a known problem, not just a fictitious one, not one that is a figment of the imagination, and if it is a known problem why don't they do something about it and why do we have to use our efforts to pass legislation to force them to do something that they should be doing on their own. Thank you. Mr. WAXMAN. Thank you very much. Mr. Wyden. Mr. WYDEN. Thank you, Mr. Chairman. Just one very quick question, Senator, and I appreciate your ex- cellent statement. It seems to me that what you have said is that this problem is one of political judgments. The scientific evidence is very clear. This isn't a question of not being able to go forward be- cause of budget cuts. What has happened is the Department has made a political judgment not to go forward with an aggressive program. That is why kids are getting hurt. It is politics pure and simple. Senator METZENBAUM. I think that is correct, because I know of no reason. If there was some legitimate reason not to go forward, not to slam the door shut, then I could be sympatico. I could under- stand it. But in this instance it seems to me that for some reason somebody has been able to sell a bill of goods that is the wrong bill of goods, and I think the critical question is: Would you be willing to let your children or grandchildren ingest aspirin at the time of chickenpox or flu? And, if not, then why would you as a public offi- cial or an industry spokesperson sit here and argue against this mandatory matter? Mr. WAXMAN. Thank you. Mr. Bates. Mr. BATES. No comment. Mr. WAXMAN. Mr. Scheuer. Mr. SCHEURER. I just want to thank the distinguished Senator from Ohio for coming here. He can always be counted upon not only for wisdom and insight and high order of intellectual acumen, but sheer unadulterated guts, and that is frequently a scarce com- modity in these precincts. We appreciate your coming. PAGENO="0291" 285 Senator METZENBAUM. Coming from you, Mr. Scheuer, I appreci- ate it very much. Thank you very much. Mr. WAXMAN. Thank you very much, Senator. I would now like to call forward four sets of witnesses to come and testify as a panel. First, John and Terry Freudenberger, presi- dent of the National Reye's Syndrome Foundation; Dr. Joel M. Taubin, vice president of the National Reye's Syndrome Founda- tion; George and Diane Dumigan from New Haven, CT; Jimmy and Gail Happle from Florence, SC. Will you all come forward and please take seats up here. We want to welcome you to this hearing today. We appreciate your being with us. We want to hear from each of you very briefly on the problem. It would be appropriate to start with Dr. Taubin. STATEMENTS OF JOEL M. TAUBIN, M.D., VICE PRESIDENT, NA- TIONAL REYE'S SYNDROME FOUNDATION; JOHN E. AND TERRY FREUDENBERGER, PRESIDENT, (NRSF); JIMMY AND GAIL HAPPLE, FLORENCE, SC; AND GEORGE AND DIANE DUMIGAN, NEW HAVEN, CT Dr. TAUBIN. Thank you, Congressman Waxman. We are all here for really one purpose because we care and we all in one way have been touched by a loss or an ailment affecting our children or child with it. There is no question that we have been searching and trying to understand why our child died. Greg was age 11, in 1978 had chickenpox. We didn't think much about it. He developed the symptoms of chickenpox, and the rash started to improve. He had the muscle aches, the headache, the rash. Our physician said watch him, give him some fluids. He had some headaches, low-grade fever, and, as you say, we reached for the aspirin bottle. We gave him aspirin at that time, and within 24 to 48 hours he developed all the classic symptoms, which I didn't recognize at that time, of Reye's Syndrome. The illness lasted for 2 weeks in the in- tensive care unit. It was so intensive that my wife Sonya and I stayed there for 2 weeks. I remember back in medical school, going to a grand round of medical lectures on Reye's Syndrome, being told at that time by the department of pediatrics it is such a rare disease I will prob- ably never see it. I didn't see it until it happened to my son, and I am certainly well aware of it now. Since then, as a very active member of the Reye's Foundation trying to get the awareness through what the disease is, the symptoms, and always search and say what happened, what did we give Gregory? Was it something in our house, our environment? Was it something in my body, would my other daughter at that time develop the same thing, never knowing until the past several years that the association and now the real association with a drug that is so common-it is a good drug, we use it in other forms of medicine, but it is so common that everyone takes it for headaches, for playing sports, for nervous tension. Before a meeting like this you may take four aspirin sort of with- out thinking, and certainly no one really calls their physician and says, "Do I need a prescription?" You don't need one. Everyone has it on their shelf, everyone has it in their drawer in the office, and PAGENO="0292" 286 take aspirin. So we keep searching, keeping looking. And now we found something, something when you say: Gee, we gave it to our son, can we stop another parent from losing children. Is there any- thing that can prevent or inhibit this dreaded disease. And it is an intensive disease. The child is well, absolutely well, playing sports, doing well in school, and develops a routine flu or a virus or chickenpox. You worry a little bit about it, but then it goes on to its devastating dis- ease. Within .24 hours the child is in a coma. Arid it is devastating to lose a child. There is nothing worse, ever, than having a healthi child die of some disease. And even worse, if you kno* it may be preventable. The question, and the reason we are here, is to help support this legislation and to make awareness, not the physician, they should know about it now. It is in the journals now. It is given throughout the conferences. The residents at our hospitals now are aware of it, emergency room doctors are aware of it. Even the parents are becoming aware of it now. They are saying: I want to give him something else. I know I heard, but I know something about aspirin. What about the parents that don't know something about it or the parents on a weekend or an evening, maybe a 19-year-old who may be in college, may not have had a parent around; he may de- velop some symptoms and take some aspirin off the shelf. No pre- scription needed with that. How can we stop it? We have got to look for something with this. I think the question that was raised here today, and I asked the members of the other foundations, the Aspirin Foundation or the aspirin companies, would they give their child or grandchild or a child of any kind aspirin. And I can't imagine one of them saying: I have no problems. I give him aspirin. I just can't imagine somebody coming before this committee or coming to me personally face to face and saying: I have no problem with that. The statistics aren't really in, and I have no fear about giving them aspirin. If they do that, then they can sit at this table. I appreciate the efforts. I strongly urge the members of this com- mittee and everyone here to think twice and say we have got to make some effort and stop it here. Thank you. Mr. WAXMAN. Thank you very much. Mrs. Taubin, did you want to add anything? Mrs. TAUBIN. No, thank you. Mr. WAXMAN. Mr. Freudenberger. STATEMENT OF JOHN E. AND TERRY FREUDENBERGER Mr. FREUDENBERGER. Mr. Chairman and committee members, I want to preface my statement by saying thank you. From the bottom of my heart, I appreciate the time you are spending to help solve the problems associated with Reye's Syndrome. I am here today as a parent of a child who was killed by Reye's Syndrome. I am also here as the founder and president of the National Reye's Syndrome Foundation. But most of all, I am here to represent the children of this country. PAGENO="0293" 287 The cause of my concerns may be that little bottle of children's aspirin that was always in our medicine cabinet at home. That little bottle of aspirin may be the reason that our daughter Tiffinni died in 1973. I have been fighting Reye's Syndrome for the past 12 years by building the National Reye's Syndrome Foundation~ Brief- ly, the foundation is made up of 130 chapters located in 40 States. We raise and provide moneys for two purposes: One, to save lives through increased awareness, and number two, to eliminate Reye's Syndrome as a medical problem through research. The foundation started as an all-volunteer organization of par- ents, and has grown to the extent that we now need a paid staff to maintain the day-to-day operations. The fight against Reye's Syn- drome has been plagued by mistakes and misinformation. In the very beginning someone gave Reye's Syndrome the label "rare." Now everyone including members of the media call Reye's Syn- drome "rare." Even the Surgeon General, in his public service announcement, is calling Reye's Syndrome rare. We are not dealing with a rare disease. We are dealing with a disease that struck 175 children in 1 year in Ohio alone. We are not recommending that people be warned of a disease that strikes rarely, but rather that they be warned of a disease that strikes all too frequently and often fatally. In 1974 the National Institute of Health also made a mistake that delayed recognition of Reye's Syndrome as a medical problem. They refused to allocate research moneys to Reye's Syndrome be- cause they didn't think that Reye's Syndrome was a significant medical problem. NIH no longer holds that view, but Reye's Syn- drome research was delayed for many years because of it. The study that implicated Reye's Syndrome was a mistake in planning. The only reason the study was conducted was because the Centers for Disease Control fiscal year was ending, and the CDC hadn't spent all of its allocated money. A quick phone call was made, an agreement reached, and within a month a Reye's Syndrome study was undertaken. The next mistake was made by the Food and Drug Administra- tion, when the Food and Drug Administration yielded to the aspi- rin manufacturers pressure and reversed its decision to label aspi- rin containing medicines. The aspirin manufacturers disputed the validity of the original study, and aggressively opposed labeling, to the extent that they even filed a lawsuit against FDA. In addition, they formed an organization that they called the Committee on the Care of Children, to give themselves an anony- mous and more credible platform to oppose aspirin's implications in Reye's Syndrome. The proposed legislation is trying to avoid yet another fatal mis- take. The conclusion that this committee must finally reach seems simple. First, all of the principals including the aspirin manufac- turers are in agreement that all aspirin medicines should be la- beled. All that needs to be decided is whether you want a clear, strong statement or whether you want to trust the judgment and the motives of the aspirin companies. If a mistake is to be made this time, I urge that that mistake be made on the side of caution and on the side of children. I urge that PAGENO="0294" 288 you recommend and support the proposed labeling legislation. Thank you. * [Testimony resumes on p. 306.]. Attachments to Mr. & Mrs. Freudenberger's prepared statement follow:] PAGENO="0295" 1979 - l98~ REPORTEb REyES SyNbROME CASES PAGENO="0296" PAGENO="0297" 291 198# RE~JE'S JNL~ROME CASES. REPORTEI) TN OBZO PAGENO="0298" 292 ttfi©Lu~ill Reye'~s Syndrome * ~ * ~ I "a disease that affects the liver and brain. I 426 N. Lewis, Bryan, OH 43506 419/636-2679 1984 SCHOOL AWARENESS CAMPAIGN In November of 1984, the National Reye's Syndrome Foundation, of Bryan, Ohio, sent copies of the `1984 School Awareness Bulletin" to over 16,000 school superintendents in the country. The superintendents were asked to make sure that each and every child in the school district took the information home. To date, the National Reye's Syndrome Foundation has received responses from across the country in regard to the information. The tabulation of the return post cards completed by school officials indicates that over 6,000,000 homes have received the information concerning Reye's Syndrome. The. national office has been inundated with telephone calls from parents across the United States whose children have brought the awareness bulletin home. They want additional information about the syndrome, or they have a sick child who needs prompt medical treatment. The general public wants accurate information and is frustrated by the fact that so little is known about Reye's Syndrome and is greatly concerned about the aspirin issue. PAGENO="0299" 293 ~dy rT~' I.., f,,,,,~ ~Jj BE WISE ABOUT REYE'S Lt~J® * AWARENESS BULLETIN The flu or various symptoms identified as influenza occur more frequently during the winter months. Influenza is a viral infection, and as such, warrants our special attention because a fatal children's disease is associated with it. The disease, Reye's Syndrome, affects children from infancy through adolescence and can develop 3 to 5 days after the onset of the chicken pox, an upper respiratory illness, or other viral infec- tions. It affects the liver and brain, is non-contagious and is often misdiagnosed as encephalitis, meningitis, diabetes, poisoning, drug overdose, or sudden infant death. After a viral infection has seemingly run its course and the child is feeling better the following symp- toms should be treated as serious and as possibly the first indication of Reye's Syndrome. Anti-nausea medication may mask the symptoms of the disease and because of the possible association of aspirin with Reye's Syndrome, parents should consult their physician before using these drugs. Watch for these symp- toms, usually occuring in this order: * PERSISTENT OR CONTINUOUS VOMITING * LISTLESSNESS (LOSS OF PEP AND ENERGY, DROWSINESS) * PERSONALITY CHANGE (SUCH AS IRRITABILITY, COMBATIVENESS OR SLURRED SPEECH) * DISORIENTATION (UNABLE TO IDENTIFY WHEREABOUTS, OR FAMILY MEMBERS) * DELIRIUM, CONVULSIONS A child's life can depend on ~ diagnosis. Reye's Syndrome should be suspected in any child with chicken pox who vomits repeatedly. Phone your physician immediately if these symptoms develop and tell him you suspect Reye's Syndrome. If your doctor is not available take your child to an emergency room promptly. Two liver function tests (SGOT/SGPT) can be done to determine the possibility of Reye's Syn- drome. There is a 90% chance of recovery when the syndrome is treated in its earliest stages by physicians and nurses experienced in the treatment of Reye's. Epidemiologic research has shown an association between the development of Reye's Syndrome and the use of aspirin for treating the symptoms of influenza-like illnesses, chicken pox, and colds. The U.S. Sur- geon General, the Food and Drug Administration, and the Centers for Disease Control recommend that aspirin and combination products containing aspirin not be given to children 18 years of age and under during episodes of these illnesses. The NRSF is a non-profit, tax-exempt organization with chapters in forty states. The NRSF has pioneered the movement to disseminate knowledge about the disease in an effort to aid in early diagnosis. and also provides funds for research into the cause, cure, care, treatment, and prevention of Reve's Syndrome. For more information contact the NATIONAL REYE'S SYNDROME FOUNDATION, P0. BOX 829AB, BRYAN, OHIO 43506, OR CALL 419/636-2679, 800/233-7393, OHIO RESIDENTS CALL 800/231-7393. 84.i5 copy,Ight ~i9S4 TOo Natlooot Rays's SyRO~oa,s Fo~nd~tio~, B,yan, Ohio 43506 PAGENO="0300" 294 WINTER 1984 Vol 8, No. 2 t~fi©ro~ll * `~ ~ - -~ ** P.O. Box 829 ________ Bryan, Ohio 43506 419-636-2679 CA disease that affects the liver avd brain ~©d~fi©r~ inthe~ CHILDREN HELPING CHILDREN THROUGH BALLOON LAUNCH Elementary school children in Leipsic, Ohio launch 1,000 helium filled balloons tagged with Reye's Syndrome information to kick off National Reye's Syndrome Week. PAGENO="0301" 295 PRESIDENTIAL NOTES Resolutions passed by the Senate and the House proclaimed November 12-18 as National Reye's Syndrome Week for 1984. Chapters across the country held special events, provided programs and disseminated Reye's Syndrome information. This has also helped to provide coverage of Reye's Syndrome in such publications as November issues of Women's Day and McCaHs. Recently we have been hearing about Reye's Syndrome on tel- evision shows such as "Good Morning America" and "Nightwatch." The new 800 telephone Hot Line is in operation at the national office! With funding from the Dana Wigutoff Mem- orial Foundation, the hot line was installed in the National Office in October. The toll-free telephone numbers will be included in all our updated brochures and the 1984 school "Awareness Bulletin." Once the number is in circulation, we expect to be inundated with telephone calls. Par- ents will now have the capability to call and have all of their questions answered at no charge to them. We are proud to be able to offer this service to the public and are deeply grateful for the grant to make the existence of the hot line possible. The national office has been quite busy the past few months. In addition to planning for the 800 hot line, and the usual flow of requests for information, the "1984 School Awareness Cam- paign" was recently completed. This has been the single largest project undertaken by the National Reye's Syn- drome Foundation. Because of this pro- ject, millions of people across the country will be more familiar with Reye's Syndrome and have the 800 hot line at their fingertips. As previously mentioned, the "Because You Need to Know" bro- chure has been updated and is availa- ble. A section concerning the use of aspirin has been added. Our medical director, Dr. William Schubert, has approved the information and we feel it will answer many questions concerning the aspirin issue. This year a nationwide fundraising project was created through the vision of Val and Bob Carroll, of our East Cen- tral Missouri Chapter. Foundation members and friends from across the United States have sent recipes to the Carroll's who have typed, catagorized and forwarded them to the national office. The "Sunrise Cookbook" will be available in February at $7.50 with over 400 recipes. Comparable books have sold for $12.00, so this is a good buy. The books will be available from the national office or affiliate chapters. The Eleventh Annual Meeting will - be held June 26-30, 1985 at the Long Island Marriott in Uniondale, New York. At the banquet, we will be pres- enting the second annual Elaine J. Lasky Humanitarian Service Award. Nominations may be made by submit- ting a one page biography on a volun- teer to the national office no later than April 10, 1985. Another year is drawing to a close and we have taken great steps toward our goal of alerting the public to the dangers of Reye's Syndrome. But we still have a long journey ahead of us because our ultimate goal is the eradi- cation of the disease. Now is the time to renew our vengeance against this iilness and walk forward with a strong, determined spirit, a spirit dedicated to the conquest of eliminating Reye's Syn- drome as a threat to our children. I would like to express my apprecia- tion for your continued support of the Foundation's effort. Without each of you, our battle would not have gained the strength it has achieved. Thank you all. - We look forward to seeing you in New York!! incerely, E. Freude rger President PAGENO="0302" 296 A DECADE OF SERVICE The Tenth Annual Meeting of the National Reye's Syndrome Foundation of Bryan, Ohio was held June 21-22, 1984, at the Hyatt Regency Ohio Cen- ter, Columbus, Ohio. The meeting marked a decade of service to the gen- eral public and the medical community. The TenthAnnualMeetingwasheld in conjunction with the Fourth Interna- tional Conference on Reye's Syndrome which was conducted by Dr. J. Dennis Pollack, past Scientific Advisory Board Chairman of the National Reye's Syn- drome Foundation. Researchers and scientists from throughout the world attended the conference. Representa- tives from Australia, Japan, England, and Canada presented research data at the symposium. One scientistattending was Dr. Grame Morgan, an Australian Pediatrician, who co-authored theorigi- nal report with Dr. R. Douglas Reye, that appeared in Lancet which pres- ented their initial findings of the disease during the 1950's. - Two doctors from the United King- dom described the occurrence in Eng- land and stated that the current mortality rate w80%. The reasonfor the high mortality rate in the United King- dom, the doctors stated, is the fact that the disease has onlystarted to be recog- nized there in recent years. Reye's Syndrome remains a world problem with cases being reported in Europe, Asia, Japan, Thailand, Africa, and India. Honored guests at the banquet of the Tenth Annual Meeting included past Scientific Advisory Board Chair- man Dr. J. Dennis Pollack, Donald Lan- thorn of the Ohio American Legion and John Maynard, District Office Director of the office of United States Senator Howard M. Metzenbaum. The banquet was opened with wel- coming remarks from Mr. William Myers, representing the office of Columbus Mayor Dana Rhinehart. Mr. Myers, the Health Commissioner for the city of Columbus, presented a brief listing of achievements for which the capitol city of Columbus is known. Wel- coming the Foundation members and guests to the state was Dr. David Jack- son, Director of the Ohio Department of Health. Dr. Jackson focused his address on a number of achievements of the organization, and the work accomplished in the state during the last 10 years because of the efforts of the National Reye's Syndrome Foundation. The guest speaker for the banquet was Dr. Nelson Krause. Dr. Krause is well known in the Columbus area, appearing on weekly television and radio talk shows. He addressed the audience briefly on preventative medi- cine, prescription drug usage, and basic health standards. Audience participa- tion was engaged and Dr. Krause ans- wered several questions concerning a variety of subjects. Highlighting the two day activity was the awarding of the Eighth Annual Research Grant by Dr. Thomas H. Glick, Chairman of the National Reye's Syndrome Foundation's Scientific AdvisOry Board. The 1984 recipient is Dr. Doris Trauner, Associate Profes- sor, Department of Neurology and Pediatrics, University of California at San Diego, who will be working with structures within body cells which are called mitochondria. Dr. Trauner will be studying the effects of the influenza B virus, both alone and with aspirin or acetominophen, on mitochondria structure and function. Dr. Trauner will also be working with a natural body substance called carnitine, presently thought to be helpful in the treatment of Reye's Syndrome. Awards were presented to chapter presidents in recognition for their out- standing efforts and accomplishments during the past year. The first Elaine J. Lasky Humanitarian Service Award was presented to Elisabeth M. Osborne, President of the South Kan- sas Chapter, Anthony, Kansas. The award was established in honor of a longtime Foundation Trustee and Pres- ident of the Chicago Chapter, Elaine J. Lasky, who died in 1983. The Humanit- arian Service Award will be presented annually to a Foundation member who has exemplified the work and dedica- tion displayed by Elaine Lasky. Dr. Joel Taubin, Vice-President of the Foundation, on behalf of the Board of Directors of the National Reye's Syn- drome Foundation, presented John and Tern Freudenberger with a special tribute for their service, effort andcom- mitment. The Freudenbergers were honored with a plaque renaming the annual research grant to be known hereafter as the Tifinni Freudenberger Memorial Research Grant. Since 1974, the Freudenbergers have fought a long unending battle against Reye's Syndrome. Foundation members and guests viewed a video tape with a personal message from Senator John Meicherof Montana. The Senator was instrumen- tal in introducing S.74 (The Reye's Syn- drome Act of 1983.) Senator Meicher stated that prior engagements pre- vented him from attending the Tenth Annual Meeting and commended the Foundation for all the fine work and effort that has been demonstrated dur- ing the past decade. Members of the National Reye's Syndrome Foundation enjoy the banquet of the Tenth Annual Meeting which was held in Columbus, Ohio, June 22, s984. PAGENO="0303" 297 Workshops were held Saturday moming in the meeting rooms of the Hyatt Regency. The first workshop was conducted by Gary Honnert, of the Ohio State University, where he is head of all television public service announcements for the school and acts as news media consultant to the Uni. versity. Mr. Honnert presented chapter representatives and members with a general overview of public appearance techniques including directional help in speaking, dressing and preparing mate~ del for a television news interview. The second workshop of the morn~ ing was conducted by Dr. Charles Dygert, Ohio State University. An out~ standing motivational speaker, Dr. Dygert conducts workshops and seminars nationwide with tremendous acceptance. Through the workshop with Dr. Dygert, audience members learned to recognize their own personal strengths as Dr. Dygert clarified self perception, the effect of criticism on motivation, and the effects of human chemistry on one's behavior. The activities concluded Saturday afternoon with the general business meeting of the Foundation. It was announced at the businessmeetingthat the Foundation had been the recipient of agrant from iheDana WigutoffMem~ orial Foundation to fund an 800 hot line number. The Eleventh Annual Meetingof the National Reye's Syndrome Foundation will be held at the Long Island Marriott, in Uniondale, New York, June 26-30, 1985. ~a Syndrome * II' SEALS AVAILABLE The blue and white logo of the NRSF has been made available as a seal which can be used on note paper, sta- tionery or as an added touch to sealed envelopes. You can use them inside greeting cards to indicate in a subtle, attractive way your support of the National Reye's Syndrome Foundation. Cost is $5.00 per 100 seals, plus a 75~ postage and packaging charge. For ordering, send checks payable to: National Reye's Syndrome Foundation, P. 0. Box 829, Bryan, Ohio 43506. (Actual size 1" x 1%"). Set a good example by spreading awareness and use the seals on every- thing you mail out! - Mr. Gary Honnert,above center, leads discussion withchapter members during aworknhop des~gned to help chapter members become more familiar with media techniques and presentations. I 8 1994 Mr. John E. Freudeeberger president National Reye's Synderave Foundation, Inc. 426 North Lewis Bryan, Ohio 43506 Dear Mr. Freudenberger, It gives me great pleasure to send greetings to everyone attending the Tenth Annual Meeting of the National Beye's Syndrome Foundation. The mystery of Reye's syndrone is a threat to the health and lives of our children. We are heartened that fewer canes of the disease worm reported in 1982 and 1983 thun in previous years for which figures had been formally collected. Continuing efforts tq broaden our knowledge and to educate Americans about this disease will help protect the health of our children. I send my congratulations toever yone associated with your work and my best wishes for its continuation. Sincerely, PAGENO="0304" 298 BETH OSBORNE RECEIVES SERVICE AWARD On June 22, 1984, the National Reye's Syndrome Foundation was proud to present the first Elaine J. Lasky Humanitarian Service Award to Beth Osborne, President of the South Kansas Chapter, Anthony, Kansas. Beth would like to share the following thoughts with all the members and friends of the Foundation: Shocked... numbed... excited... elated... overwhelmed.., and humbled are but a few of the many emotions I experienced a split secondafter hearing my name announced as the first recip- ient of the ElaineJ. LaskyHumanitarian Service Award. Even now, months later, lam still at a loss for words. How do I express those deepest of feelings? For me, it comes through tears. Tears have a language all their own. On June 22, 1984 they spoke louder than any words could. Their message was one of deepest gratitude and appre- ciation to all those responsible for this special unforgettable moment in mylife. lf I begin to name the individuals I'd like to thank, I would risk leaving someone out, I do not want that to happen. So many have contributed in varying degrees. Iwant to thank each of you for your involvement in this special award. I especially want to thank the Lasky family for permitting the establishment of this award. Although I never had the opportunity to meet Elaine, I believe she and I shared the same vision, the same dream and goal concerning each fight confronting her with every ounce of her being. A dear friend of Elaine told me she did not give up her dreams and visions when the"goinggot tough." I shall always treasure this special award. It is overwhelming to realize what it stands for, and very humblingto gain a glimpse of the high standards -Elaine achieved. Those of you who knew Elaine have been especially blessed. May you share with thoseofus who did not know her, the special gifts and qualities she has shared with you. Beth Osbome South Kansas Chapter Anthony, Kansas HEALTH AND HUMAN SERVICES ATTACKS PRO-ASPIRIN AD The first Elaine J. Lasky Humanitarian Service Award was presented to Beth Osborne, President of the South Kansas Chapter,Anthony, KansaS. Presenting the awardwereLarry Lasky, left, President of the Chicago Chapter and Foundation Trustee, and right, Dr. Joel Taubin, Foundation Vice-President and President of the Washington Metropolitan Chapter. On Monday, November 5, the Food and Drug Administration denounced a television announcement distributedby the Committee on the Care of Child- ren, (CCC) as seriously misleading and accused the organization of undermin- ing federal efforts towarnparentsof the suspected link between aspirin and Reye's Syndrome. The television spot is preceded by Reye's Syndrome. This mysterious dis- an announcer's voice saying "Stay ease wounded both of our hearts. Yet, tuned for a medical bulletin on Reye's we've both desired to make our expe- Syndrome." The ad does not point out rience with Reye's Syndrome positive that health officials have been warning and productive. I envision the day, as that aspirin increases the risk of con- I'm sure Elaine did, when this dreaded tracting the disease. stalker of our youth will be forever Joining the FDA in its' criticism of conquered. the ad were officials of the Centers for May the Elaine J. Lasky Humanitar- Disease Control, the American ian Service Award be an inspiration to Academy of Pediatrics and Dr. Edward every chapter leader, every member of Brandt, Assistant Secretary for Health the National Reye's Syndrome Founda- and Human Services, who said the ad lion. May we strive for the highest point `flies in the face of scientific evidence." of commitment, dedication, and service Dr. Brandt's office is coordinating the in ourcommunities, states and country. federal study of Reye's Syndrome and May we NOT become discouraged aspirin. The FDA recommends that when we are tired, misunderstood and until current studies are completed, feel alone. May we gain new strength children who are ill with chicken pox or and encouragement in knowing that flu should not be given aspirin. Since one woman, Elaine J. Lasky, fought 1982, the FDA has aired television PAGENO="0305" 299 announcements warning parents to exercise caution in the administering of medication. The disputed ann~incement does not mention the possible aspirin link. Instead, it states only that "we do not know that any medication has been proven to cause Reye's." Focusing on that statement, federal officials as6erted that the Committee on the Care of Children is supported by the drug industry. The ad was prepared and distributed by the CCC, a private organization that was formed in 1982 when the aspirin studies became national headlines. Last year, the CCC brought an unsuccessful lawsuit against the FDA to try to stop it from carrying out an educational programlinkingthedisease to aspirin. The CCC lawyers also have threatened legal action against televi- sion stations that broadcast FDA public service announcements. The CCC has threatened drug stores that made use of voluntary warning labels on aspirin packages as well. The Committee on the Care of Children is headed by Neil Chayet, a Boston lawyer, who reportedly organ- ized a similar group about 12 yearsago. That organization was called the Com- mittee on the Care of Diabetics and it fought efforts to tell diabetics that they might not need drugs to control their disease. Diet and exercise alone are capable of controlling many cases of diabetes. Chayet was unable to be reached for comment, but his office referred calls to Camille Oldenberg, administrator of another Chayetorgan- ization called the International Science Exchange. Oldenberg acknowledged that the Committee on the Care of Children was launched with pharma- ceutical industry funds channeled through the International Science Exchange. REYE'S SONG TOUCHES REALITY When Wayne Hagood told the story of his daughter Sonya Lee's fight with Reye's Syndrome, he touched the hearts of many of his co-workers. Per- haps touched the most by the tragic death of the 12 year old Lee was Ed Stockton, an engineer from Philadel- phia, who returned to his motel room after hearing the sad story and wrote the following song in memory of Mr. Hagood's daughter. Since that day, the words have been put to music and copyrighted by Mr. Stockton. Thank you, Daddy, flee! okay I really am much better today. My cold's all better and I'm feelin' fine, I think I'll go out in the bright sunshine. Daddy, Daddy, my tummy's sore. I've never felt this way before. The room is spinnin' round and round, I think I'd better go lie down. No! Daddy, I won't go For a ride in the car, Oh, NO, NO, NO! Daddy, where are you takin' me? To a room they call emergency. Daddy, where did the doctor go? He hasn't come back for an hour or so. He says that he thinks I'm on drugs - But I'm not, cause I hate em! I'd rather eat bugs! CHORUS: Won't somebody save the children from the devil in disguise - Tell the parents and tell the doctors that the demon's name is REYE'S. Just look at your little children - With their wide bright innocent eyes. And let your doctors know and let your neighbors know - And maybe we can stamp out RE YE'S Daddy, why won't the doctor try To find out ~f I've really got REYE'S? My body's hurtin~ every place And Daddy, I can't see yourface. I can't talk Daddy, but please be near. I'm afraid that soon I won't be here. Daddy, Daddy, I love you - Lord Jesus, take me home with you. I wrote this song for a girl named Lee whose life ended in tragedy. Her dad told the doctors he thought it was REYE'S But they didn't believe him until she died. So, I'm trying to save the children from the Devil in disguise. And I'll tell anyone who'll listen that the Demon's name is REYE'S. You see, I've looked to my own little children, into their deep blue, loving eyes, and I've prayed to God that everyone know arid no more would diefrom RE YE'S. And let your doctors know, and let your neighbors know - That we've got to stamp out REYE'S That we're gonna stamp outREYE'S x,py,ightrd 1984 Edoa~d St,okt,,,, 12 year old Sonya Lee Hagood PAGENO="0306" MY EMPTY SPACE by M. Bernice Stengel Like a summer day without the bril. liance of the sun. Like an amusement park without a merry-go.round. Like a kiss without a hug. So is my life without Nicole. U Nicole Marie Stengel Time passes. Things change. I change. Yet, the empty space stays stubbornly in place. The void is there, despite son Scott's embarking upon the threshold of his manhood. Emptiness continues as littleAngela talksand talks and talks in the discovery of her three year old vocabulary. The void is vast at times, minuscule at others, but always present. Nicole would be ten now. Horror describes the realization that she has been dead for more than four years. Memories of a mature six year old. Of a child with a bright future. Of a stubborn little girl determined in her destinations, unconcerned by discipli- nary deterrents. Confident in some situations, Mommy's baby in others. Always ajoy, even in her stomping, mad feet and her sassy, pouting mouth. Paper work. Crafts. Drawing. A stack of construction paper and a rollof cellophane tape could fill her day with a multitude of creations. Writing letters and presenting pictures to her family made her face shine with a smile. Shy in an almost painful way when outside of her haven home. Many never heard her sweet voice. Memories of words she uttered are with me. Oh God, how I wish I could make my mind recall the tones she used in her wonder- ful expressions. Her presence is near at times. Dis- tant at times. But always there. A spirit so special that I can almost... but not quite see her. Of all my senses, the one that longs for the baby girl most is my touch... To hold her, hug her, kiss her. If Ihad held her real tight, clutched to me, could I have enclosed herspirit in that sick little body and kept her? No! Nicole is free. Free from the body that she thought too tall. Free from the body that had to go to school. Free from the body that had to be around others. Free to be wherever, whatever, whenever, however... But always pres- ent to her Mommy in that vacant, hurt- ful, empty space. CELEBRITY GOLF TOURNAMENT In August of 1983, bright, lively 16 year old Jamie Beth Slavin became a victim of Reye's Syndrome. In dedica- tion of her daughter's memory, and in vengeance of this mysterious disease, Jill Slavin organized the first Reye's Syndrome celebrity golf tournament with the help of professional tour vete- ran Gail Toushin. The tournament, co.hosted by Har- vey Korman and McLean Stevenson, was the first golf event held in the Uni- ted States to benefit the National Reye's Syndrome Foundation. Thirty celebrities joined one hundred and ten golfers in a five man scramble at El Cabellero Country Club, a private well landscaped course which lies to the north of Los Angeles, on the fringes of Laurel Canyon. NRSF co-founders John and Tern Freudenberger attended the event which was held June 17. Among the celebrities participating in the event were Jack Lemmon, Jerry Vale, Monty Hall, Alex Trebek, Jack Carter, Fred Decordova, Kevin Hagen, Johnny Yune, Donny Most, Jamie Farr, Tom Poston, Peter Marshall and Hal Linden. A banquet was held in the evening and several of the celebrities enter- tained the group with a floor show which was emceed by Korman and Stevenson. Musician and composer David Clark lead his 14 piece string orchestra in a piece of music he com- posed in the memory of Jamie Slavin. His tribute, entitled "Adagio for Jamie" was a very emotional, moving part of the evening. Numerous items were raffled off after the dinner. One of the items on the auction block was an all expense paid trip for two to Ceasars Palace in Atlan- tic City, including limousine serviceand a deluxe suite, all donated by Buddy Hackett. The tournament was backed with a $10,000 contribution from a corpora- tion in Los Angeles called Data Pro- cessing Enterprises. Each golfer received a matching garment and duffle bag, calculator, pen, lighter, two golf balls, golf towel, celebrity golf bag tag, and a Reye's Syndrome celebrity golf shirt complete with the NRSF logo. The tournament was a tremendous success and plans are underway forthe 2nd annual Celebrity Golf Tournament which will be held June 18, 1985. Har- vey Korman and McLean Stevenson will again co-host the event. 300 McLean Stesenson, Harsey Korman and Jill Slavin greeting a guest at the Jamie Beth Slavin Memorial Golf Tournament. PAGENO="0307" KRISTI by Bud Shaffer Kristi Kristi Kristi Thoughts of you make our eyes grow misty A little known disease called Reye's Syndrome Took your life and placed you in God's kingdom You were a child in years only You were a very special grown up young lady Your absence causes Mom, Dad, Sister and Brother to be lonely When you were dressed up you were a very pretty young lady AROUND THE COUNTRY EASTERN DISTRICT DISTRICT VICE-PRESIDENT KATHY SPEECE Reynoldsburg Chapter, Reynolds. burg, Ohio, held a garage sale in June. Teresa, Chapter President, received a contribution from the J.C. Penney Community Service Award Program. This is a program for Penney's employees and she was nominated by her supervisor. Baltimore Chapter, Edgewater, Maryland, is promoting awareness through brochure distribution. The Awareness Bulletins are going out with the aid if the State Health Department. You touched the hearts of many during your short life span You were thoughtful and kind to the young ~nd old with an instinct of a mother We shall never forget your lastsummer when you were trying to get a tan You loved to pester, kid and laugh with Sister and Brother Kristi Kristi Kristi Thoughts of you make our eyes grow misty A little known disease called Reye's Syndrome Took your life and placed you in God's kingdom We all prayed and prayed for a miracle with a bleeding heart You were a special child in our eye You have given us many precious memories that are locked in our heart You must have been more of a special child in God's eye Our hearts still ache for you Help us to ease the pain Please Lord, tell us what to do And understand her death was not in vain Kristi Kristi Kristi Thoughts of you make our eyes grow misty A little known disease called Reye's Syndrome Took your life and placed you in God's kingdom Delaware Chapter, Wilmington, Del. aware, reports that area school nurses are again helping to distribute aware- ness through the local schools to help the chapter's educational program. Washington Metropolitan Chapter, Potomac, Maryland, held their second annual square dance and barbeque in June which helped to raise a whopping $26,000 for the chapter. JoelandSonya Taubin planned, organized, and imple. mented the event which was supported by many of their friends and family. Chapter members have been busycon- ducting awareness in the greater Washington, D.C. area. Ocean County Chapter, Toms River, New Jersey, implemented awareness programs during observation of National Reye's Syndrome Week. Northeast Division Chapter, Phila. delphia, Pennsylvania, has conducted several awareness programs. Kathy Zajkowski received support from the Mayor of Philadelphia and the Gover- nor of Pennsylvania in regard to pro- claiming Reye's Syndrome Week in the city and state. 1,000 helium balloons were released by students in two differ- ent school systems. The balloons con tamed Reye's Syndrome information and were sent up during Reye's Syn. drome Week Loretta George Memorial Chapter, Glendale, NewYork, heldanannual tag sale netting the chapter a profit. They are in the process of conducting their annual membership drive along with a 301 Kristi Shaffer Teresa Murray, center is shown receicing a $100 check from the Columbus Catalog Center for the Reynoldsburg Chapter of the National Reyc's Syndrome Foundation. PAGENO="0308" Around the Country (Continued) raffle drawing. This year the prize will be a choice of either a VCR or $500 in cash. Awareness presentations are also being given to area groups. Virginia Beach Chapter, Virginia Beach, Virginia, gave a presentation to a Da~ Care Center with 45 parents of children attending. The Day Care Cen. ter made a donation to the chapter and held a "TrikeAThon" for Reye's Syn. drome in November. Other speaking engagements are being given to groups. Dayton Area Chapter, Dayton, Ohio, held their eighth annual St. Patrick's Day Dance which was a huge success this past March. A raffle was also con ducted during the dance which helped to raise over $2,500. Western Buckeye Chapter, Leipsic, Ohio, is busy working on the next celebrity Auction. A sausage and pan. cake breakfast is planned and presenta- tions are scheduled for the winter months to various groups. 1,000 bal. loons were released by three area schools in observation of National Reye's Syndrome Week. North Central Kentucky Chapter, Jeffersontown, Kentucky, reports that last spring a doctor from the State Department of Health published two articles about Reye's Syndrome and included information about the NRSF slide/tape program. As a result the pro- gram has been used in at least 10 hospi- tals, clinics, etc. all over the state. A Bike.A.Thon was held for the second year. There were 26 participants and the local papers gave the event plentyof news coverage. They recently had a raffle and booth at an area festival. Northwest Ohio Chapter, Tiffin, Ohio, received an annual gift of $2,000 which was presented on behalf of the employees of the Whirlpool Corpora- tion. Slide presentation is being utilized at a number of speaking engagements. Suffolk County Chapter, Hunting- ton, New York, has had several garage sales during the summer raising funds for the chapter. Members recently held a Theatre Dinner and Raffle. The chap- ter hopes to make this an annual affair. The chapter is continuing to advertise through the "Pennysaver", which is a free flyer distributed to the community door to door, featuring ads from var- ious stores and area groups. The Hun- tington Township PTA Council ran an Awareness Forum during Reye's Syn- drome Week. Members also conducted awareness programs for ambulance attendees during Reye's Syndrome Week. Tn-County Chapter, Peekskill, New York, held a bowling tournament this past spring. Awareness programs have been given to PTA's, and Nursing Schools. Brochures have been distrib- uted in the libraries throughout the county. Michigan Upper Peninsula Chap- ter, Ishpeming, Michigan, is busydistri- buting literature to area doctorsoffices. The local Jaycees will be helping with a dance that is beingplannedforJanuary. Canisters were placed in local stores during Reye's Syndrome Week. Berks County Chapter, Reading, Pennsylvania, is giving presentations to local schools in the area. Several more are on the schedule. Rhode Island Chapter, East Green- wich, Rhode Island, distributed 1,000 Reye's Syndrome flyers in July at a local festival which also was an opportunity to set up donation canisters. An aware- ness program is planned for a "New Neighbors Club" which consists mostly of young mothers. A program was recently given at the local hospital. The chapters annual spirit raffle raised sev- eral hundred dollars. Central New England Chapter, Fitchburg, Massachusetts, made a Reyc's Syndrome Float for the Fouith ot July parade which won second 302 Dayton Area Chapter members enloy their annual St. Patrick's Day Dance along with National President John Freudenberger and National Secretary Tern Freudenberger. Members attending included: Rowone(L-R): Kathy Speece, Cheree VanDyke, Peggy Matthews, and Pat Marlin. Rowlwo: Dan Cordova, Etma Evans, Jack Matthews, Ginger Brockman, Gene Brockman, Nancy Eckstein, and Tern Freudenberger. Row three: Bill Eckstein, John Freudenberger, George Evans, John Van Dyke, Bob Speece and Bob Martin. Chapter President Bernice Stenget, far left, watches as twenty-sis children peddle the,, wa~ through the second annual Bike-A-Thon. PAGENO="0309" SOUTHERN DISTRICT DISTRICT VICE-PRESIDENT MARILYN ANKENEY McDowell Chapter, Columbia, Ten- nessee, has been keeping busy with speaking engagements and distributing awareness literature. Middle Georgia' Chapter, Warner Robins, Georgia, recently held a raffle and raised $1,600 with the help of the Haygood family who were in charge of the event. The raffle had miscellaneous items, prizes and a microwave oven. During Reye's Syndrome Week, the chapter attracted media attention by conducting a balloon release with the local school children at the courthouse. Dallas-Fort Worth Chapter, Dallas, Texas, is presently conducting a solici- tation mailing in the greater Fort Worth and Dallas areas. South Carolina Chapter, Columbia, South Carolina, is pleased to announce that the NRSF has been accepted into the Charleston Combined Federal Campaign which is the largest local in CENTRAL DISTRICT DISTRICT VICE-PRESIDENT ROBERT CARROLL, JR. Chicago/DuPage County Chapter, Chicago, Illinois received support from the Distributive Education Students of Lake Park High School who held another BowlA-Thon in September for Reye's Syndrome. It is always a suc- cessful event and helped to raise $3,700. East Central Missouri Chapter, Amold, Missouri, has had its hands full with new son Robby Carroll, but the chapter is planning several fundraisers and have a good schedule of presenta- tions. The 4th Annual Dance was held October l9and raisedover$2,800. Sev- eral hospitals have been contacted for in-service presentations. Southwest Illinois Chapter, Edwardsville, Illinois, reports that a large schedule of presentations for the fall campaign are planned. A presenta- tion to the Lewis and Clark College of Nursing class on September 14th marked the fourth time they have appeared before the group. A November 10th dance and raffle was held and raised$1,100. CitySteelTorch Club made a contribution to the chap- ter of $1,650. Southeast Iowa Chapter, Washing- ton, Iowa, reports that the Theta Lambda Sorority made a nice contribu- tion to the chapter. Area awareness programs were conducted during Reye's Syndrome Week. Western North Dakota Chapter, Dickinson, North Dakota, is busy promoting Reye's Syndrome aware- ness in the area. The chapter's local 303 Around the Country (Continued) the state! A brochure distributed by the place. Two fund raisers are planned; chapter was the key to the alert reac- the second annual"RunforReye's"and tion of a mother in having her child the fourth annual dance which will be diagnosed early! held along with a raffle of donated Greater Lubbock Area Chapter, prizes. An awareness program will be Lubbock, Texas, held a garage and given to student nurses and flyers will craft sale. They are busy distributing be distributed to area doctors' offices, awareness materials. Maine Chapter, Auburn, Maine, con- Central East Coast Florida Chap. ducted theirannualsoftballtournament ter, Merritt Island, Florida, recently in June and raised about $1,000. A had a booth at a Flea Market which dance last spring helped to raise $1,500 helped to raise funds for the chapter for the chapter. In late October they and distribute awareness literature. raffled a Cabbage Patch doll as part of They conducted a Reye's Syndrome the Maine Mall Community Bazaar. balloon release during Reye's Syn- Their junior board is planning a dance drome Week and have been working for the area teens. with pediatricians in the area. Eastern Lake Erie Chapter, Erie, Pennsylvania, had a full schedule for Reye's Syndrome Week. Their annual Walk-A-Thon was held. Two skating rinks in Erie, the United Skates of America and Erie Skating Rink donated all profits to the chapter from one day during Reye's Syndrome Week. Allnine local McDonald's restaurants in the Erie area displayed Reye's Syndrome canisters during the week and one local McDonald's donated one full days prof- its to the chapter. Cooperative Education Students from Lake Park High School join together to help fight Reye's Syndrome during their fall Bowt-A-Thon to benefit the Chicago Chapter. Wisconsin Lakeshore Chapter, Reye's Syndrome Emergency Line is Wauwatosa, Wisconsin, participated in quite busy and information is being dis. the Health Fair in Milwaukee and dis- seminated in this manner. tributed many Spanish brochures. The Southwest Iowa Chapter, Red Oak, chapter had a booth at a Health Fair in Iowa, is gearing up for an extensive October. A fund raising raffle of a Cab-, awareness campaign which was con bage Patch doll is being held at the Jay. ducted through the schools this fall. cee Women's Convention. Local health Sac-Ida Chapter, Arthur, Iowa, is departments have been requesting promoting Reye's Syndrome aware- more brochures. ness in the area. PAGENO="0310" Four State Area Chapter, Fouke, Arkansas, was the recipient of a slide projector from the local American Legion Auxiliary along with a screen and carrying case. Chapter has distrib- uted brochures and Emergency Room posters in New Mexico. Arkansas Children's Hospital in Little Rock is maintaining close work relationship with the chapter. Many requests for literature have been received lately. The chapter is planning another Music- A.Thon with the local Baldwin dealer this year. South Central Wisconsin Chapter, New Lisbon, Wisconsin, is involved with a two day presentation/meeting to be held shortly. They hada full schedule of presentations this fall. South Kansas Chapter, Anthony, Kansas. Beth Osborne plans to attend an all day conference sponsored by the Kansas Association for the Education of Young Children, Inc. The chapter's "Display Racks" featuring poster boards with brochures have been requested by the Family Practice Cen. ter in Wichita. The chapter has been contacted by many pre-schoolteachers throughout the state for information. The Wichita Branch has been doing a super job promoting Reye's Syndrome awareness and has held a fund raiser. They also have a bake sale planned which will be held at the Wichita court- house. All the items will be donated. The group also appeared at the November 10th 2nd Annual Parent's Fair which is sponsored by KSN-TV Channel 3 in Wichita. The chapter pushed awareness heavy again this year during Reye's Syndrome Week and have several fundraisers planned. PSA's will be distributed to radio sta- tions. The group is grateful to Tern Cross who works with them in making their own PSA's for the Kansas Agricul- tural Network. The chapter urges anyone who is interested in finding an address for the Satellite Station in their area to contact the national office. The Elk City Oklahoma Branch of the South Kansas Chapter has also been busy. Deanna Sweetin has worked with the Jaycees on a fundraiser recently. The "Singing Wilkersons" from Silver Dollar City provided the entertainment and the event netted the branch over $725. South Central Nebraska Chapter, Farnam, Nebraska, had a full schedule of presentations lined up this fall. Some of the programs are 75-100 miles away. The chapter is very proud of the fact that Nebraska became a reportingstate this past summer. Southeast Kansas Chapter, Coffey- yule, Kansas, had a presentation sche- duled in August with visiting Nurses Association and reports a good sche- dule of lectures are booked. WESTERN DISTRICT Southern California Chapter, Hacienda Heights, California is pleased to announce that Reye's Syndrome is now a reportable disease in California! Jim Johnson and George Robeson spearheaded the effort through letters and presentations made before various committees. All the chapters in the state were contacted and input from everyone was helpful in making this possible. Thank you all for a job well done!! A Skate-A.Thon this past spring helped to raise funds for the chapter and was a huge success with many youngsters participating in the event. This chapter held their annual Bowl-A- Thon. This event is sponsored by Foot- hill Beverage and Budweiser and has always made a nice profit for the chapter. Northern Montana Chapter, Chi- nook, Montana, received a donation of 30 Charlie Russell (local artist) framed prints which will be used to help raise funds for the chapter. They are partici- pating in a fair and a rodeo. Speaking engagements are scheduled during the winter. Central California Chapter, Clovis, California, reports that local stations are interviewing the ChapterPresident, Greg Pullen and he is pleased to say that the public service announcements are still being shown. The flyers will be sent home through schools this year. Flathead Lake Area Chapter, Pablo, Montana, has had many successful meetings in the last couple of months. The Health Agency and preschool groups have shown interest. Also the Indian groups are schedulingprograms. The public was invited to attend a town meeting on Reye's Syndrome in November. San Francisco Bay Area Chapter, Pleasanton, California, will have an opportunity to appear on a cable televi. sion network. Chapter President Betty Mathias was asked to appear on the program which will focus on Reye's Syndrome and the aspirin issue. 304 NRSF EXPANSION The Foundation is encouraged by continued support of individuals interested in fostering the goals and programs of the organization. The newest affiliates are: Greater White River Area Chapter, White River, Arizona, organized by Ray and Mary Courser. Carlsbad Chapter, Carlsbad, New Mexico, formed by Gene and Anita Bryan. Shawn McClure Tibbetts Memorial Chapter, Montgomery, Alabama, started by Gary and Sharolyn Tibbetts. Tn Valley Chapter, Tarzana, California, organized by Nancy Vaccaro and Jill Slavin. PAGENO="0311" 305 CUT AND TAPE TO YOUR MEDICINE CHEST FOR KIDS' SAKE... BE WISE ABOUT REYE'S! ~ Reye's Syndrome usually appears after a flu-like Infection, ~ upper respiratory infection, or chicken poo. The early signs are tsu ally Continuous uomiting, listlessness, loss of pep, aggressiveness, Contusion, and irrational behavior. Medicines at the very least van mask symptoms. E~I ~ ~ Child anti-nausea or lever Phone your doctor immediately. ~ Abnormal Liuer Tests: SOOT and SOPT ___________ strongly sugges: a diagnosis of __________ Reye's Syndrome. Time is important' Early diagnosis is VITAL. C Copyright, 1983 Naffonat Reyss SyndromeFoandaffon a Brpan0hfo43506 a (419)636-2679 ~ National __________ fl~j Reye's Syndrome Nan-PeeRS Org b*b 11 Foundation U.S. POSTAGE ilk? P.OBox829 PAID U.~ Bryan, Ohio 43506 P.m, No. 197 Bryas OH 43506 PAGENO="0312" 306 Mr. WAXMAN. Thank you, Mr. and Mrs. Freudenberger, for being with us. Mr. and Mrs. Happle. STATEMENT OF GAIL HAPPLE Mrs. HAPPLE. First of all, we lost our child February 6 of this year. Mr. WAXMAN. Excuse me, but would you please pull the micro- phone a little closer. Mrs. HAPPLE. So this may be real difficult for me, because I am still not real strong. We have not been able to move back into our home. We are working. But I feel that it is something that I can do for her. She was an only child. I have a lot of time on my hands now. They don't let you put but so many flowers in a mausoleum, so you can't do much there. But our town is small, and I will spend this time making sure that the children in our town do not take aspirin for anything, because our child had not been that sick. She only had a little cough. We gave her Congesprin, which contains aspirin, the equivalent to a baby aspirin in each tablet. We had been doing that all week. On Thursday she went to school all day. She threw up at school, but she cleaned it up herself and didn't even tell anyone about it. When she got home she told us. She continued to throw up. On Friday we called her pediatrician. He prescribed a suppository be- cause we could not keep anything in her. There was so much flu around that he did not want us to bring her to the office. And I was also sick with the flu. My doctor didn't want me to come out to the office either. He phoned in my prescription. On Saturday morn- ing she was still throwing up. She watched TV. She ate some crack- ers and drank ginger ale. By the time we got to the doctor at 10:30 she was already delirious. So it happens very fast. They sent us directly to the Medical University in Charleston. We were there by 1:30. They immediately started treatment, after doing two of the blood tests, to make sure that that is what she had. And when I say started treatment, they don't wait and see; by the time we saw her again, they had already put a probe in her brain so that they could monitor the pressure to enable them to keep her fluids in the right proportion, so that her blood pressure would stay stable as the pressure went up. On Sunday the pressure went so high that her brain was dam- aged irreparably then. In fact, the doctor has told us then from Sunday on she was probably brain dead. Because of this-and they hyperventilate them, trying to keep their blood pressure up-her lungs then got a hole in it, and the air was getting into her body cavities, so then her heart did not work properly. So then a tube had to be inserted and get rid of the air. Her kidneys failed. They had to put her on dialysis. And the kidneys did start to act again, but nothing like it should have been. On Tuesday night, because we did not leave the hospital except for brief times to change, and the nights were the times that we stayed in the room as long as we could with her, because they didn't limit your time at night. In the daytime they didn't limit your time, only if they were doing something to her or to another PAGENO="0313" 307 child, you could not be in there. But on Tuesday night the monitor quit working. It just would not work at all. We prayed that it didn't mean what it did. On Wednesday morning the doctors came to us and they had done another CAT scan, and they told us that she was brain dead, and that they felt they should unhook the respirator, which she had been on from the very beginning, and so we agreed to let them do that because we had seen her suffer so much. And within just a matter of minutes all of her body functions ceased. But it is something that happens so fast, and parents don't know enough to even recognize the symptoms until it is too late. And it is not rare, because she went to a very small school, and they lost a child in that school last year. They have two teachers who have lost children to Reye's Syndrome as far back as 10 years, and she had had aspirin. So I feel that if I had another child, I would never buy aspirin or an aspirin-related product again, because what she had happened so fast. Mr. WAXMAN. Thank you very much for sharing that story. How old was she? Mrs. HAPpLE. She would have been 7 on Monday. Mr. WAXMAN. Thank you very much. We would like to hear from Mr. and Mrs. Dumigan. If you could, please pass the microphone. STATEMENT OF GEORGE DUMIGAN Mr. DUMIGAN. Good morning. Thank you very much. My name is George Dumigan. Our daughter Jill got sick wtih Reye's Syndrome and still is. On January 3, the same symptoms that you had, just like lightening it happened. She had the flu, she is getting over from the flu, she wants to go out and she wants to play, and she can't go out and she can't play. We take her in to our local doctor. He rushes her immediately to St. Raphael's Hospital in New Haven. Within about 10 minute's she is there. She is diagnosed within about 1½ hours. She is rushed over to Yale-New Haven Hospital which is the treatment center locally. She has been in Yale-New Haven-well, let me give you a little bit of the background too. We go in there and we have the same anxiety, the same tension, the same every- thing that you are feeling and anyone else is feeling when they see their children hurting. We are told 3 to 4 days something is going to happen, or possibly 6 to 12 days, at the outside chance-16 to 22 days, 16 to 22 days, right? The first 3 to 4 days we are up all night and all day. Diane is either up at nights or I am up at nights, or she is up in the day and I am up in the day. Three to four days pass. We watch the monitors. We see the brain pressure go up to whatever, forties, thirties, fifties, whatever it is. We see all the other regulators. We are watching it. Three to four days pass and that is past. We are saying to ourselves, well, isn't it supposed to get better? Isn't it sup- posed to get better? Six to 12 days pass, the same thing, 6 to 12 days watching the monitor go up and down, blood pressure go up and down, every- thing else. After the 12th day passes we are saying, well, it is going to be 16 to 22 days, hey, you know, that is it. Sixteen to 22 days PAGENO="0314" 308 pass. What happens still? She is still on the monitor. We are still watching the brain pressure. We are still watching the blood pres- sure, and everything else. After 30 days the doctors are saying: We don't really know what to tell you, because no one has been this way before. After 35 days the same thing. After 40 days the same thing. After 42 days, 43 days, what happens is she starts to come out of it, and she starts to come off the medication and off everything else. What is happening with her right now is she is in Newington Children's Hospital in Connecticut. She has been taken from Yale- New Haven, and I can gladly report as a parent that at least she is living. She is in Newington Children's Hospital, and she is talking. She is walking, one of the other functions that we take for granted. Let me just tell you one other thing, too, before I finish. More than likely, in looking around at the ages of people in this room, you are probably all 25 to 45 or 50 years old. More than likely you have been brought up with the TV ads: Take two aspirin, fruit juice, get sleep, and what is going to happen to you is you are going to get better. Well, do you know something? In many cases that may be true, but it is not true in all cases. It is not true in all cases. And it strikes me that if there is a relationship between the taking, the ingestion of aspirin and the getting of this dreaded viral disease, Reye's, if there is some connection then you should know about it. You should know about it so that your children don't get the same thing. Something else. One night about the 20th night, the 25th night into the whole ordeal Diane was talking with one of the doctors there and saying what about this, what could we have done differ- ently. Obviously, feeling as every parent probably would in here, what did we do wrong. What could we have done differently to change this. One of the doctors turned around to her and said, you know, it's very similar to aspirin poisoning, very, very similar. We have heard statements from Congressman Waxman this morning limiting the age to 19. You don't have to be a teen-ager or an infant to get it. You can be older and still get it. Do you know something-you can be you and still get it. Right here, right now, you can be you and get it by taking it. Does it happen in all cases? No. Can it happen? Yes. Should you be aware of it? Absolutely. Thank you very much. Mr. WAXMAN. Thank you very much, Mr. and Mrs. Dumigan and Mr. and Mrs. Happle. Your children have been affected this year, this flu season. Of course, you didn't know taking aspirin was any- thing dangerous. The same was true of the Freudenbergers and Taubins, although they experienced the same thing some time ago. You just didn't know. Now let me ask you-maybe I will address this to Dr. Taubin- you are not only a parent but a physician. I don't know if you are a pediatrician or not. Are you? Dr. TAUBIN. No. Mr. WAXMAN. What would you recommend to worried parents when they hear about something called Reye's Syndrome, that they PAGENO="0315" 309 never heard about before, and they want to protect their children from Reye's Syndrome? What should they do? Dr. TAUBIN. I think you have to believe in what you hear through your pediatricians, through TV now and through PTA groups. Several years ago we tried, and I became the National Vice President of Reye's Foundation and John and I have worked throughout the country for awareness and for research projects in trying to let family members, not only the pediatricians or family doctors aware of this disease. It was very difficult 4 or 5 years ago to have PTA groups hear us. It was very difficult to have pediatricians hear us because, as you are so well aware, I had never seen a case. Four or 5 years ago these were two sentences in a pediatric book saying you will never see it again. Mr. WAXMAN. Now that they know about it, people have heard about it, what should parents be aware of? What do you tell par- ents? Dr. TAUBIN. What we tell parents now is if in a symptom com- plex, if they have a flu or a viral syndrome we know what those are, the muscles ache, the head aches, a little nausea or chicken- pox, don't take aspirin or aspirin products. There are many over- the-counter aspirin products. If the child gets very ill, call your pe- diatrician. If he says to you-we tell this on the phone when they call, they say for the fever, high fever take aspirin, say is this Reye's Syn- drome. Is there a question? Many parents are aware of it now. We don't have to treat every symptom; you don't treat every fever or muscle ache or headache or a sore throat with a drug. Most of them get better. The country is so involved in taking medication, this is one case where you push away and say, gee, don't take it. It will hurt you rather than help the situation. If there is any question in your mind, you call your pediatrician. If he doesn't know, and it is possi- ble he may not know the symptoms, then go to your nearest emer- gency room and hopefully they will know the symptoms. If you are not sure at all, don't take it. Mr. WAXMAN. Mr. Dumigan, when did your child take the aspi- rin? What date, approximately? Mrs. DUMIGAN. The first few days of January. Mr. WAXMAN. The first couple of days of January, around the time the Secretary was saying she acknowledged the fact this was a problem and we had to do something about it and started to talk to the aspirin manufacturers about some voluntary action on their part to warn people. If you picked up an aspirin bottle and it said on that label "If you are looking at flu symptoms, consult your physician," would that have meant anything to you as parents then? Mrs. DUMIGAN. I don't know whether I would think about it that much. If it just said contact your physician if she was sick in the middle of the night-I mean those things happen. You just give it to them in the middle of the night. Mr. DUMIGAN. Can I respond on that too? Mr. WAx~N. Sure. PAGENO="0316" 310 Mr. DUMIGAN. Different people respond differently to informa- tion. If you say to some people, look, hey, you don't take aspirin period, under these conditions, getting over flu or getting over chickenpox, that works. That works. With other people it may not necessarily be the case. You may have to say to them, hey, don't take aspirin when getting over from these conditions, and here is the reason why. We know now in the country the question, the authority that doctors had 50 years ago when they said, hey, don't do this, is not always taken by people the same way. So you may have to give rea- sons for not doing it now. There is no question about it, that if you put a label on the aspi- rin, that would work for a lot of people, no question about it. And pediatricians should still know that, hey, the reason you don't take it is this. These things can happen from it, and that is why not to do it. When our child went in January 3 to Yale-New Haven, you don't read the newspapers, you don't watch TV or anything else. By Jan- uary 8, 9, 10 a lot of people were calling up and saying, "How is Jill', and we're saying, "Well we don't know how Jill is. She is much the same." "Did you give her aspirin? Did you give her aspirin?" That was the question that was echoed over the phone time, and time, and time again. And the answer was "Yes; we gave her aspirin. Yes. Is it so dif- ferent from what you would do? Is it so different from what you would do?" "Probably not. Probably not." The awareness that was made through the TV, the newspapers certainly helped a lot of people, no question about it, and I think it would have helped us too. Mr. WAXMAN. Mr. Freudenberger, you are the chairman of the parents' organization, and later in the hearing today we are going to receive testimony from a group called the Aspirin Foundation. They are going to tell us that a Reye's parents' group oppose a mandatory aspirin label. Do you agree with that statement? Is that your position? Mr. FREUDENBERGER. No; that is not my position at all. There are three parent groups combating Reye's right now, that I am aware of, the National Reye's Syndrome Foundation in Bryan, OH, the Reye's Syndrome Society of Michigan, with whom just last week we agreed to merge, and those are two largest groups. There is another group based in Denver that is a very weak group, a small group, and has always yielded to the Aspirin Foun- dation's. It was last year when the aspirin, or 2 years ago when the Aspirin Foundation's opinion that there shouldn't be any labeling, the Denver group thought that there shouldn't be any labeling. Mr. WAXMAN. So there is evidently a parents' group that seems to--- Mr. FREUDENBERGER. They are weak and they need the money of the Aspirin Foundation, I believe. Mr. WAXMAN. I wasn't aware there was another parents' group, but you are saying there are other parents' groups. Two of the groups do support a warning label and for whatever reason the third one takes a different position? PAGENO="0317" 311 Mr. FREUDENBERGER. Yes. Mr. WAXMAN. Some industry spokesmen have criticized this leg- islation as unnecessary and needlessly frightening to consumers. Do you agree? Mr. FREUDENBERGER. No, not at all. We have been faced with that kind of idea for a long time. From the very beginning, when we were driving home from the hospital after Tiffinni had just died and I said to Tern, "We have got to send out letters to doctors and tell them what Reye's Syndrome is," so that is what I have been doing for over 12 years now, telling people what Reye's Syndrome is, and you go into a community and you get resistance. You go to the school nurse and you say, "Hey, we ought to hand this out." And she goes to the county health department and talks to the doctor there, and too frequently we hear, you know, "We don't want to panic the community." You know what their defini- tion of "panic the community" is? That doctor is going to get some phone calls. You know, there are kids that are going to be sick and they are going to get a phone call whether to use aspirin or not. And I say that when you are a doctor you are committed to that. You know, you are committed to treat people, and ignorance is no way to solve a problem. Mr. WAXMAN. Let me say to all of you that in the time that I have been chairman of this Health Subcommittee, over and over again I have been impressed by the fact that people who know the most are the people who have had to live with the consequences of an illness or disease. More than the doctors and more than the drug manufacturers and more certainly than the government offi- cials in charge of protecting the public health, because they have taken the time through the painful experience they have had to try to understand why things aren't being done that should be done. I can't imagine anything more frightening than having a child with Reye's Syndrome, and I would rather have a warning on aspirin bottles to warn a parent about this danger, even though it may scare some people. That is exactly what should happen. The fact you have been willing to come here today and share your own personal experiences with us has been very helpful to us. I know that you have committed yourselves to working to inform other parents and the medical community and the Secretary of Health and Human Services and everyone else that this could have been avoided in your circumstances, and you want to see it avoided with other families so they don't have to go through what you have gone through. Mr. Wyden. Mr. WYDEN. Thank you, Mr. Chairman. I want to commend all of you for your great courage and your tenacity. It seems to me that it shows a special strength, to be out continually working for changes. I only have one question. You have all been directly affected by this and you have dealt with gov- ernment, basically at every level, to get solutions to this situation. Do you think that, by and large, government has been responsive? Has government been listening to the concerns of parents? Mrs. DUMIGAN. No, I don't think government has been respon- sive enough. I, too, am in the medical profession. I am a nurse, and PAGENO="0318" 312 I didn't know that much about Reye's Syndrome other than the name, and I don't think anybody who hasn't experienced it or seen it in an intensive care unit can imagine it. You just can't imagine what your child is going through. They have a tube into their brain. Our daughter had four ventriculostomies into her brain at different times. They have at least three or four IVs going into their veins or arteries. They can be on dialysis. They lose weight. My daughter developed bed sores from the time that she couldn't be moved because of the terrible pressure in her brain. I mean, I see patients and it is just devastating when you see children like this. It is the most intensive therapy I have ever seen, and I don't think government has been responsive. I think we need a label warning that says Reye's Syndrome, and people really need to know what Reye's Syndrome is, not just a name but they need to know the devastation that this wreaks on a family and the child. Mr. WYDEN. Would any one else care to comment? Mr. FREUDENBERGER. If I might comment, I have been working with government for 10 years, and like some of your comments today, I don't know why we couldn't have had labeling already at the start of this flu season, and in those 10 years what I have had to learn is to be patient. It just takes a long time, and I don't think it needs to take a long time, and I think I am seeing more and more response from government, and I think there is still more needed. Mrs. FREUDENBERGER. We have been hearing a lot of the com- ments this morning directed to parents, but in the last few years we have seen a large increase in the number of Reye's Syndrome cases that have occurred in late adolescence, and this warning is very important for the children in this country who are self-medi- cating. We need that warning on there, because when they are sick, they are away, they are going to go and put their hands on a bottle of aspirin as fast as they can. They are not going to ask their parents if they can take something. They are going to go ahead and do it. That label has to be on there for them as well. Last year in Ohio we lost two adults, one 19-year-old and one 27- year-old man. It is happening in the adult population. We are not recognizing it in children as well as we should be, and we are cer- tainly not detecting it in the adults, but it is there, and one day we will know a lot more about Reye's Syndrome than we know right now. Mr. WYDEN. I really appreciate that comment, because it seems to me that probably this evening millions of Americans of all ages are going to head home and reach for an aspirin bottle, and what you have said is that we need a little bit better information before we make that decision. I think the Federal Government just dragged its feet. I am not sure whether it is bureaucratic bumbling or just plain indifference, but clearly it has got to change, and just the fact that all of you are here to deliver this information because you have been directly affected is going to speed up that process, and I thank you for being here. Mr. WAXMAN. Thank you very much. Mr. Bates, any questions or comments? PAGENO="0319" 313 Mr. BATES. The only question I had is the circumstances that have occurred and what you members of the panel have had to live through is hard to even imagine. Certainly everyone would have to try and empathize and sympathize with the situation. I was curi- ous, with the Reye's Syndrome organization that you founded, and that some research is being done, how much do we know in terms of the conditions or the kind of individual that would be susceptible to the aspirin. It seems to me that in terms of the use of aspirin, the tremen- dous use of asprin, and even if it is not a rare disease, that it seems to strike only at random or certainly not everyone who takes aspi- rin gets Reye's Syndrome, I am just curious as to what research and what more should be done in that area to try and determine more about it. Anyone who has any knowledge on that? Dr. TAUBIN. One of the problems we have is it is not a totally reportable disease. When you get out statistics from the Communi- cable Disease Center they say there is a certain number of cases. They are not reported. The disease, if it is classic, you may not miss it. A pediatrician may not. They take children to the emer- gency room. During the flu season we talked to an emergency doctor. Well, he has the flu. It is overwhelming. The problem we have is that it masquerades as a disease. A teen- ager who goes into the emergency room screaming and cursing and yelling, the first thing you think of is not Reye's Syndrome but they are going to think of a drug overdose. The pediatrician told us that they develop vomiting and head- aches and irrational behavior with screaming and lethargy and sei- zures and you think of a meningitis or infection of the brain, not Reye's Syndrome. How many cases in this country are sitting in just hospitals or small hospitals that are called something else. They are never called Reye's Syndrome and because of that they are given aspirin in the hospital. We all know we have been through cases of chil- dren being tied down in a psychiatric hospital-one in Maryland a couple of years ago where the child eventually died and the autop- sy showed Reye's Syndrome. How many physicians have seen this and are unable to report it? We have a pediatrician here in the area who tried to report to CDC approximately a number of 13 or 14 cases about 3 years ago and was sent back on a CDC form saying document more forms. He got so disgusted he didn't send it back. You have a listing in our journals in CDC of Reye's Syndrome. There maybe more and more unreported cases or cases masquerading as another disease. More and more because the child may not have all the classic symptoms. They may say I am not going to bother my physician at 2 o'clock in the morning. One of the big things we have to do is better report diseases, a better way for the physician to send to the CDC or to the local State department, health department, a means of identifying known cases of Reye's Syndrome. There are five stages. There is the now considered stage zero in which there is minimal symptoms of headache, you get a little vomiting and they get better with this. How many children who have a cold, a little flu symptoms, you wouldn't think of calling your pediatrician. Let me call your teach- PAGENO="0320" 314 er and stay home for a day or two, take a little fluids, a little weak soda, and maybe some aspirin and you will get better tomorrow. How many of these cases took the aspirin and developed Reye's Syndrome in such a mild, mild stage of Reye's Syndrome that could be totally stopped. There isn't a member of this board here or other members of the family life with the rest of their lives knowing we gave something that our children and the child here-how can you forgive us? I don't want to be here. None of us want to be here. We have a rea~~ to be here and hopefully there will be no more parents sit- ting here. You have to start now. You have to give a child or the parents a chance to survive and live because it is the most devastating illness you are going to see. I will never forget it and our family will not. The only hope we have and support we have is we as family mem- bers and our other children say you have got to do something now, you can't worry about how much money they are going to lose to the aspirin people and wait for more studies and more studies and more articles to come out, more letters to the editor. I see in our field of medicine that you cannot to that. There is a problem, you stop the problem now, and be aware of it, and if there is a reason not to give it, why take a chance and wait for 15 journals to come out. Thank you. Mr. WAXMAN. Mr. Scheuer. Mr. SCHEUER. Well, Mr. Chairman, I want to express my appre- ciation to these witnesses who have come and tell them how deeply touched I have been to hear their testimony. It is almost a heart wrenching-it is a heart wrenching experience, especially for anyone who is a parent. I raised four kids. I realize how lucky I was and how lucky my four siblings and I-the five of us-were, because the principal on which my parents raisd me and I raised my four kids was if it hurt on the outside you put vaseline on it, if it hurt on the inside you take a couple of aspirins. How lucky we were we didn't have a case of Reye's Syndrome in our family. I am concerned with this notice. I am concerned that it doesn't tell us enough. It says don't take aspirin if your child has symp- toms of influenza, chicken pox or flu. I wonder how many Ameri- can parents at every educational level-I have three university de- grees, and I have raised four kids-I couldn't tell what the symp- toms are for influenza, chicken pox or flu. How many parents do? I think if you stopped a thousand people at the corner of 42nd Street and Broadway, you would be lucky to find five of them who could even give you a rough estimate of the symptoms of influenza, chicken pox, or flu. So I am sending up an early warning signal, a yellow flag, I don't think we are telling parents enough. I think we have to tell them what the symptoms are that they have to watch out for. Normally we take aspirin when we don't feel very good. That could be a headache. That could be a little temperature. We have to distin- guish between these symptoms for we all are used to taking aspirin as sort of a magic potion for a mild symptom of some kind. We have to be far more selective and I think there is a real edu- cational job to do with parents and also with adults apparently, PAGENO="0321" 315 and I am not at all persuaded that the notice goes far enough. I would like to see some kind of listing of the kind of symptoms that we must be aware of and-- Mr. WAXMAN. Would you yield? I think you make an excellent point. I am interested to hear from the next panel of pediatricians and other, physicians, what those symptoms are. Also, how the warning label, was negotiated with the industry by the Secretary of Health and Human Services. It does not say don't take aspirin for symptoms of these illnesses, it simply says if you have these illness- es, consult a physician before taking aspirin. So there is very, very little information that is there. But I think you raise a good point-what are those symptoms, how are they different, how would anybody know if you have a headache or nausea or a backache or muscle ache whether it is from flu or-- Mr. SCHEUER. Or a slight temperature. Mr. WAXMAN. Or a slight temperature, or from a whole range of possible illnesses. Most likely what you do is pop an aspirin and hope you get better. Mr. WYDEN. I happen to agree completely with what you are saying. It seems to me we have got an enormous education job to do and this warning is just one piece of the job that we ought to do. There is a lot of resources out there. For example, we are going to hear, I understand, from the retail pharmacists, who said that they feel that there is a role they can play in helping to educate the public. So I think the gentleman is right on point. I see this as just one piece of a very large educational undertaking that we have got to do in this area. Mr. SCHEUER. I thank my colleague. Mr. WAXMAN. Mr. Bates. Mr. BATES. Well, in trying to react to the comment, I certainly wouldn't know the symptoms of any of these things either, but then as I think about this, the more we put on here-I think Hap- ple's statement is one that I would take, it is overreaction. I would say I am not going to use aspirin for anything because I don't know enough about the symptoms, I am not taking any chances. I think that probably is the reaction of a number of people so that the as- pirin sales aren't going to drop a little, they are going to drop a lot, and I think that the idea of consulting a physician may be a good idea, but I certainly think this warning is minimal. I think maybe how it should be worded or the extent of the infor- mation there, that is why I was sort of probing on the research that has been done on what is it in aspirin that activates or causes the Reye's Syndrome, and I suppose we will get into that as we go along. Mr. WAXMAN. I think these are important issues to explore. Mr. SCHEUER. The warning does say it is a salicylated product, which nobody understands, and it doesn't help them very much, but it doesn't give them the information they need to know when they can safely take aspirin, and it is a health and comfort in the overwhelming majority of cases I suppose. But we have got to have the hard numbers to know when we can take it safely and enjoy its 52-266 0-85--il PAGENO="0322" 316 health and comfort enhancing effects and when we have to avoid it like the plague. And I honestly think that we know all about-we are told about salicylate, which I am probably pronouncing badly, don't have the remotest idea what it means. That is not the relevant information that we need. We have to know what the symptoms are so we can get the benefits of aspirin for most of the time when we could take it safely, have that early warning signal for the few times, but the highly important times when we must avoid it. We must have the specific knowledge to avoid it. And probably I think Congressman Bates is right, it probably can't be done on a label. We have got to crank this into our health education-and we have improved our health education vastly in the last decade or so-but this certainly is something we can think about and I don't think we can stop with the language that is on that label. To my mind, it is insufficient and leaves out critically urgently needed information. Mr. WAXMAN. Thank you, Mr. Scheuer. Let's hear from other witnesses today what they think ought to be the appropriate actions to be taken by Congress and then we will see what legislation we ought to be passing. But I think we all so far are at least of the opinion that action so far may not be strong enough, what was negotiated by the Secretary is certainly inadequate. Thank you very much, this panel of witnesses, for being with us. We appreciate your willingness to share your views with us and your experiences. I would like to call forward a panel of Dr. Sidney M. Wolfe, di- rector, Health Research Group, Dr. Albert Pruitt, FAAP, chair- man, Committee on Drugs, American Academy of Pediatrics, ac- companied by Dr. Harry Jennison, executive director, American Academy of Pediatrics. STATEMENTS OF SIDNEY M. WOLFE, M.D., DIRECTOR, PUBLIC CITIZEN HEALTH RESEARCH GROUP; AND ALBERT PRUIVF, M.D., FAAP CHAIRMAN, COMMITTEE ON DRUGS, AMERICAN ACADEMY OF PEDIATRICS, ACCOMPANIED BY DR. M. HARRY JENNISON, EXECUTIVE DIRECTOR Dr. WOLFE. I know I had a great deal of difficulty emotionally listening to what we have just heard. A number of parent whose children have died or been brain damaged have called me during the 3 years since we have started working on it and I guess it is particularly frustrating to me. We are in the middle, as you know, of legal action against the Government to require warning labels, particularly a phrase stating that we are, if not 100 percent, close to 100 percent certain we have got an identifiable agent-aspirin- that can prevent a disease. It is a classic preventive medicine, yet we have got a really unethical, illegal and moral response by the Federal Government and its partner, the aspirin industry. Nothing can more clearly highlight the need for this legislation than the statements by parents whose children died or became brain damaged as a result of Reye's Syndrome. No parent would ever give or have given a child aspirin for treatment of chicken pox PAGENO="0323" 317 or flu had they known of the strong association between the use of aspirin in these circumstances and the greatly increased rjsk of contracting Reye's Syndrome. Especially tragic is the plight of over 610 children, 175 now dead, who have gotten Reye's Syndrome since the beginning of 1982, sev- eral months after an October 14, 1981 CDC-Centers for Disease Control-Advisory Committee recommended that the use of aspirin "should be avoided" for treatment of chickenpox or flu. Almost all of these children had been given aspirin. Their deaths and injuries were thus preventable. The evidence that aspirin is strongly associated with Reye's Syn- drome is now based on five studies, four of which were completed over 3 years ago. Three years ago, Public Citizen Health Research Group petitioned FDA to require warning labels on all aspirin con- taining products and later, along with the American Public Health Association, filed a lawsuit against FDA. In remanding the case back in the U.S. Federal District Court, the U.S. Court of Appeals said, of HHS's November 1982 reversal of its earlier plan to require warning labels: The record evidence indicating that industry pressure precipitat- ed this reversal is parti~ularly troubling in that the pace of agency decision making may jeopardize the lives of children. . . . The cur- rent record strongly suggests that the pace of agency decision making is unreasonably dilatory. All scientific evidence in the record points to a link between salicylates and Reye's Syn- drome. . Over 2 months ago, HHS Secretary Heckler asked the aspirin makers to voluntarily: First, immediately remove any labels which recommend that as- pirin products be used to treat flu or chicken pox in children or teenagers; Second, further label all aspirin products to indicate that there is a possible association between the use of aspirin and the onset of Reye's Syndrome in children and teenagers, and that aspirin prod- ucts should not be used in those cases unless a physician is first consulted. That subset of aspirin makers who belong to the Aspirin Founda- tion later "voluntarily" agreed to put warning signs in drugstores. First, child and adult aspirin products with labels still recom- mending flu as an indication for aspirin use. As of this week, the following nationally distributed aspirin prod- ucts were found in drugstores with labels recommending use for treatment of flu: Children's aspirin: St. Joseph's, Bayer. Adult and therefore teenage aspirin: maximum strength Anacin; regular, maximum and arthritis strength Bayer; regular and extra strength Bufferin; Excedrin. Thus, Secretary Heckler's first request for immediate removal of such labels is not being taken seriously since it is voluntary. Second, relabeling all aspirin products to warn against use of chicken pox, or flu, because of the increased risk of Reye's Syn- drome: PAGENO="0324" 318 Secretary Heckler's second request has been met with equal en- thusiasm by the aspirin industry. A survey by phone of 53 drug- stores in 31 States found that no store had aspirin products with labels. The voluntary promise by the Aspirin Foundation to label newly manufactured products has not yet showed up in the stores, nor when it does, will the labels mention Reye's Syndrome. Third, the Aspirin Foundation promise to voluntarily put warn- ing signs in stores: Of the 53 stores surveyed this week, only 17 had posters, many of which had come from the American Pharmaceutical Association, the pharmacist organization which sent members a warning poster 1½ months ago. In other words, over two-thirds of the stores had no warning poster. In summary, the voluntary program is a cruel disaster. During this heavy flu and chicken pox season, no aspirin purchased in this country has warning labels and some of the biggest selling products actually recommend use for treatment of flu. Because HHS has failed to require mandatory warning labels, the introduction and passage of H.R. 1381 is very important. By taking into account interim warning labels, advertising, signs in the stores and the labels for future manufactured products, it covers four crucial areas which have been left largely unimple- mented as a result of the voluntary approach. H.R. 1381 also recog- nizes that many people don't have a doctor to go to and that many who do, don't consult her/him for chicken pox or flu. Thus, the straightforward language that "this product should not be given," rather than "consult your doctor" is quite appropriate. In conclusion, there is little doubt that many of the hundreds of children and teenagers who have died or suffered brain damage from Reye's Syndrome would be alive and healthy today if the Reagan administration had not yielded to pressure from the drug industry 2½ years ago and canceled its plan for mandatory aspirin warning labels. Thank you. I would like to make a couple of comments concerning the kinds of things that at least are likely to be said, because we have seen the people from the industry and the apologies from the govern- ment testifying and talking over and over again for 3 years on this issue. I am getting sick and tired of hearing from the aspirin industry and from the government that there are flaws in the studies. If there are flaws they are minor. The main flaws are in the people who have stopped the government from issuing warning labels 2½ years ago. There are flaws in terms of the health of what the gov- ernment has not done. There are flaws in the morals and ethics of Dras and anyone else who participated in any way to block some- thing that could have saved the lives of many children and pre- vented a lot of brain damage. The studies that have been done, particularly the last two, the one that was completed, the first part of which was completed a few months ago, and the one completed over 3 years ago, will go down as landmarks in the ability to use case control studies to de- termine the cause of illnesses. PAGENO="0325" 319 I think one of the most frightening things, as recently as 1984, the beginning of this year-last year-about 40 to 45 percent of the parents were still giving their children aspirin for treatment of chicken pox or flu or similar symptoms. That is the proof that the voluntary, the educational approach as opposed to automatic warn- ing labels, that we need the full scope of every kind of possible way of reaching these parents. Thank you. Mr. WAXMAN. Thank you very much. Dr. Pruitt. STATEMENT OF ALBERT PRUITT, M.D., FAAP Dr. PRurrr. Mr. Chairman, members of the House Energy and Commerce Health Subcommittee, I am Dr. Albert Pruitt, chairman of the Department of Pediatrics at the Medical College of Georgia, and chairman of the Committee on Drugs of the American Acade- my of Pediatrics. I represent more than 27,000 pediatricians who today comprise the Academy. Our interest in the relationship between aspirin and Reye's Syn- drome dates from 1981, when we published a notice in our newslet- ter apprising the membership about the possible association be- tween the administration of aspirin to children with influenza and chicken pox and the subsequent development of Reye's Syndrome. In February 1982, we issued in our newsletter a similar warning to all members. In June 1982, after further data became available on studies in Ohio, Michigan and Arizona, all showing an association between aspirin and Reye's Syndrome, a special report was pub- lished in "Pediatrics." This statement said in part: Aspirin should not be prescribed under usual circumstances for chidren with van- cella or those suspected of having influenza on the basis of clinical or epidemiologi- cal evidence. . . Inasmuch as salicylates are over the counter preparations, educa- tion of parents to their avoidance in influenza and varicella requires a total commu- nity effort. We urge that the appropriate governmental agencies undertake appro- priate review and necessary action to inform the public at large. We also believe that manufacturers of salicylates should cooperate in informing prospective users of the relationships detailed in this report. Since 1982 when that statement was published, and to a degree at the urging of the American Academy of Pediatrics, a carefully designed research study was undertaken by the United States Public Health Service to ascertain whether the administration of aspirin would continue to show association with Reye's Syndrome. With the advice, of a committee of the Institute of Medicine, Na- tional Academy of Sciences, chaired by Dr. Floyd Denny, a distin- guished pediatrician and Fellow of the Academy, with expertise in infectious diseases research, a protocol for a multicenter study was developed by the Centers for Disease Control, and the pilot study began in February 1984. The results of that pilot study have now been presented. Mr. Chairman, we believe that there is today more reason than ever to warn the public, and especially young adolescents, about the association between aspirin and other pediatricians and Reye's Syndrome. A surprising number of Reye's Syndrome patients in the pilot study were young adolescents who presumably took adult strength aspirin without physician advice. Aspirin can no longer be PAGENO="0326" 320 regarded as an appropriate medication for flu for a child or young adult, nor should it be taken for an illness which might be chicken pox. Because aspirin is largely self-medicated by young adults, it is important that the labeling read by the consumer be unambiguous on this point.~ The American Academy of Pediatrics supports label- ing which provides current information about the relationship be- tween aspirin and Reye's Syndrome, and we therefore support the intent of this legislation. Also, as a scientific organization, the appropriate Academy com- mitteés have been asked to review the complete data and make a determination if those data are sufficient to warrant immediate steps by the Federal Government. We are undertaking that review now. Please recognize that the data review is a different proposi- tion from taking every precaution to protect our children now. We are here testifying to the latter. The Academy was asked for comment on HHS Secretary Marga- ret Heckler's announcement of the voluntary labeling approach. We supported that. Yet we remain deeply concerned that the mes- sage about aspirin and Reye's Syndrome get to the consumer, and this has caused us to question the effectiveness of voluntary label- ing. Accordingly, we have met recently with representatives of the Food and Drug Administration to press for progress in this area. We recognize the urgency of definitive actions, and would hope this hearing will serve as the necessary catalyst to encourage a suitable response by FDA and the industry. Ideally, we feel this would happen without legislation, but as a practical matter, it may not. Outside of the labeling issue at hand, research in this area must be continued and a full PHS study must follow. In the interim, the Academy will continue to state its position that aspirin not be pre- scribed for children or young people with varicella or influenza. It is our intention to work with you, Mr. Chairman, in the speedy res- olution of this issue. When our children are at risk, they most cer- tainly deserve the benefit of any doubt, and we are confident that through your leadership, appropriate public policy will be forth- coming. I appreciate the opportunity to address the committee, and I would be glad to answer questions. Mr. WAXMAN. Thank you very much, Dr. Pruitt. Dr. Pruitt, Dr. Jennison, Dr. Wolfe, let me commend each of you and your organizations for the strong stand you have taken with regard to trying to prevent this particular disease and others as they affect children and to press for effective action that will ac- complish that goal. Let me ask you, Dr. Pruitt-the question came up earlier about symptoms-if I were a teenager and I got a headache or felt nau- seous or felt muscle aches, or if I were a parent and heard my child complaining about, these kinds of symptoms, how would I know if it is chicken pox or a virus-flu-or something else? Under what cir- cumstance would I be able to make a decision that aspirin would be appropriate? Dr. PRurrr. I think it is important to note that there are really no specific symptoms for the diagnosis of influenza. We all know that with influenza, one might have low grade fever, usually have PAGENO="0327" 321 muscle aches, and/or have a headache, but it does not necessarily mean that every time you have those symptoms that you have flu, a virus infection. There are numerous other respiratory viruses that can cause similar symptoms. Chicken pox is a bit of a different matter. Once the lesions, the rash occurs, then the diagnosis is obvious. Prior to the development of the rash, however, it is very nonspecific. There is usually some low grade fever. Oftentimes there is a history of exposure to other children with chicken pox, which can be a help to you. But it is not possible to make an absolute diagnosis of influenza simply by examining the patient. It is very helpful if you know there is influenza in the community. Then there is a reasonable epidemiologically to suspect that influenza infections are around. Mr. WAXMAN. Is there a simple over-the-counter medication that I could give my child when he has some of these symptoms, other than aspirin? Dr. PRUITT. I think Dr. Taubin made a very important point, and that is that we need to be careful not to over-medicate children. There are many, many times with most infectious illnesses, that are nonbacterial, the child probably doesn't need any medication. We overtreat fever. We overtreat other symptoms. I think this also provides us an opportunity to evaluate whether or not a medication is actually needed. Mr. WAXMAN. Dr. Wolfe, if the child is just uncomfortable and you want to do something to relieve the pain, maybe to lower the fever, what could a parent do? Dr. WOLFE. Well, as you know, there is really no evidence what- soever that there is an association between acetaminophen, which is the active ingredient in Datril or Tylenol and Reyes. I would agree with Dr. Pruitt that this country and many others are over- medicated societies, whether it is tranquilizers or pain killers or fever lowerers or whatever. I think in many or most of the circum- stances no medication is indicated. I would agree with Dr. Pruitt that if one wants to make a defini- tive diagnosis as a pediatrician or anybody else, of influenza, there isn't any specific set of symptoms. You are really in a sense asking the other question, what kinds of things that might be i'~iiuen- za-- Mr. WAXMAN. I appreciate the statement that we most likely can forego any medication with children and they will get well and we are certainly taking minimal risk of a side effect from a drug if we don't give a child-- Dr. WOLFE. That is the active ingredient in Tylenol, Datril, and it is the nonaspirin. In fact, the companies that were the biggest sell- ers of children's aspirin several years ago, anticipating that eventu- ally as hard as they would try, they would lose this battle-a lot of dead children in the interim-started selling very vigorously nona- spirin products. So that you have children's products, Bayer and St. Joseph's nonaspirin. I think nonaspirin has become a more famil- iar word than acetaminophen. What it is is another ingredient or chemical that can lower fever and treat pain, which is not aspirin, which is not linked in any way to Reye's Syndrome. Mr. WAXMAN. Are there nonaspirin pain killers? PAGENO="0328" 322 Dr. WOLFE. And fever lowerers. Like Kleenex and Jello it is be- coming a generic name. Mr. WAXMAN. A nonaspirin pain killer, fever reducer is it less available, can I buy it? I know this kind of risk is a possibility. Dr. WOLFE. One of the issues that has been raised-I think it is something to think about-but it affects such a small number of children, juvenile rheumatoid arthritis, a severe form of arthritis, which starts at a young age, the best treatment for this is aspirin. However, even when these children are getting an illness like this, if they were to call their pediatrician and they would probably be told to discontinue it. So I think that the answer to your question is that even though we can't make the definitive diagnosis of influenza a lot of times, for reasons Dr. Pruitt that by adding a very tiny amount to the label or to the thoughts and to the educational campaign that would include, for example I mentioned colds, coma, fever, head- ache, intestinal problems as examples of symptoms, any one of which might indicate something that really is the flu, we would be more communitative. I think it is interesting that a poster that was to be sent out a month ago to 47,000 junior highs, high schools and 2 year colleges by the Food and Drug Administration, was canceled, destroyed at the request of the aspirin industry because it had a phrase in it "other viral illnesses." The Government wanted to go beyond chicken pox and flu and include a phrase which would have at least broadened the scope and terms of people looking at the poster. That was destroyed. It has now been replaced and now, I am told, sent out in the last few days. There was an effort to make more communicative what the Gov- ernment was doing, which has, as you pointed out, a number of other flaws. The industry didn't like it, therefore, it was canceled. Mr. WAXMAN. Let me ask a very straightforward, simple ques- tion of you, Dr. Pruitt. You are a pediatrician, patients want to know from you as a pediatrician. If my kids get sick during this flu season, should I give them an aspirin? Dr. PRUITT. No, sir. Mr. WAx~N. Mr. Bates. Mr. BATES. No uestions. Mr. WAx~N. Let me-one point I was impressed by-we always think of children. We are talking about teenagers, up to 21 years old, who are self-medicating. These are people being conditioned by all the ads we have seen on television over the years, got a pain, take an aspirin. Is the advice that you would give to a college stu- dent under the age of 21 with some of these symptoms, to avoid as- pirin as well? Dr. PRurrr. I am not really comfortable placing an age limit on it. If we had been discussing this matter several years ago, we would have thought, well, Reye's Syndrome is very uncommon in the older adolescent, therefore, the older adolescent probably is not at risk. Now, as we look at more recent data I think the older ado- lescent is at risk. So I don't know that we can establish an upper age limit. Dr. WOLFE. There has been much more success because the typi- cal Reye's patient has been portrayed of someone 5, 6, 7, 8, 9, in PAGENO="0329" 323 reducing the number of cases of Reye's in the younger age group. It has fallen off considerably. In the 10 and above age group there has been almost no change at all because those people did not get the message. So I think I would agree. I think in the national sur- veillance data, 2 percent of the cases were over the age of 20, but certainly putting an age limit may mislead one person and that would be one too many taking aspirin for treating of influenza or chicken pox. Mr. WAXMAN. I didn't want to get into questions on the science in terms of the strong feelings whether it is scientifically proven or not, that there is this link between aspirin and Reye's Syndrome because I gather you are all satisfied that there is enough of a link-as the Secretary was satisfied-there is enough of a link for us as prudent people to make some judgment to warn parents and others not to take aspirin for these flu and chicken pox symptoms. Is that a correct statement? Dr. PRuIrr. Certainly we don't believe that aspirin is a sole cause of Reye's Syndrome. There are a number of factors which play a role in the development of Reye's Syndrome. Mr. WAXMAN. You feel satisfied with the science about the link- age between aspirin and Reye's Syndrome that you would recom- mend obviously to avoid taking aspirin for these symptoms? Dr. PRuIrr. That is correct. We are recommending two things. One is that, and the other is that this other study proceed, the study which has already been planned by illS. Mr. WAXMAN. Absolutely. Now, the American Academy of Pediatrics supported the volun- tary effort by the Food and Drug Administration and the Secretary of Health and Human Services because you wanted something. You got it. Is it adequate? Dr. JENNISON. Let me tell you what we have had. We were asked very shortly after the Secretary announced the volunteer labeling programs what our opinion was and our office at the academy re- sponded, yes, that is a step obviously in the right direction. Since that time, our technical committees have been trying very hard to understand the more recent data and have advised us that they are deeply concerned about how the labeling process will pro- ceed. On that basis, you heard Dr. Pruitt describe the meeting we had with Assistant Secretary of Health, Dr. Mason and FDA repre- sentatives just a little over a week ago to express that concern. Mr. WAXMAN. You are concerned about it and you have ex- pressed that to the Department of Health and Human Services rep- resentatives. Of course, we would rather people do what they ought to be doing and what is best calculated to inform the public rather than have to pass legislation. But I don't feel that this voluntary negotiated settlement is adequately reaching most people. Dr. JENNISON. Could I add an additional comment, if I may, be- cause several of our committee members may have raised the ques- tion of the improved public education and the parent group spoke very eloquently to this. I would have to say the Reye's Foundation folks have probably done the best job of trying to get information out. We in the academy have made a strong effort. We would like to work with them, but I want to point out this group is sophisti- cated. PAGENO="0330" 324 We have been labeling cigarettes for 25 years and there are quite a few people in the room that haven't found it made them stop smoking. Labeling is not enough, and I hope in your deliberations you will keep clearly in mind that it is the responsibility of the Federal Government, the responsibility of the volunteer agencies, and it is certainly the responsibility of the academy, as a scientific medical organization, to be on the forefront of public education. Mr. WAXMAN. Dr. Wolfe, what do you think about the other as- pects of the administration's attempt to educate the public aside from the labeling part? Dr. WOLFE. No one has ever advocated one means of educating the public on anything, this included. I think we have certainly always supported every possible creative thing being done, whether it is signs in stores, supermarkets, whatever. The problem is, that to the extent that they are voluntary, some will do them and some will not. That is why I think 3 years ago when the evidence was strong enough-and we are not talking about perfect evidence be- cause there is rarely perfect evidence-when it was strong enough for a Government advisory committee to say October 18, avoid use of aspirin. As soon as that threshold was reached, everything should have been done possible to educate people, including mandatory warning labels. The separation out of it is enough evidence to tell people not to do it, but it is not enough evidence to put warning labels is a ridiculous dicotomy. So we believe that even though labels alone might not do the trick, labels alone are absolutely necessary for many people who don't go to a doctor-it is an over the counter drug-most people will not call a doctor, many tens of millions, as the Census Bureau points out, don't have health insurance and may not have doctors. Mr. WAXMAN. It is inadequate in your opinion, based on what is being said under this voluntary agreement and on what your own survey indicates. Is it because the approach is voluntary, that more is not being done? Dr. WOLFE. Not only is it not being done, when you have it on a voluntary basis you sort of come begging, as Secretary Heckler and FDA and take whatever you can get. The label that the Aspirin Foundation agreed to doesn't mention Reye Syndrome. One of the parent's eloquently stated that the more explicit it is, the more they would pay attention to it. If there is no mention of Reye Syndrome, let alone Reye Syndrome is often fatal, people would pay less attention to it and yet, they have agreed because it is voluntary to let the industry put-there have been too many instances where pamphlets were burned a year or two ago, these posters were destroyed last month-that indicate that as long as it is voluntary, as long as the Government doesn't take the thing seriously enough to require warning labels, even their public education campaign is flawed. The statements aren't strong enough, as you pointed out. Mr. WAXMAN. In other words, the Secretary of Health and Human Services has given the aspirin industry a veto over the most effective way to inform the public because they have to be satisfied before they would permit the Government to go forward? PAGENO="0331" 325 Dr. WOLFE. That is right. There are two instances. The one with the posters being destroyed last month and another I believe was 1½ year ago where a huge number of hundreds of thousands of pamphlets were too strong to please the aspirin industry and were recalled, not sent out, and reprinted with a more watered down version. You are right. Not only have they vetoed mandatory labels, they vetoed some of the stronger elements in the educational campaign. The words "strongly associated" was in this poster. It was taken out. Mr. WAXMAN. Dr. Pruitt, we are going to hear later from a group called the Committee on the Care of Children. Are you familiar with that group and do you associate yourself either with their views or are you in any way affiliated with them? Dr. PRurn~. I personally am not affiliated with the Committee on the Care of Children. Mr. WAXMAN. And Dr. Jennison, how about you? Dr. JENNISON. No affiliation. We are a group of 27,000 members and I am well aware there are those out-- Mr. WAXMAN. Are you aware of their views on this issue? Dr. JENNI5ON. Oh yes, very clear. Mr. WAXMAN. Do you associate yourselves with their views? Dr. JENNISON. Not in the slightest. Mr. WYDEN. Just one for either you, Dr. Pruitt or Dr. Jennison. Is there any tangible scientific evidence which would indicate that the Administration's approach thus far is sufficient to protect the public health? Dr. JENNISON. Well, I can say to you that in the meeting that we had with Dr. Mason and representatives of FDA, there was out- lined before us a rather comprehensive sort of monitoring program which I am told is to commence at some future time. I am sure someone will comment on that later, but you are asking for tangi- ble evidence? Mr. WYDEN. I think you two have been very careful in saying that the voluntary program is only the beginning, but from all you have seen in the Administration. Is any credible scientific evidence which supports their position that what they have done thus far is sufficient? Dr. JENNISON. I don't know how you could comment on terms of scientific evidence. I can only say to this date we have made our- selves available to help with the development of language or label- ing or things like that and we haven't been asked to examine any particular products. Mr. WAXMAN. Thank you very much, gentlemen. We appreciate very much your testimony. We will look forward to working with you on this issue and the legislation as we move it forward. Thank you very much for being with us. I would now like to call forward Dr. Frank Young, Commission- er, Food and Drug Administration, accompanied by Dr. Dowdle, Mr. Scarlett, and Mr. Michels, representing the Department of Health and Human Services. We want to welcome you to the sub- committee meeting today. We are looking forward to your testimo- ny. Your full statement we will make part of the record in its en- tirety. We would like to ask you to summarize that statement. PAGENO="0332" 326 STATEMENT OF FRANK E. YOUNG, M.D., Ph.D., COMMISSIONER, FOOD AND DRUG ADMINISTRATION, PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICE, DANIEL MICILELS, DIRECTOR, OFFICE OF COMPLIANCE Dr. YOUNG. Thank you very much, Mr. Chairman. I appreciate the opportunity to be here and to listen to the concerned comments of the parents. I believe that you share, as I do, the concern that this dread sym- drome is met and met vigorously. It is a tragedy, and as both a parent and physician, I can identify clearly with their concerns and great pain that was felt in listening to these discussions. Let me begin by emphasizing two key points. We feel that we have under the leadership of Secretary Heckler forged a significant degree of public/private sector cooperation that addresses both the short-term and the long-term considerations. I would like to raise the two points that we feel are very key for this hearing. First, the definitive scientific data are still not avail- able, as you know. The existing data were derived largely from pre- vious state epidemiological studies which demonstrated a possible association between aspirin and Reye's Syndrome and the signifi- cance of which was uncertain, and from a more recent limited Public Health Services pilot study. The pilot study compared the aspirin by 30 cases of Reye's Syn- drome with that of 140 controls. The pilot study found nearly all the Reye's Syndrome cases had aspirin exposure. That is compared to only about 45 percent of controls. While highly suggestive and consistent with previous studies, procedural changes and the rela- tively small size of the pilot project means that its findings should not be considered definitive. The larger and more positive full scale study is now underway. Accordingly, the evidence needed to sup- port the mandatory labels is not in our view available at this time. Second, there is a voluntary labeling and extensive public educa- tion program underway, and I will describe that more fully in just a few moments. I will skip the chronology of the events only to point out two things: The first public health announcement that I made was made in the fall of this year at the onset of the flu season and was made on Reye's Syndrome. Your 5-minute time does not allow that to be shown, but I do have the tape here if you wish to see that. Second, the meeting that was first approach and raised by the American Academy of Pediatrics, in which they were first exposed to the data, was started when I was in the Naval Bethesda Hospi- tal with a temperature of 104°. I felt constrained, though not being able to be there, started the conversation by phone personally, and have stayed and remained committed to dealing with this very im- portant medical problem. These are the things that were undertaken in regards to dealing with this disease: First, the pilot study was to be released and was released, and very rapidly we saw the program appear in Morbidity and Mortali- ty Weekly Reports and followed subsequently in the Journal of the American Medical Association. We felt it extremely important to get out posters, and I have some displays of some of these that PAGENO="0333" 327 were put out on Reye's Syndrome very, very early, as well as send- ing letters to doctors, to consumers, to consumer groups, to phar- macists, and other people that might be able to influence bringing this view to the American public. We have also published recent information of the pilot study in the current issue of the FDA Consumer magazine. To ensure coop- eration from the media, the Secretary took the unusual step of con- tacting the heads of the major media asking their assistance in in- forming the public of the pilot study results. She also wrote to health professional organizations, hospital administrators, and some 173,000 physicians about the new data. In this regard we consider the professional community, especially those in pediatrics, to be the most important vehicles in conveying this type of information. We felt that although the data was not conclusive at this time, it was imperative to inform, even at this stage, the American public and follow the approach that we are de- scribing here. We reasoned, therefore, that because the data was not complete, that it was not appropriate to develop a mandatory requirement for labels. I am pleased to inform you that two events have oc- curred: First, we have put out a large number of posters, letters, and in- formation, as I described and as my full testimony shows. Second, we have assurances from members of the Aspirin Foun- dation that the labels will be in place as of the next flu season. As you know, we do have a labeling from Plough and St. Joseph's Aspirin, and they did withhold shipment and put a sticker on im- mediately on those bottles, on those boxes, while the changes in la- beling was occurring. As you know, it takes a while for labeling and artwork to be put in place and that period of time would exceed the time that would be required for this flu season to pass, and we felt that it should be out as rapidly as possible and if label- ing isn't .ready for this flu season, that we must have the public education brought forward. But I did want to show you this for one change that was made so far. Finally, we have sent a letter to the aspirin making firms throughout the country, whether or not they are members of the Aspirin Foundation, with a questionnaire. I submit this as well as all other information that we have put forward for the record, so that we wish to be able to get-the direct input about what they plan and to close the loop, the very important loop that was men- tioned here, namely reaching all of the aspirin firms through this volunteer effort. I would be most interested, as an educator, to learn of your thoughts as to ways that we might be able to better influence the public. We are monitoring this-this is the first time that a volun- teer effort has been monitored. We not only have taken early points, as Dr. Wolfe mentioned-but also these posters were just sent out within the last month to month and a half. We want to find out how long it takes for penetration, how long it takes for shelf life and I would be delighted to share these results with you and receive any suggestions that you or your staff or your subcom- mittee members have in determining best how to educate and inform the American public. PAGENO="0334" 328 I have also with me, Daniel Michels, who is the Associate Direc- tor for Compliance in the Center for Drugs and Biologics, Mr. Tom Scarlett, who is our Chief Counsel, and Dr. Walter Dowdie, from the Centers for Disease Control, who was instrumental in discuss- ing and determining this study. I would be glad to answer questions or have you direct questions to any of the members of the administrative panel. Thank you. [Testimony resumes on p. 345.] [Dr. Young's prepared statement follows:] PAGENO="0335" 329 STATEMENT BY FRANK E. YOUNG, M.D., Ph.D. COMMISSIONER FOOD AND DRUG ADMINISTRATION PUBLIC HEALTH SERVICE DEPARTMENT OF HEALTH AND HUMAN SERVICES W. Chairman: I am pleased to be here today to discuss with you H.R. 1381, the "Emergency Reye's Syndrome Prevention Act of 1985." As part of my testimony, I will also describe what steps the Food and Drug Administration (FDA) has taken as well as address, in general terms, the questions you raised in a recent letter to Secretary Heckler concerning the voluntary progran being undertaken by leaders in the aspirin industry. I will be glad to provide a more specific response to those questions, either *here today or as a submission to the record. I am accompanied by Dr. Walter Dowdie, Director, Centers for Infectious Diseases, Centers for Disease Control, Mr. Tom Scarlett, General Counsel of the Food and Drug Administration, and Mr. Dan Michels, Director, Office of Compliance. Let me begin by emphasizing two key points. The first is that, under Secretary Hecklers leadership, we have successfully forged a significant degree of public-private sector cooperation thataddresses both short-term and long-term considerations. Second, as a physician and parent, I can assure you that I have not rested, nor will I rest, until I have convinced myself that we are taking all the appropriate steps. In fact, the first public service announcement that I made after becoming Comissioner was on Reye syndrome. Our efforts include an intensified nationwide program for alerting American parents and teenagers of the possible association, focusing efforts on teenagers PAGENO="0336" 330 who self-medicate and therefore are in a different risk group, and arranging a longer term effort to make appropriate revisions in the labeling of aspirin and other salicylate-containing products. Here I would note that this effort augments our prior educational program for this year's flu season which had been in effect since November 1984. As has been our practice for the last three flu seasons, we have tried to plan our public awareness campaigns to coincide with National Reye Syndrome Week and the beginning of the flu season. Results have occurred as exemplified by a decline in sales of single entity aspirin products for children during the flu-season for the last several years. Also doctor recomendations for the use of aspirin for the treatment of flu and chicken pox in young children declined 72 percent between 1980 and 1983. These trends probably suggest that our public education efforts have succeeded in reaching consumers and health care providers. Before describing the specifics of the voluntary precautionary program which has been initiated, I will first address the bill which you recently introduced. H.R. 1381 As you know, H.R. 1381 would require that the labeling of any drug which contains a salicylate include a warning that that product should not be given to individuals who have `chicken pox, influenza, or flu symptoms" because of the association between salicylate and the development of Reye syndrome. Under the bill, a drug containing a PAGENO="0337" 331 salicylate which did not bear this warning on its labeling would be misbranded under the Federal Food, Drug, and Cosmetic Act. The drug would also be misbranded if manufacturers, packers or distributors (including retailers) failed to include the warning in any advertisements or other printed and descriptive matter about the drug. We agree wholeheartedly that the American people, and especially parents and teenagers, should be made aware of the dangers of Reye syndrome, its possible association with aspirin use, and the fact that early detection and intervention is critical to the process and treatment of this condition. We believe, however, that the proposed legislation is unnecessary for two reasons. First, the definitive scientific data are still not available. As you know, the existing data were derived largely from previous State epidemiological studies which demonstrated a possible association between aspirin and Reye syndrome, the significance of which was uncertain, and from a more recent, though limited, Public Health Services (PHS) pilot study. The pilot project compared aspirin use by 30 cases of Reye syndrome with that in 140 controls. The pilot study found that nearly all Reye cases had aspirin exposure, as compared to only about 45 percent of controls. While highly suggestive and consistant with previous studies, procedural changes made and the relatively small size of the pilot project means that its findings should not be considered definitive. The larger, and more dispositive, full scale PHS study is now underway. Accordingly, the evidence needed to support mandatory labeling is not, in our view, available at this time. PAGENO="0338" 332 Second, there is currently a voluntary labeling and extensive public education program underway. There are strong indications that this effort will be fully successful in protecting the public health. There has been a dramatic reduction in the number of cases of Reye syndrome at the same time that there has been a significant decline in the sales of single entity aspirin products for children. We do not know whether these are casually related events or caused by changes in physician practicing patterns such as giving different parental advice, earlier detecton of adverse sypmtoms during flu or chicken pox, or other unknown factors. Whatever the reason, however, this decline has occurred without any legislation. Furthermore, if the voluntary effort continues to succeed, and we are confident that it will, a mandatory approach will not be warranted. CHRONOLOGY First Public Awareness Campaign In May 1982, based on the results of several epidemiological studies, the Department of Health and Human Services concluded that there was sufficient evidence of a possible association between the use of salicylate-containing products, such as aspirin, and Reye syndrome to warrant notifying physicians and parents. Reye syndrome is characterized by vomiting and lethargy which may progress to delirium and coma and, in some instances, death in children and teenagers who are recovering from flu or chicken pox. In past years, approximately 600 to 1,200 cases occurred annually in the United States, mostly in children and teenagers. Death results in 20 to 30 percent of the cases, and brain damage has been reported in many of the children who survive. PAGENO="0339" 333 To disseminate this information, Secretary Schweiker directed the FDA to undertake an educational campaign to inform consumers of this finding. However, because there was considerable scientific controversy in the medical community over the studies, we determined that additional research to identify more. definitively this relationship was needed before we could conclude that a warning label should be required. While these new research efforts have been underway, we have continued as in past years with our public awareness campaign to alert consumers of this important public health information. The Public Health Service Study To investigate the possible relationship between Reye syndrome and various exposure factors, including the use of aspirin and other salicylate-containing products, former Secretary Schweiker directed the Public Health Service to develop a plan for further research in this area. Under the plan, the study would be conducted by the Public Health Service Reye Syndrome Task Force. The study and the data generated would be reviewed, critiqued and monitored by the Institute of Medicine of the National Academy of Sciences. This new study called for a pilot phase to determine the study feasibility and establish methodology; to be followed by a full-scale investigation. The pilot study phase has now been completed, and the data have been reviewed and analyzed by the Institute of Medicine. The results of the study, although not conclusive, appear to show an PAGENO="0340" 334 association between ~the use of~ salicylate and the onset of Reye syndrome in children and teenagers. The Secretary~ s Actions Upon receiving the Institute of Medicines report, Secretary Heckler issued a statement on January 9, 1985 strongly urging parents to follow the advice of the Surgeon General and consult a physician before using aspirin in children or teenagers in cases of flu or chicken pox. She also emphasized the need to vigorously pursue the full..scale study in light of the results of the pilot study. That work is now underway. To ensure that all children continue to be given the fullest protection while we await final scientific conclusions, the Secretary announced four additional steps to be taken. First, the pilot study was to be released for review and analysis. As noted, the results of the study were sumarized and published that same week in the Morbidity and Mortality Weekly Report, and republished in the Journal of the American Medical Association on February 8, 1985. Second, FDA would vigorously pursue expanding and extending its public education efforts. Specific steps would be taken as soon as possible to inform teenagers who often self-medicate. * Third, the Secretary would contact media leaders throughout the country, asking them to use every possible resource to help broadcast this message. PAGENO="0341" 335 Fourth, aspirin manufacturers would be asked to voluntarily revise the labeling of their aspirin products to further alert consumers about the advisability of using aspirin products to treat flu or chicken pox in certain age groups. On January 11, 1985, the Secretary announced that representatives of the major aspirin manufacturers had agreed to cooperate with the FDA to develop new labeling for aspirin products. Details of this voluntary effort are described further below. IMPLEMENTING THE SECRETARY'S CHARGE At that point, we moved as quickly as possible to implement the Secretary's charge, involving both our own public education efforts and discussing with leaders of the aspirin industry what steps they would be taking. Our efforts were intensified because of the time of year these new scientific data became available. Knowing we were already at or apprQaching the height of the flu season, we felt it imperative that we take steps to alert parents and teenagers as soon as possible, including the large number that already had aspirin or aspirin-containing products in their medicine cabinets at home. We therefore adopted a two-pronged approach: First, we increased consumer awareness campaigns, involving both FDA and the industry. This includes public service announcements, special mailings, and special posters. Particular emphasis was placed on getting the industry and retailers to use `shelf PAGENO="0342" 336 posters" because it is expeditious and eye-catching; we have used this approach in the past in the device area for educating consumers about the risk of toxic shock syndrome in connection with the use of tampons. Moreover, we knew that a considerable period of time (longer than was available to us this flu season) would be necessary to make available relabeled aspirin products, and of course not even that would affect already-purchased medicines. Second, we pursued voluntary labeling changes to the products themselves. This involves both deletion of the "flu" indication for children's products and warning against use of the product in children and teenagers with flu or chicken pox without medical advice. Our goal is to have these changes in place prior to the comencement of next year's flu season. Let me now describe each of these efforts for you in more detail. Consumer Awareness Efforts The Government's expanded public education program ordered by Secretary Heckler has included newspaper columns, radio public service announcements, posters and newspaper advertisements. The newspaper columns were in English and Spanish and were sent to more than 10,000 newspapers. The radio announcements were used by at least 1,000 stations from coast to coast. Moreover, 43,000 posters have been sent to all junior and senior high schools and colleges, this being in PAGENO="0343" 337 addition to the 120,000 posters sent out in November 1984. Because the results of the pilot study had implications for older teenagers not observed in the previous studies, special emphasis was placed on targeting this specific group in our educational efforts, whenever feasible. An article providing updated information with regard to the results of the pilot study was also published in the current issue of the FDA Consumer magazine. To ensure cooperation from the media, the Secretary took the unusual step of contacting the heads of the major media asking their assistance in informing the public of the pilot study results. She also wrote to health professional organizations, hospital administrators and some 173,000 physicians (internists, pediatricians, familypractitioners and emergency medical doctors) on the new data. In this regard, we consider the health professional community, especially pediatricians, to provide one of the best vehicles for conveying this type of information, especially to parents. I have also provided background information on the recent pilot study to the major health professional organizations and have asked them to share the information with their membership. I should note here that the Mierican Pharmaceutical Association has initiated a Reye syndrome warning campaign. They have issued-a Dear Pharmacist letter enclosing a poster to its 50,000 members. We greatly appreciate their disseminating this important information. PAGENO="0344" 338 In addition, through our consumer outreach program, we are providing updated educational materials which reflect the results of the pilot study. The organizations within this network have the capability to reach over 20 million people. The Aspirin Foundation has also coordinated the activities of its member companies and has developed its own educational program. Its nationwide campaign includes television and radio public service announcements which make reference to the possible association of aspirin use and the development of Reye syndrome. The campaign also includes a Reye syndrome poster in two sizes, developed by the Aspirin Foundation, to be placed in retail establishments throughout the United States during the 1985 flu season. We especially encouraged the use of this poster as an efficient and effective mechanism for comunicating this important public health message. A major attraction of this approach is that one generic shelf poster can provide a uniform health message coverin9 virtually all the aspirin products being sold in that particular area of the store. In this way, shelf posters are extremely efficient and cost-effective. It can also be implemented expeditiously, given that members of the Aspirin Foundation have volunteered to use their considerable sales forces to visit major grocery stores and pharmacies throughout the nation and seek to have the posters prominently displayed. PAGENO="0345" 339 I have included copies of the relevant documents of both Government and industry efforts to disseminate the information for inclusion in the record. At this point, I think it only appropriate to note a special thanks to Giant Foods for taking the lead among retail establishments and producing their own posters and shelf labeling. The Giant materials have been in place since late January and include a main poster and tear-off literature attached to the shelves which gives more detailed information. These efforts have been followed by other retailers such as Safeway, Walgreen, Thrift, Osco, and People's Drug Stores. We applaud this excellent public service effort. We believe that this private sector effort together with the Government's educational campaigns for the last three years and the recent publicity generated by the release of the pilot study results will be an effective vehicle for making the general population aware of the possible association between Reye syndrome and aspirin. I have with me today the video public service announcements prepared by the Aspirin Foundation and the FDA which I would like to show at this time. Labeling Revisions In conjunction with the educational materials which have already been disseminated, the major aspirin manufacturers have agreed to revise the labeling of their aspirin products. A warning statement will appear on PAGENO="0346" 340 all medicines containing aspirin by fall 1985. Specifically, all such products will bear the statement: "Warning: Consult a physician before giving this medicine to children, including teenagers, with chicken pox or flu.' In addition, the labels for children's aspirin products will be revised to delete all references to flu. Plough, Inc. of Memphis, Tennessee, maker of St. Joseph aspirin and non-aspirin products for children, which is not a member of the Aspirin Foundation, has developed its own voluntary precautionary labeling program. A part of its program includes the labeling revisions for children's products which will bear the following warning statement: "Warning: Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin may increase the risk of developing this disease. Consult a doctor before use in children or teenagers with flu or chicken pox." Plough, Inc. has also begun placing an abbreviated warning sticker on all stocks shipped from its plant and intends, in addition, to include in its packages an insert bearing information which identifies the symptoms of Reye syndrome. This program was begun on January 9, 1985. In addition, those products manufactured since that date will bear the revised labeling. PAGENO="0347" 341 In an effort to reach other manufacturers of aspirin and salicylate-containing drug products to advise them of these voluntary initiatives, we have written to all drug manufacturers registered with FDA. The purpose of this letter is also to update our drug listing files and ascertain whether, and to what extent, these firms intend to join in this nationwide campaign. We fully expect the rest of the industry to follow the type of responsible and public spirited labeling revisions being instituted by members of the Aspirin Foundation and Plough, Inc. A copy of this letter will be submitted for the record. FOLLOW-UP EFFORTS To determine whether the efforts 1 have just described have been effective, we will monitor compliance of the voluntary program and the success of our combined educational campaigns. We plan to conduct a telephone survey of U.S. households on consumer awareness of this issue. Survey results will be representative of telephone households in the United States which have children 19 years of age and younger. A parent or responsible adult will be interviewed as to their knowledge of a possible association between aspirin and the development of Reye syndrome in children with flu or chicken pox. Information will be obtained on their awareness of this association, how they became aware (i.e., source of information) and whether they, in effect, believe the message. Data will be analyzed by age of respondent, household income groups, education level and race. PAGENO="0348" 342 The Agency has a contract which will enable it to start collecting information as soon as the appropriate clearances are obtained for the questionnaire. We anticipate that we will have data within 30 to 40 days of the beginning of data collection. I would caution that this survey should be viewed as a preliminary attempt to get early feedback on the effect of our educational efforts and to obtain valid baseline data for future survey work. However, I will gladly share with the Subcomittee our~ results in monitoring the true effectiveness of our current educational effort and its effect on use of the product. I would also appreciate learning from you your thoughts about the types of programs that may be most helpful in determining the educational value of our programs. Second, we are prepared to conduct a more definitive survey later once these educational efforts have become fully operational if we deem that further feedback will help us.modify our informational and educational programs. As an educator I am concerned that we establish as rapidly as possible what programs are most effective in reaching the public. VOLUNTARY LABELING I know, Mr. Chairman, that in your letter of January 11, 1985 to Secretary Heckler, the Subcommittee expressed its concern that we had reached a decision to rely on a voluntary approach rather than requiring mandatory labeling. I would like to try to put our decision, and the reasons for it, into perspective. PAGENO="0349" 343 When the State studies suggested a possible association with salicylates, we concluded that physicians and parents should be informed. As attention focused on the details of the studies, we determined that new studies were necessary to resolve the scientific dispute over whether the studies did in fact demonstrate an association between Reye syndrome and salicylate-containing drugs. Also, we concluded that although public information efforts were justified, the evidence was sufficiently questionable to warrent more stringent action. Now the pilot phase of the new study has been completed. Although the pilot phase is not conclusive and must be considered preliminary, its findings may indicate an association between the use of aspirin and the onset of Reye syndrome in children and teenagers. Because we continue to believe that it is important that consumers receive the most up-to-date information, we have intensified our educational campaign and asked the aspirin industry to undertake voluntary initiatives to amplify the message. However, both the Institute of Medicine and the Public Health Service have concluded that the full study should be completed before drawing more definitive conclusions about an association between Reye syndrome and salicylates. Our deliberations have been careful and thoughtful. We have tried to base our public statements and our decisions on the most accurate and complete analysis of the scientific evidence available to us. The resolution of the scientific dispute which has surrounded this PAGENO="0350" 344 extremely complex issue is crucial, and we are hopeful that the study underway as well as other basic research on Reye syndrome will provide us with the additional information to definitively resolve this controversy. Nevertheless, even in the face of this uncertainty, we have acted quickly to take steps we felt appropriate to protect children during their most vulnerable years. CONCLUSION Let me conclude by saying that I do understand your concern, and I truly believe that we are striving to reach the same goal. We must protect the health and safety of our children. They are our future. Our t~tmost concern is *that the actions we take be in the best interest of these children and their parents who will be affected by our decisions. We believe that the steps we have already taken to inform the public of the dangers of Reye syndrome and its possible association with salicylate use as well as the voluntary labeling and public education initiatives undertaken by the private sector responsibly addresses this important public health problem. Thank you Mr. Chairman. This concludes my prepared testimony. I will be happy to answer any questions you may have. PAGENO="0351" 345 Mr. WAXMAN. Thank you very much, Dr. Young. Let me see if I understand the situation. You don't feel you had enough data to say conclusively that there is a link between aspi- rin and Reye's Syndrome, and, therefore, you didn't want to re- quire mandatory labels. Is that correct? Dr. YOUNG. That is correct. We did not feel that we had the evi- dence at this time to unequivocally establish a link and go toward mandatory labeling. Mr. WAXMAN. You felt that there is a strong enough public health danger that the public should be informed of the probable link between aspirin and Reye's Syndrome? Dr. YOUNG. That is correct, and I felt that in November, upon coming into FDA, and felt similarly and more definitively, as this additional pilot study came forward. Mr. WAXMAN. Because you didn't want to go with a mandatory label, you pretty much left the aspirin industry to control what would be on that label, because they had to agree. They didn't want to agree to anything that would hurt their sales, so therefore, you have a warning label that simply says if you have these symp- toms, talk to your doctor about them. How would anybody know that has anything to do with Reye's Syndrome? Dr. YOUNG. I was trying to summarize my statement. I will use two other points from that. Mr. WAXMAN. You don't really need a statement for that. How would you expect anybody, how would you expect anybody as a pa- tient or grandparents, to know if you weren't the Commissioner of FDA, that a label that doesn't say don't use this aspirin product for flu or chicken pox syndromes-how would you know that you shouldn't use aspirin if it simply says consult your physician if you have the flu or chicken pox symptoms? Dr. YOUNG. Surely. First-- Mr. WAXMAN. Do you think anybody would know from that in- formation that they shouldn't use aspirin? Dr. YOUNG. I think labeling is only part of the total program and that was brought forward very clearly by the representatives of the American Academy of Pediatrics and by others. I went back to look at this issue and tried to compare some other events that have oc- curred by both congressional hearings-and this is related to the study on Premarin that I will introduce for the record. It shows the effect of a congressional study, a Senate hearing, physician label- ing, and the Patient Package Insert Labeling. The drop in use was not necessarily completely related to labeling, and the same was true in saccharin. We felt that by getting out a variety of educational programs and these types of hearings, we will make a big impact on the public. [Testimony resumes on p. 361.] [The study referred to follows:] PAGENO="0352" 346 Reprinted from Banbury Report 6: Product Labeling and Health Risks © 1980 Cold Spring Harbor Laboratory Estrogenic Drugs - Patient Package Inserts LOUIS A. MORRIS Food and Drug Administration Rockville, Maryland 20857 Prescription drugs are among the most carefully controlled consumer products. The consumer must visit one highly trained professional to receive a prescription and a second to receive the actual product. The government closely reviews pharmaceutical development, testing, and manufacturing; .all pharmaceutical industry labeling and promotional materials undergo federal scrutiny. Of course, itis no accident that this amount of societal control is directed towards prescription rugs. Their therapeutic potential is phenomenal, as are the consequences of theIr misuse. Yet, with all the potency of pharmaceuticals, the consumer receives little in the way of labeling information about these products. The name and some brief directions for use are provided in a small label typed by the pharmacist. Warnings, precautions, side effects, and other important information are rarely provided (L. Morris, unpubl. results) and frequently forgotten if orally conveyed (Ley and Spelman 1965). These considerations prompted the Food and Drug' Administration (FDA) to require that patient.oriented labeling (also known as patient package inserts [PPIs]) be dispensed with certain prescription drugs, the most notable being oral contraceptives and estrogen drugs. Data regarding the effectiveness of PPIs for these drugs may serve as an important source of information for determining the impact of labeling for other prescription drugs and other consumer products. The Institute of Medicine (IOM) of the National Academy of Sciences recently reviewed data on PPI effectiveness derived from a number of sources, such as consumer and professional preference surveys and clinical studies of prototype patient leaflets (IOM 1975). This paper will focus solely on evalua- tions of the federally required oral contraceptive (OC) and estrogen PPIs. This limited focus provides the most concrete and generalizable information on the effects of a government-required label for a consumer product. Those interested in a more thorough review should consult the IOM report. ORAL CONTRACEPTIVE PPIs In the late 1960s evidence began accumulating about the dangers of OC use, especially the risk of possibly fatal blàod clots. In addition to revising labeling PAGENO="0353" 347 24 / L. A. Morris directed toward health professionals, FDA required that specially prepared labeling be made available to OC users. The rationale for the OC PPI was one of patient consent (Schmidt 1973). The purpose of the information was to allow consumers to make an informed choice about their birth control method. The PPI was deemed necessary because OCs are used by healthy women for non- therapeutic purposes and are associated with serious risks. There are alternative means of contraception without such risks. In light of these special circum- stances, written information directed to the consumer was seen as a method to assure that decisions about birth control methods could be made on the basis of accurate, information regarding the effectiveness of various methods and their risks. The original r'~quirement specified that two types of printed materials be made available to patients: a relatively brief insert to be distributed with birth control pifis and a longer brochure to be distributed by the physician upon patient request. The insert was delivered to the patient in the drug container. Manufactuiers of each brand printed their own version of the inserts which differed in shape, size, and extensity of information. However, for all brands, there were nine required sentences of information, set off in a box that preceded all other material. This boxed material summarized the important precautions about OCs. It contained information about the blood clot warnings, referred women to their physician and to the brochure, and cautioned that OCs were of no value for venereal disease. The basic brochure was printed by the American Medical Association (AMA) and distributed to physicians. It contained 22 paragraphs of information about possible adverse reactions, the risk of blood clots, what to do about missed periods, other considerations, and a summary. Manufacturers printed longer brochures, with additional material about the menstrual cycle, fertiliza- tion, and directions for use that followed the basic 22 paragraphs of information. In 1975, FDA completed a national survey of OC users to evaluate the effects of this PPI and brochure (Morris et al. 1977; Mazis et al. 1978). This survey constitutes the most detailed knowledge to date on the effects of a FDA- required PPI. Since the purpose of the PPI was to increase informed decision- making, the questionnaire solicited information about receipt, readership, use, and effects of the insert and brochure. Women, aged 18.44, currently using the pill were eligible to be interviewed. Over 23,000 households were contacted in a national probability sample to complete interviews with 1720 OC users. Only female interviewers were used and several call-backs were made to assure acceptable response rates. Completed interviews or patient ineligibility was determined at 86% of the households where contact was attempted. Each respondent was asked if she received the insert or brochure and if so, whether it was read. In a previous regional survey of OC users `(Fleckenstein et al. 1976) only 64% of the respondents filling out questionnaires said they 52-266 O-85----12 PAGENO="0354" 348 Patient Package Inserts / 25 received a copy of the PPI. In the present survey, respondents were shown copies of the PPI and brochure for their brand of birth control pill with the contents made illegible. When asked in this fashion, 93% of the respondents said they had received a copy of the PPI, but only 35% said they received a copy of the brochure. If respondents received the brochure and insert, the great majority said they read the insert (95%) and brochure (94%). As shown in Table 1, most reported that they read the information when they first took the pifi. This trend was more pronounced for the brochure compared to the insert. About one-fifth recounted that they read the insert when stimulated to do so by some event, such as receipt with a refill, a missed pifi, or when they did not feel right (presumably to discern if their discomfort was due to the drug). Although a substantial majority reported reading the PPI, it is not clear how carefully the material was read or how well it was remembered. Women may have merely glanced at the material and tossed it away. To determine knowledge transmitted, respondents were shown the insert for their brand of birth control pills with the boxed information made illegible. They were asked to recall what information was contained in the box.About half (54%) correctly recalled that the insert mentioned risks of clots, which was the most serious warning at that time. However, 87% said that the box contained directions for use of information, which appeared in most inserts but did not appear in the box. Thus, people tended to remember what they considered the most impor- tant information about OCs, but they were not able to identify the contents of specific sections of the insert. One may speculate that people extract infor- mation from the PPI and fit it into their own existing cognitive structure. When asked to describe specific sections, they reconstruct the answer based upon their memory. The site for specific material may be of little value to Table I When OC Information is Read . Reade rs (%) insert brochure First took pill 78 88 Each refill 11 6 Missed pill * 6 2 Don't feel right 4 3 Can't reach MD 1 2 Other 14 13 Don't know 1 * 2 No response 3 2 PAGENO="0355" 349 26 I L. A. Morris consumers and, therefore, may not be retained. People may believe that dosage directions are important and, thus, believe that this material is located in the important sections of the insert. To discern how the inserts may have affected patients' behavior, respond- ents were asked if the insert or brochure increased or decreased the frequency of physician contacts. About three quarters said there was no change in the pattern of contact, 10% reported a decrease, 5% an increase, and 9% did not answer or said they did not know. Interestingly, PPIs have been criticized both for decreas- ing physician contacts (and thereby interfering with the provision of physician services) (R. Lanzillotti and R. Blair, unpubl. results) and for increasing physi- cian contacts (and thereby increasing the costs of health care) (Gross 1978). Thus, not only are the behavioral results of interest, but it is important to understand the reasons for observed patterns of results. In the present survey, OC users were also asked if the insert or brochure contained information that led to contacting their physicians. Twelve percent of the insert readers and 6% of the brochure readers said it did. Many of the questions directed to the physi- cian were prompted by effects not mentioned in the patient information but experienced by the respondent; for example, spotting, bleeding, breast sore- ness, weight gain, and what to do about missed pills. These results, combined with data on readership and knowledge about OCs, suggest that the PPI serves two basic functions. First, the PPI is initially read by most people to obtain a general knowledge of content. At this time some important information may enter the patients' memory and augment existing knowledge stores. For drugs like OCs, women may already have a set of beliefs about use and effects. For other drugs, especially those not used before by the patient, the PPI may help formulate a more complete set of impressions. However, there is incomplete memory for details and the patient may then use the PPI for its second function, that of a reference sheet. The reference function appears to be an infrequently utilized but extremely impor- tant aspect of PPI usage. One may speculate that as one first begins using the pill, side effects may occur that need to be put in perspective. Other events, such as missed pills or less frequent (but more serious) side effects, may occur after longer usage of the pifi. For these events the individual may again consult the insert. Finally, women were asked to compare the insert and brochure and state which was their preferred source of drug information. The brochure was pre- ferred to the insert by an 89% to 3% margin. Longer inserts and brochures were preferred to shorter ones. In addition, respondents said they would like more information in the insert and the brochure, especially information about risks of using the pill. Only 16% of the women receiving the AMA brochure said they kept it for future use compared to about half of those receiving the longer manufacturer's brochure. PAGENO="0356" 350 Patient Package Inserts / 27 The results of this survey were utilized by FDA to revise its policy regard- ing the OC PPI. The brochure and insert were lengthened to include new infor- mation about cardiac and cancer risks. In addition, distribution of the brochure was changed. Rather than distributing it through the physician upon patient request, FDA required that it be distributed along with the insert at the time the drug was dispensed to patients. The implications of this survey must be carefully interpreted. Women overwhelmingly preferred the longer brochure to the insert. When asked which type of information they would prefer included with other drugs, 67% cited the brochure and 20% the insert. In addition, there are some indications that lack of information, rather than conclusions about listed material, causes confusion for OC users. The sample was composed of younger and more highly educated women than representative in the female population. Thus, we cannot be certain that sick, older individuals share these preferences with respect to drugs used to treat disease conditions. Yet, even if they did, patient preferences may not fully predict how people will react to and utilize information on other drugs. It is necessary to obtain patient responses to various forms of information. Knowledge and behavioral differences attributable to various forms of information that was stated as related to individual preferences would allow more meaningful interpretations. A study by Rand Corporation to collect this type of information is currently underway. ESTROGEN PPIs In 1977, FDA required manufacturers of estrogenic drugs to distribute PPIs. The requirement was prompted by epidemiological studies indicating an increased risk of endometrial cancer withprolonged usage of the drug. In addi- tion, estrogen usage is often quasi-elective, in that many women take the drtig for menopausal symptoms where it is not therapeutically necessary or necessary for only short periods of time. FDA estimated that in the mid-1970s several million unnecessary patient-years worth of treatment were being dispensed (Burke et al. 1977). The PPI was part of a larger information campaign directed at professionals and patients to reduce the use of estrogen in treating conditions where it was neither effective nor medically justified (FDA 1979). The PPI written for estrogens was 35 paragraphs long and frankly dis- cussed the risks of estrogen use. The insert contained information about symp- tOms of the menopause, the use of estrogens to prevent swelling of the breasts after delivery, the dangers of estrogens (such as~cancer of the uterus, other cancers, gall bladder disease, and abnormal blood clotting), a warning about birth defects from estrogen use during pregnancy, side effects of estrogens, and a summary. The PPI has been criticized for its tone and comple)dty. Critics maintain that it serves merely to frighten women without improving the quality of care or patient decision-making. Several authors-have estimated reading levels PAGENO="0357" 351 28/ L. A. Morris at 8th grade to college level (Liguori 1978; Pryczak 1978; Smith and Adams 1978). Data on the effects of the estrogen PP! is presently limited to several small studies and market research data on pharmacy sales. A larger evaluation of the estrogen PPI is currently underway as part of the Rand study previously men- tioned. In that study the current estrogen PPI is compared to rewritten versions to discern how changes in writing style affect patient knowledge and other behavioral effects. MARKETING DATA Oral Premarin®, the largest selling brand of estrogens, has maintained a constant- ly high percentage of the estrogen market throughout the past several years. Figure 1 displays pharmacy sales for this drug for a 6-year period. Data is derived from the National Prescription Audit, a monthly survey of 800 pharmacies con- ducted by IMS America of Ambler, Pennsylvania. Events that might be expected to influence drug usage are identified. This graph denotes some of the difficulties 3 DECEMBER 975 1W CANCER STUDIES PUBLISHED \ ~ I JANUARY-MARCH 1576 SENATE HEARINS5; FDA DRUG BULLETIN WARNING / NEW PHYDICIAN LABELING REDUIRED I OCTOBER 1971 PATIENT PACKAGE INSERT REQUIRED 0 I I I I I I I I I I I I I I I I I I * "~* ~ ~ "~* ~ QUARTERS Data from IMS America's National Prescription Audit Figure 1 Oral Premarin®: Total retail prescriptions dispensed at 1.25 mg-strength. (Data from IMS America's National Prescription Audit.) PAGENO="0358" 352 Patient Package Inserts /29 that face researchers in discerning the effects of various information programs. The PPI requirement followed a number of events that appear to have initiated a decrease in sales of the most popular dosage of the drug. It is impossible to discern the independent influence of the PPI. Is the apparent leveling of the decreasing sales trend in the summer and fall of 1977 (prior to PPI requirement) due to a spurious fluctuation, part of a seasonal variation in sales, or is it due to the decreasing influence of previous informational influences? The data suggest that the PPI may have contributed towards this downward trend. One has no way of knowing what sales levels would have been without the PPI. PATIENT STUDIES In addition to marketing data, studies have been conducted on the distribution, understandability, and other effects of the estrogen PPI. The first question of interest is whether patients actually receive a PPI when they fill a prescription. The oral contraceptive PPI is prepackaged by manufacturers in consumer- sized containers. Estrogen PPIs are delivered to pharmacies as separate leaflets, thus requiring dispensers to place a leaflet in each package given to patients. Recently FDA completed a survey of 271 pharmacies in 20 cities (Morris et al. 1980). Observers filled prescriptions for conjugated estrogens and requested a PPI if none was delivered spontaneously. Results indicated that the PPI was spontaneously delivered 39% of the time. Observers were more apt to receive the PPI in larger-volume chain stores (59% of these stores) compared to independent pharmacies (30% of these stores). If requested, 94% of the stores dispensed a PPI. The most frequently offered reason for not spontaneously dispensing the PPI was that it was forgotten. The 39% rate for spontaneous delivery of the PPI is disappointingly low. It is doubtful that many women would request the PPI. Thus, this survey suggests that in the absence of prepackaging, some efforts reinforcing the health professional's role in PPI dispensing are needed. Although we may assume there is approximately a 4 in 10 chance of any individ- ual receiving a PPI for estrogens when a new prescription is filled, we do not know the cumulative probability that an individual taking estrogens would have received a copy of the PPI at some time during the course of treatment. Assuming that the PPI is delivered at some point to the patient, it must be understood to some degree for it to have its desired effects. The ability of the PPI to communicate important messages was examined in a study of 117 pharmacy college freshmen (Russel et al. 1978). Written and oral instructions about estrogens were compared. People receiving either oral or written instruc- tions scored better than controls (receiving no information) and slightly better than a group receiving both oral and written instructions. Contrary to most research showing increased effectiveness of drug communications when both PAGENO="0359" 353 30 I L. A. Morris oral and written modalities are used (Morris and Halperin 1979), this study indicated that simultaneous presentation could produce distraction and less effective information transfer. Most subjects receiving the PPI said the material was easy (87%), very clear (8 1%), and that they understood most or all of the information (94%). The PPI had higher scores on clarity measures compared to verbal or combination presentations, although the difference between oral and written presentations was not significant. There were also no significant differ- ences between groups on questions relating to concern about taking estrogens. All three groups receiving information did better than controls on a knowledge test. In a second study of the estrogen PPIs, outpatients were given the PPI, asked to read it and told they would be interviewed in 2 weeks (N. Ferencz, unpubl. results). Of the 112 subjects questioned, 90 said they read the PPI carefully, 10 said they glanced at it, and 12 said they did not read it. Relevant dangers of estrogens appeared to be remembered by most patients. Sixty percent remembered information about the uses of estrogens, 86% remembered informa- tion about its dangers, 67% about its side effects, and 2% remembered to avoid estrogen use during pregnancy. Data on patient compliance were also gathered. Twelve of the 100 people reading the PPI said they did not follow the physi- cians' directions, whereas five of the 12 women not reading the PPI were not compliant. The author did not define his measure of noncompliance. A third study of the estrogen PPI focused on responses of 154 patients offered the drug as treatment for postpartum breast engorgement (Udkow et al. 1979). Most women (79%) received the PPI at the time of delivery (in the labor or delivery room) or soon after delivery, about 13% received it in the physician's office, and 8% never received the PPI. The questionnaire was left with women after delivery. Women who read the insert attempted and correctly answered more questions about estrogens. Readers generally judged the insert as easily readable (78%), not unnecessary (91%), and not too detailed (72%). About half (45%) felt the PPI was too long and 17% felt it was too short. Comparing readers to nonreaders, the PPI did not appear to affect the risk-benefit assessment of estrogens nor did it lead people to refuse to take the medication. These latter three studies suggest that patients judge the estrogen PPI as easier to understand than reading tests and professional judgments. Perusal of the estrogen PPI suggests that there are many multisyllabic words and long sentences, elements that would lead to high reading-level estimates. It is also evident that many of the concepts are difficult to understand. Yet most women tested judged the material to be useful and understandable. One may postulate that the people in these studies may have been more motivated to read the PPI than women who were not going to be questioned about it. However, motivation to read is not necessarily directly related to PAGENO="0360" 354 Patient Package Inserts / 31 patient understanding (although one could postulate a higher degree of informa- tion processing for high motivation materials). Another possibility is that reading tests may lack reliability and predictive validity (Morris êt a!. 1980). Thus, it may be difficult for people to understand many of the specifics, but upon reading they retain global impressions and an understanding of some key issues. A third possibility is that the studies undertaken so far have not been conducted on representative samples and, therefore, are not generalizable to most of the women taking estrogens. DISCUSSION In reviewing these data elements it is clear that judgments about the success or failure of PPIs as warning labels will be dependent upon the criteria chosen. To ascertain objective criteria for success or failure, one must be cognizant of the purpose of the PPI. The oral contraceptive PPI was intended to inform women of risks and benefits to aid in informed decision-making. The FDA surveys suggest high levels of reported receipt and readership. However, the degree or manner in which PPIs affected decision-making is unknown and awaits further study. Results for the estrogen PPI are more heterogenous and controversial. The estrogen PPI was written to dissuade inappropriate drug use. It was one of several interventions undertaken to accomplish this objective. On a gross measure of retail sales, there is a decreased use of this drug. However, it is not known if those dissuaded from use of the drugs are the individuals most at risk from cancer. Interestingly, Jick reports evidence that endometrial cancer fell 27% nationwide from 1975 to 1977 (Jick et al. 1979). However, even if correla- tional evidence exists regarding the benefits of decreased estrogen use, the role of the PPI in influencing this effect is unknown. The OC and estrogen data suggest some interesting applications and directions for future research. The most important communications problem for PPIs is getting patients exposed to the information. Packaging inserts with the drug is one effective method. Other cost effective methods need to be examined to increase exposure rates. It is clear that only a small proportion of information presented on the PPI is actively remembered by patients. One can speculate that people remember what they think is most important. Perceived importance is apt to be determined by the patient's existing needs, goals, knowledge, and beliefs. It is also apt to be influenced by the label itself. With products like specific drug entities, people may have a relatively low initial knowledge base. The manner in which the PPI is structured can help formulate perceptions about the relative importance of various pieces of information. Thus, labels should be written with a few clear objectives in mind so that the most important information will be effectively PAGENO="0361" 355 32 / L. A. Morris stressed. Furthermore, we need to understand more about what patients cur- rently know about drugs. Important information should be presented in a fashion that will be assimilated into the patient's memory. Future research is also needed to clarify some of the inconsistencies that appear to have grown from this literature. For example, why does the PPI score fairly well when people are asked to rate its value and clarity, but reading tests indicate it is difficult to understand? If the PPI does at least contribute toward a downward sales trend, how does it do this if it is dispensed to only about 4 of 10 people filling prescriptions? It is possible to generate numerous hypotheses to account for these data - Certainly evaluations are necessary to further test the impact of PPIs. The estrogen data points toward the need to utilize multiple methods of assessment so that a more complete overview of PPI impact can be obtained. Finally, one may speculate how data on PPIs might be generalized to products other than prescription drugs. Certainly there are some similarities; PPIs seek to communicate technical information via a written channel. However, there are some important differences. Patients (individuals who delegate product selection to a physician) rather than consumers (who make their own product choices) are the recipients of the information. The risk-benefit nature of prescription drugs make side-effect and warning information important aspects of the communication. Thus, patients may be more motivated to read this information (although I know of no data to support this) but may necessarily be exposed to fear-arousing information. Given these important differences, perhaps the most generalizable set of results would be those pertaining to the communication value of PPIs. An understanding of the ability of different types of PPIs to generate desired levels of knowledge would ii:icrease our understanding of how information is processed. Behavioral and attitudinal effects of PPIs are probably much less generalizable, given the unique aspects of prescription drugs compared to other consumer products. ACKNOWLEDGMENTS The author gratefully acknowledges the assistance of Ivan Barofsky, Mike Mazis, and lloyd Millstein for their suggestions on an earlier draft. The views expressed here are solely those of the author and do not necessarily reflect the policies of the Food and Drug Administration. REFERENCES Burke, L., D. Crosby, and C. Lao. 1977. "Estrogen prescribingin menopi~use." Paper presented at American Public Health Association, Washington, D.C., November. PAGENO="0362" 356 Patient Package Inserts / 33 Fleckenstein, L., P. Joubert, R. Lawrence, B. Pastner, J. Mazullo, and L. Lasagna. 1976. Oral contraceptive patient information: A questionnaire study of attitudes, knowledge, and preferred information: sources. J. Am. Med. Assoc. 235:1331. FDA (Food and Drug Administration). 1979. Update on estrogens and uterine cancer. FDA Drug Bulletin 9:2. Gross, A. 1978. Assessing the value of information for patients-letter to the Editor. J. Am. Med. Assoc. 23:240. IOM (Institute of Medicine). 1979. Evaluating patient package inserts. (79-05), August. National Academy of Sciences, Washington, D.C. Jick, H., R. Watkins, J. Hunter, B. J. Dinan, S. Madsen, K. J. Rothman, and A. M. Walker. 1979. Replacement estrogens and endometrial cancer. N. Engl. J. Med. 300:218. Ley, P. and M. S. Spelman. 1965. Communications in an outpatient setting. Br. J. Soc. Clin. Psychol. 4:114. Liguori, S. 1978. A quantitative assessment of the readability of PPIs. Drug Intell. Clin. Pharm. 12:7 12. *Mazis, M., L. Morris, and E. Gordon. 1978. Patient attitudes about two forms of printed oral contraceptive information. Medical Care 16:1045. Morris, L. and J. Halperin. 1979. Effects of written drug information on patient knowledge and compliance: A literature review. Am. J. Public Health 69:47. Morris, L., M. Mazis, and E. Gordon. 1977. A survey of the effects of oral con- traceptive patient information. 1. Am. Med. Assoc. 238:2504. Morris, L., A. Myers, and D. Thilman. 1980. Application of the readability concept to patient-oriented drug information. Am. J. Hosp. Pharm. (in press). Morris, L., A. Myers, P. Gibbs, and C. Lao. 1980. Estrogen PPIs-An FDA survey. Amer. Pharm. NS2O :318. Pryczak, F. 1978. Applications of some principles of readability in the prepara- tion of patient package inserts. Center for the Study of Drug Develop- ment, Rochester, New York. Russel, W., R. Roberts, D. Bradley, J. Marshall, and H. Glazer-Waldman. 1978. "Patient package inserts: A study of communication techniques." Paper presented at the American Association of Hospital Pharmacy Meeting, San Antonio, Texas, December. Schmidt, A. 1973. "Dimension of changes in the FDA." Paper presented at the Pharmacy Advertising Seminar, Chicago, Illinois, September 13. Smith, T. and R. Adams. 1978. Readability levels of patient package inserts. Am. J. Hosp. Pharm. 35:1034. Udkow, G., L. Lasagna, M. Weintraub, and Z. Tamoshunas. 1979. The safety and efficacy of the estrogen patient package insert: A questionnaire study. J. Am. Med. Assoc. 242:5 36. PAGENO="0363" 357 34/ L. A. Morris COMMENTS SCHULTZ: Was a patient supposed to get the brochure from the doctor? MORRIS: Doctors were supposed to give out the brochure upon patient request. We believe that some doctors may have handed it out routinely, others may have given it only upon request, and other doctors may not have given it out at all. Some doctors never even knew it existed. Another possibility is some women may have gotten their pifis from clinics where they are dispensed from bulk packages. McGUIRE: Did you check that 93% for false alarm recognition by holding up a phony labeling also and asking "Did you get this one?" MORRIS: No, we didn't go that far. In an earlier survey people were asked "Did you get a copy of it?" By that survey only 66% said they ever received a copy of the insert. The difference between surveys may be due to recall and recognition testing, or it could be that people didn't know what was being referred to in the recall test. If we were to have only the recall data, it would have led to totally different conclusions. Luckily, we had recognition data which we feel is more accurate. I don't know the extent to which people may have over-remembered or tended to say "yes." RHEINSTEIN: The brochure was simply made available to outside salesmen to give to doctors, like any other service item, wasn't it? MORRIS: Yes. I think most companies did print the brochure. Also, the AMA distributed millions of them to doctors. WALDEN: Well, FDA required the companies to print and distribute them but we couldn't require the doctors to give them out. SCHULTZ: During what period of time was the brochure distributed to doctors? MORRIS: From 1970 to 1977. FABRO: The brochure actually was a part of the information that the patient was given in the early `70s when discussing alternative methods of contra- ception. Now everybody discusses the benefits and risks. In 1980, this is a big issue. PAGENO="0364" 358 Patient Package Inserts /35 SCHULTZ: Why did you change the distribution point of the brochure? MORRIS: FDA now requires that the brochure be distributed with the drug rather than available upon request. The only authority we have in terms of requiring labeling is if it's dispensed with the drug. Also, people over- whelmingly preferred the brochure to the insert. WALDEN: Lou, are you saying that labeling is working then? MORRIS: From looking at the recent data, my impression is that the PPI seemed to influence the trend but there's no way of knowing to what extent. This is aggregate data. What we want to do with estrogen labeling is dissuade usage for people who don't need the drug, or are on it for long periods of time. We don't know who's not using the drug. We also don't know the mechanism. PPIs may have influenced the doctor rather than the patient. Maybe the doctors don't want their patients to see it. We don't have a good feeling for how the information is working. I think we need to know more about that. SCHULTZ: Is the use of estrogens for engorgement reduction an approved use? MORRIS: Yes. In the JAMA study (Udkow et al. 1979) women were offered estrogens and given the insert the day after delivery for postpartum breast engorgement. Twenty-four hours later they were asked if the wanted to take th~ drug. Only five or six people refused it-two refused it because they read the PPI. It really wasn't the best of circumstances for an evalua- tion study. This study has lots of problems with it. However AMA cited that study as a reason for opposing PPIs. RHEINSTEIN: All of the ifi effects that the insert talks about have to do with long-term use of estrogen, so it's not surprising that the AMA came out and said that "this doesn't change behavior, therefore it's not useful." It didn't change behavior because nothing in it was relevant to that situation. MORRIS: One of the problems with PPIs is that all drugs are used with differ- ent indications in different ways. WALDEN: You've got to study some other kinds of drugs and PPIs because you've got a terrific bias here. Oral contraceptives have to do with improv- ing sex, and estrogens, by and large, have to do with sex after menopause and how to improve it. That provides a tremendous bias, don't you think? PAGENO="0365" 359 36/L.A.Morris - MORRIS: Yes. I presented the data on estrogens and oral contraceptives because that's where we've done our regulations. We've done some clinical studies using prototypes and our next step is to acquire about ten PPIs that vary in uses and populations, and reasons for PPIs and study them. SCHULTZ: I'd be interested in learning more about the experience with giving the brochures out in the doctor's office for diethystilbestrol (DES). Do you know any more about that? MORRIS: Unfortunately, that regulation was never enforced because the company that manufactured that pill issued PPIs only for DES used as the "morning after" pill. SCHULTZ: It never was enforced? WALDEN: That's right. FDA invited marketing of the "morning after" pill with DES, but nobody ever did it. I always had the impression-I am certainly no expert-that it doesn't matter all that much, that an estrogen is an estrogen is an estrogen. DES was used because it was synthesized and therefore a low-cost estrogen. FABRO: It appears at the present time that estrogenic activity may not always be associated with neoplastic activity, and vice-versa. References Udkow, G., L. Lasagna, M. Weintraub, and Z. Tamoshunas. 1979. The safety and efficacy of the estrogen patient package insert: A questionnaire study. J. Am. Med. Assoc. 242:536. Patient Information on CAFERGOT® (ergotamine tartrate and caffeine) tablets, NF (KAF-er-got) PLEASE READ BEFORE TAKING CAFERGOT PAGENO="0366" * ORAL PREMARIN TOTAL RX'S DISPENSED, BY STRENGTH SEMIANNUALLY-~-4973 THROUGH 1980 1ST CANCER STUDIES PUBLISHED SENATE HEARINGS; FDA DRUGBULL~11JN WARNING NEW PHYSICIAN LABELING REQUIRED PPI REQUIRED S 5, 1' r SIX MONTH PERIODS Legend L~ 0.3 MG X 0.63 MG 0 125 MG ~ 2.5 MC PAGENO="0367" 361 Mr. WAXMAN. That is why we are holding this hearing, because I don't think we are going to have much available to the public by way of Government action that would inform them of the dangers if understood. Labeling does have some significance in the overall information to the public and this label that you have as part of a voluntary effort is about as meaningless a label as I could possibly imagine. Dr. YOUNG. The labels will vary. Some of the labels from Plough are very strong in the descriptions of Reye's Syndrome. Others are not as strong and merely say contact your physician. I agree there is a variability. If we try a volunteer program, the government is not, as you rightly pointed out, requiring specific language at this point. Mr. WAXMAN. Should the Government require specific language? If you can't say there is a definitive link, there is probably a link, you feel comfortable with that? Dr. YOUNG. I have no problem with the possible association, that is correct. Mr. WAXMAN. It seems to me that in every way possible we ought to inform the public. Labels are one opportunity. When a person is reaching for the aspirin, the label should have the words Reye's Syndrome, don't use it. But instead, it simply says if you have these symptoms talk to your doctor. You have other ways of communicating information. The poster I probably won't stop to read. The other one mentions flu or chicken pox. I think that is real nice. You have to read the fine print there. I haven't had a chance to read all those posters. But whatever you do is better than nothing. I am wondering how much better than nothing we have in terms of the voluntary effort by the adminis- tration. Can you tell us-you're monitoring it-what information you have? First, let's talk about the labels that you agreed to. What percentage of aspirin products on the market had warning labels as of February 28, 1985? Do you know how many complied with what you voluntarily agreed to? Dr. YOUNG. Because of pipeline issues and the fact that there was not a recall, only 1 percent would be expected to comply by that time. Mr. WAXMAN. One percent. What percentage of aspirin products still identified influenza or chicken pox as indications for aspirin as of February 28? Dr. YOUNG. Similarly, because of the pipeline and that these were used in the beginning of the flu season, we have the product labeling as described. Those indications will not be there in the next flu season. About 99 percent would have those because it is a pipeline issue. Mr. WAXMAN. Well, you are being awfully nice to the aspirin in- dustry if you are concerned about their making sure they can sell the aspirin during the flu season without disturbing their profit picture. What do you care about their pipeline if there is a product that is still going to have on the label to go ahead and use this for these symptoms, that aspirin is appropriate for these symptoms. Isn't that the wrong kind of information? Dr. YOUNG. The only way to get those out would be to recall all of those products from the shelf. That is exactly what I meant by PAGENO="0368" 362 the pipeline issue. A recall was not even contemplated at this point. Mr. WAXMAN. A recall is one way, another label on those prod- ucts could be slapped on, which you say one company is already doing? Dr. YOUNG. One company stopped shipment. Mr. WAXMAN. A mandatory sign at the point where those prod- ucts are sold certainly would be another way to inform them. I assume there was no mandatory sign imposed by the Department on retail establishments? Dr. YOUNG. That is correct. Mr. WAxM~. Do you know how many retail establishments have any kind of sign that indicates that people ought to be aware of the potential risk of Reye's Syndrome by taking aspirin. Dr. YOUNG. Yes; we have conducted a study to look at this within the early weeks of March. We studied 115 retail drug and 115 gro- cery pharmacies. I will ask Mr. Michels to comment on that study, and describe this, but I emphasize that this is very early in the process of get- ting it out, and we fully intend to follow this and find out how long it takes to get these on the shelves. The answer is that it is approximately 12 percent, but I would like him to describe how the study was done. Mr. WAXMAN. I don't want to know about the study. The result is 12 percent of the establishments you monitored have some kind of warning sign up. Mr. MICHELS. Of the 230 chain drug stores and chain grocery stores we looked at, a total of 28 stores had posters in them. Mr. WAXMAN. And what do those posters say? Or do they vary? Mr. MICHELS. There were a variety. There was the Aspirin Foun- dation posters. Mr. WAXMAN. What does the Aspirin Foundation poster say? Mr. MICHELS. If I can find it here, sir. Dr. YOUNG. We will get that directly for you. Mr. WAXMAN. I am sorry, I thought you might have that avail- able. I would be curious if there are varying signs and the Aspirin Foundation has a sign I would be interested in knowing what they say, but I gather you have varying signs, because it is all volun- tary. Dr. YOUNG. Yes. Mr. WAXMAN. Whatever anybody wants to do to inform the public, it is fine with you. There is no uniform sign agreed to. Dr. YOUNG. That is correct, and there are also some that were put out by some of the pharmaceutical corporations, I am sorry, some of the retail corporations. Giant, for example, very early put a shelf peeler on, and was ex- tremely helpful, because that was right at the point of purchase, and would not only apply to one particular brand of aspirin, but would apply to all on the shelves. These were requested to be displayed very prominently where we have the analgesics. Mr. MICHELS. Here is a copy of the Aspirin Foundation poster. I understand it is identical to that in their 60-second public service announcement. PAGENO="0369" 363 Mr. WAXMAN. Is that announcement saying there is no connec- tion proved between Reye's Syndrome and aspirin? Dr. YOUNG. We have this available, Mr. Chairman, if you would like to see it. We have both the 30-second and 60-second. Mr. WAXMAN. No, just the text. Mr. MICHELS. Not this poster, no. Mr. WAXMAN. I would like to see all of those for the record. I would like to receive the full studies and monitoring reports that you have for the record as well. Also, we sent a letter specifically to Secretary Heckler asking for certain data as well, and we would like to have that answered for the record. Dr. YOUNG. We certainly will supply that. [Testimony resumes on p. 413.] [The information requested follows:] PAGENO="0370" 364 Aspirin Foundation of America Reye Syndrome Public Service Announcements Text of 30-Second Announcement "An important message for parents of children and teenagers with chicken pox or flu. A rare but serious childhood disease called Reye Syndrome may develop in children who have chicken pox or flu. Although the cause of Reye Syndrome is not know, some studies suggest a possible association with medicines containing salicylate or aspirin. So it * is prudent to consult a doctor before giving these medicines to children and teenagers with chicken pox or flu. A public service announcement brought to you by the American Reye's Syndrome Association, the Reye' S Syndrome Society and the National Reye `5 Syndrome Foundation." Text of 60-Second Announcement "An important message for parents of children and teenagers with chicken pox or flu. A rare but serious childhood disease called Reye Syndrome may develop in children who have chicken pox or flu. Although the cause of Reye Syndrome is not known, some studies suggest a possible association with medicines containing salicylate or aspirin. So it is prudent to consult a doctor before giving these medicines to children and teenagers with chicken pox or flu. Remember, Reye Syndrome occurs even in children and teenagers who take other medicines or no medicines. It's important to be aware of the early signs and symptoms. If your child shows unusual behavior, such as severe tiredness, belligerence, or excessive vomiting after appearing to recover from chicken pox or flu, get medical help irsnediately. Give no medications. A public service announcement brought to you by the American Reye's Syndrome Association, the Reye's Syndrome Society and the National Reye's Syndrome Foundation." Doc. 3258F, Disk Oll2A PAGENO="0371" 365 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville MD 20857 April 11, 1985 `The Honorable Henry A. Waxman Chairman, Subcomittee on Health and the Environment Cormiittee on Energy and Cormterce House of Representatives Washington, D.C. 20515 Dear Mr. Waxman: This is in response to ynur letter of January 11, 1985, addressed to Secretary Heckler, regarding the ongoing voluntary progran to revise the labeling for aspirin and salicylate-containing drug products to reflect the possible association bett~en the use of these products and the development of Peyn syndrome in children and teenagers who have flu or chicken pox. As ynu know, this voluntary progran also includes art extensive public education canpaign. Recently, in appearing before the Subcornitittee t~ responded to some of the questions posed in ynur letter. We are now submitting the enclosed written responses to all of these questions to complete the record. If t~ can be of any further assistance, please let us know. Sincerel yours, Frank . o , h.D. * Commissioner o Food nd Drugs Enclosure PAGENO="0372" 366 RESPONSES TO QUESTIONS IN CHAIRMAN WAXMAN'S LETTER OF JANUARY 11, 1985 1. The percent of aspirin products on the market with adequate warning labels as of February 28, 1985, and projections as to the date when all products will be in full compliance. Answer Less than 1 percent. Based on FDA's own experience, which was confirmed by discussions with aspirin manufacturers who are members of the Aspirin Foundation of America, it was concluded that relabelino products would not be feasible during this flu season because, by mid-January, the flu season was already half over and would last only about three additional months. Instead, FDA concluded that an intensified public education caiipaign, combined with shelf posters, would be the most expeditious and effective mechanism of communicating this information to the consuming public in so short a period of time. FDA has, however, strongly encouraged the industry to relabel individual products prior to the beginning of next year's flu season. The Agency has recently been in contact with representatives from the Aspirin Foundation of America, whose eight member companies plan to voluntarily relabel their aspirin-containing drug products. These revisions would entail: (a) a warning statement which reads: "Warning: Consult a physician before giving this medicine to children, including teenagers, with chicken pox or flu" and (b) deletion of all references to flu on the labels of children's aspirin products. Our understanding is that all eight firms are currently revising their labeling. The industry members have indicated to us that the first stock with revised labeling will be available for distribution as early as June or July 1985. The goal is to have these changes in place prior to the commencement of next year's flu season. Plough, Inc. of Memphis, Tennessee, maker of St. Joseph aspirin and nxn-aspirin products for children, which is not a member of the Aspirin Foundation, has developed its own voluntary precautionary labeling progrmn. Beginning on January 9, 1985, Plough placed an abbreviated warning sticker on all stocks shipped from its plant. The sticker reads: "Consult doctor before use in children or teenagers with flu or chicken pox." Plough will also include in all packages which contain an insert information which identifies the syiiptoms of Reye syndrome. Few, if any, of these stickered packages wore likely to reach retail shelves by February 28, 1985. In addition, Plough intends to relabel all its children's aspirin_rontaifling products to include the followinq warning statements: "Warning: Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Re~ Syndrome is unknown, some reports claim aspirin may increase the risk of developing this disease. Consult a doctor before use in children or teenagers with flu or chicken pox." As with the Aspirin Foundation members, the goal is to have the new label ing in place prior to the commencement of next year's flu season. PAGENO="0373" 367 2. The percent of aspirin products on the market that continue to identify influenza, "flu" or chicken pox as indications for the use of aspirin, as of February 28, 1985. Answer We are aware that some aspirin products on the market identify influenza, "flu," as an indication for use while others do not. We believe few, if any, are indicated for chicken pox per se. However, accurate percentage figure information is not available at this time. Efforts are underway to detennine this type of information fran the responses received from the 3,264 "Dear Drug Establishment Registrant" letters describing the voluntary label inq progran which were mailed March 8, 1985 (copy enclosed). As stated in response to the first question, FDA believed that shelf posters and public education, rather than relabeling of individual products, would be possible to accomplish immediately. Also as noted in our answer to question #1, however, the Aspirin Foundation members do intend to relabel their products to delete reference to flu in the labeling of children's aspirin products, prior to the commencement of the next flu season. I should note that apart from children's aspirin, some aspirin products will continue to be labeled for use to treat influenza. Rut, as yu know, the warning statement that will appear on all aspirin-containing products specifies that a physician should be consulted before giving the product to children or teenagers with flu or chicken pox. PAGENO="0374" 368 3. Evidence that parents and physicians are becoming aware of the risks of using aspirin and are in fact avoiding the use of that drug in cases of chickenpox or influenza, and a description of plans the Department has for monitoring parental information and behavior. Answer The Agency is seeking approval through appropriate channels to conduct a telephone survey to assess constziier awareness of the issue. A questionnaire desiqned to query individuals about drug use patterns and knowledge about the use of aspirin during episodes of flu or chicken pox will be utilized. Data will be collected using a sample size of 1500 eliDible households to be identified by screening 3000 telephone households. The survey, as currently envisioned, however, does not include physicians. In an effort to get the survey underway, FDA decided that because these products are, for the most part, taken without consulting a physician, it would be appropriate and logical to target the survey towards the general consinier to ascertain awareness in our initial survey. The Agency is prepared to conduct an expanded survey after these educational efforts have become fully operational if we feel that further feedback will help modify and improve the informational and educational programs underway. It is worth notinq here that we have bequn to see some indication that the public awareness campaigns are having an effect. Sales of single entity aspirin products for children have declined notably during the flu-season for the last several years. Also, data show that doctor recommendations for the use of aspirin for the treatment of flu and chicken pox in yeung children declined 72 percent between 1980 and 1983. These trends probably suggest that public education efforts have succeeded in reaching consumers and health care providers. PAGENO="0375" 369 4. Actions that the Department and aspirin manufacturers have taken to distribute new warning labels to be placed on aspirin products already in people's homes as well as on inventories already in distribution. Answer As noted earlier, FDA felt that relabeling products already in distribution channels, or mailings to provide labels for individual home use, was not feasible at this time. Instead, the Agency expanded its public education caiipaign, with some modifications to update the information as a result of the pilot study, as the most practical way of informing the public during this flu season with respect to products already on store shelves or in people's homes. The progra~ specifically included public service announcements, posters in schools and doctor's offices, newspaper columns, and special mailings to various health and consimier organizations. The private sector has also launched public education efforts. The Aspirin Foundation has prepared public service announcements for television and radio. In addition, the Aspirin Foundation members, as well as retailers and trade associations, have distributed shelf posters to be placed at the point of purchase in grocery stores and pharmacies to cover current inventories. PAGENO="0376" 370 5. The degree of compliance of each specific aspirin manufacturer or distributor with your voluntary program. Ans wer FDA does not have data on each specific aspirin manufacturer. The Agency did, however, do a sampling of major retail establishments to assess the deqree of compliance with this aspect of the voluntary program. Specifically, during March 4 to 6, 1985, FDA conducted a nationwide inspection of 115 randomly selected major chain grocery stores and 115 randomly selected major chain drup stores to determine the effectiveness of voluntary compliance with respect to the placement and display of posters containing a warning statement of the possible association of Reye syndrome with aspirin-containing drug products. As of March 6, 1985, of the 230 combined retail outlets visited, only 28 had Reye syndrome warning posters displayed. A total of 38 posters were displayed in these 28 retail outlets. Nine posters were supplied by members of the Aspirin Foundation of America and 29 posters wore supplied by corporate offices of various retail outlets (e.g., t~iant Foods) or by the American Pharmaceutical Association (APhA). The majority of posters that were available were prominently displayed in the analgesic sections of the stores in such a manner that a consumer purchasing these products would readily see the warning statements. Some retail outlets have displayed the poster near the checkout cash register. rn addition, 5 retail outlets surveyed had had Reye syndrome warning posters supplied to them but had not displayed them at the time of FDA's visit. Our inspectors encouraged store managers and pharmacists to make use of these posters to convey this important public health information. Overall, results of the inspection indicate that posters supplied by all sources wore displayed as early as February 1, 1985, and as recently as March 6, 1985. There are a number of possible explanations or contributory factors as to why such a limited number of industry-sponsored posters have appeared in retail establishments. For example, industry sales force personnel often made posters available to wholesalers and distributors rather than to retail outlets. In addition, in some instances, there has been a reluctance on the part of retailers to display the posters due to the past controversy surrounding this issue. Finally, the time period was fairly short and may not have been sufficient to make a proqram of this magnitude fully operational. PAGENO="0377" 371 Nevertheless, the Agency did find these initial results of the poster campaign to be disappointing. Therefore, FDA officials met with the Aspirin Foundation on March 13 regarding the level of voluntary compliance observed. The Aspirin Foundation offered assurances that additional efforts, such as direct mailinos to pharmacies and grocery stores, and more vigorous canvassing by the industry sales forces are being undertaken to ensure as complete coverage as possible. We intend to perform a second inspection of retail establisirents in the next several weeks to measure the effectiveness of the Aspirin Foundation's renewed efforts with respect to posters. As you know, this private sector voluntary labeling campaign is respresentative of the eight members of the Aspirin Foundation of ~n~erica and Plough, Inc., maker of St. Jospeh's aspirin and non-aspirin for children, which is not a member of the Aspirin Foundation. As was mentioned above in responding to ouestion #2, in an effort to reach other manufacturers of aspirin and salicylate-containing drug products to advise them of these voluntary initiatives, we have written to all drug manufacturers registered with FDA. The purpose of this letter is also to ascertain whether, and to what extent, these firms intend to join in this nationwide campaign. We will also be assessing the results of this additional effort. Attachment PAGENO="0378" 372 Retail Survey--Reye Syndrome Warning Statement Posters On March 1, 1985, the Office of Compliance, CDB, FDA issued an all FDA District Office and Station assignment to determine the effectiveness of the industry voluntary informational program on Reye Syndrome. Each District Office and Station was instructed to randomly select and visit five major chain drug stores and five major chain grocery stores for a total of 230 establishments within their Standard Metropolitan Servicing Area to determine whether any Reye Syndrome posters or placards were displayed. In addition to reporting whether posters were present, the size and placement of the posters was reported. If the posters differed from those of the Aspirin Foundation of America, the Districts were instructed to report the exact language of the warning posters and to determine the source of supply. The survey was conducted during the week of March 3, 1985, and all data were received at FDA Headquarters on or before Friday, March 8, 1985. REYE SYt~1E RETAIL SURVE P&uther of Stores with Poster _______ Sub~t~. DrUg 7 2 14 16 23 Grocery 2 1 2 3 5 1~ta1 9 3 16 19 28 PAGENO="0379" 373 DEPARTMENT OF HEALTH & HUMAN SERVICES Pubtc Health Servlte Food and Drug Administration Rockville MD 20857 March 8, 1985 Dear Drug Establishment Registrant: On January 9, 1985, the Secretary of the Deparbnent of Health and Human Services requested the aspirin industry to undertake a voluntary program to warn parents and teenagers about the possible association between the use of aspirin and the onset of Reye Syndrome. As a consequence, the Comissioner of Food and Drugs met with representatives of the Aspirin Foundation of America, Inc., and Plough, Inc., at which time both organizations announced they vould launch voluntary Reye Syndrome precautionary programs. The purpose of this letter is to inform you of the voluntary labeling progress being undertaken by the Aspirin Foundation and Plough, Inc. and to. ascertain whether, and to what extent, your firm intends to join in this nationwide program. As a part of its voluntary program, the Aspirin Foundation has proposed labeling revisions for aspirin and aspirin-containing products, which include: (1) Indications for use in ~flu5 will be resoved from products packaged only for use in children (pediatric products). (2) All such products will bear the statement; "Warning: Contact a physician before giving this medicine to children, including teenagers, with chicken pox or flu." Plough, Inc. of Wasphis, Th, maker of St. Joseph aspirin and non-aspirin products for children, which is not a meniDer of the Aspirin Foundation, has developed its own voluntary precautionary program. A part of its program includes the labeling revisions for children's products proposed by the Aspirin Foundation with the, following expanded warning statement: PAGENO="0380" 374 "Warning: Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease. Consult a doctor before use in children or teenagers with flu or chicken pox." Plough, Inc. also intends to include in its packages an insert bearing information which identifies the symptoms of Reye Syndrome. The ~DA supports these voluntary precautionary programs of the Aspirin Foundation and Plough, Inc. and the labeling revisions proposed by them and urges that they be applied to all aspirin and salicylate-containing drug products intended for use in the treatment of flu or chicken pox, and/or likely to be used by children or teenagers in the treatment of symptoms coxmnonly associated with flu or chicken pox (e.g., fever, cough, headache, sore throat, sneezing, nasal congestion, rhinitis). For more information, please refer to the attached HHS Press Releases and FDP~ TALK PAPER. Should you elect to participate in this voluntary program, we would reconmend that a warming statement appear on all c~irtons, container labels, and other printed materials as the first warning for products with multiple warning statements, and that the labeled directions for use refer to the warning statement, such as "For Chicken pox or Flu see Warnings." This is consistent with the agency's position in the advance notice of proposed rulemaking that was issued on December 28, 1982 (47 FR 57886). In an effort to update our files under the drug listing regulations, we request that you answer the questions on page 3. of this letter: PAGENO="0381" 375 (1) Establishment Name Address City/State/Zip ________ ____________ ( ) (2) Respondent's Name Title Telephone No. (3) Is your firm currently involved th the manufacturing, repackaging, relabeling, and/or distribution of products containing aspirin or salicylates? Yes No If yes, please attach specimens or ~ of each container label, carton label, and accompanying labeling. Mark on each specimen or copy whether the product is manufactured (M), repackaged (RP), relabeled (RL), repackaged and relabeled (RP/RL), or distributed only (D). (4) Does your firm intend to relabel its aspirin or salicylate-containing products in conformance with the voluntary initiatives d~veloped by the Aspirin Foundation or Plough, mc? Yes No Not Applicable - * If yes, please attach specimens or copies of each container label, carton label, and accompanying labeling showing changes to be made. (5) If yes to items 3 and 4, what is your anticipated date to begin using the new labeling? * * Date_________ (6) If yes to items 3 and 4, what is your anticipated date for such newly labeled products to reach the retail market place? Date_________ Please return using enclosed envelope by 3/29/85 to; Food and Drug Administration * HFN-3l2 5600 Fishers Lane Rockville, ~5) 20857 Attn: Reye Syndrome Labeling PAGENO="0382" 376 As indicated above, we request that, whether or not you decide to participate, you submit one copy of each label, carton label, and accompanying labeling for each aspirin or salicylate-containing product currently manufactured, repackaged, relabeled and/or distributed by you. Should you agree to participate in this program, we ask that you also submit a copy of each label, carton label, and accompanying literature for each such product showing the revisions to be made. With regard to questions 5 and 6, we request that you identify the anticipated dates for using such revised labeling and when products, bearing revised labeling, will reach the retail market place. Please return page 3 of this letter and any pertinent labeling, as requested, using the enclosed envelope, by March 29, 1985. Should you have any questions you may contact Kevin M. Budicn, Assistant to the Director, Division of Drug Labeling Compliance, Office of Compliance, Center for Drugs and Biologics at (301) 443-7283. Thank you for your prompt attention in this matter. Sincerely, (7~-) Y2i Harry M. fr~yer, Jr., M.D. Director Center for Drugs and Biologics Enclosures (3): Secretary's Press Statemant, 1/9/85 rIBS Press Release, 1/23/85 FD~ Talk Paper, 1/25/85 PAGENO="0383" 377 YPe*C*ETAaY O~ H(ALTh ANO NLUAN ISSV$cU ~ assi Statement by Margaret N. Heckler Secretary of Health and Human Services Nothing is more important to Americans than the health and safety of their children and, as Secretary of Health and Human Services, I feel a special responsibility to protect the health of our nation's children during their most vulnerable years. That is why I ordered special steps to resolve the scientific dispute when some early studies showed an association between Reye syndrome and the use of aspirin for children suffering from chicken pox, influenza and flu-like illnesses. That is also why I instructed the Food and Drug Administration to pursue a vigorous public education campaign to ensure that parents were made aware of the possible link. In particular, I ordered the Centers for Disease Control a year ago to undertake a new study of aispirin and Reye syndrome. The study had two parts a one-year pilot study followed by a full-scale investigation. The Centers for Disease Control have now completed the pilot study. This study is not completely conclusive - but its findings do show an association between the use of aspirin and the onset of Reye syndrome in children and teenagers. These results make it urgent that CDC vigorously pursue the full- scale study. That work was begun last month and is now fully underway. In the meantime, I strongly urge parents to follow the advice of the Surgeon General: in all cases involving children, inclndi~q teenagers~ a physician should be consulted before using aspirin in cases of fIü~or chicken pox. It is significant that fewer children are now being struck by Reye syndrome - 190 known cases in the year ending November 1984 - while reported cases in previous years were as high as 548 (in 1980). But this does not mean we can be complacent. The disease is deadly, with a fatality rate of 26 percent last year. In addition, those who suffer from the disease are increasingly older children and teenageri, as well as young children: According to the pilot study, some 50 percent of all cases were in those over age 10, and 15 percent were in those aged 15 and older. In order to ensure that all children continue to be given the fullest protection, even while we await final scientific conclusions, I am today taking four additional steps: First, I am ordering CDC to release the pilot study immediately, and I am instrutting that it also be published as soon as possible in CDC's journal Morbidity and Mortality weekly Report. This information along with other scientific evidence will appear~in a refereed scientific journal. Second, I am asking the Food and Drug Administration to extend and expand its public education efforts -- parents must understand the need to consult a physician before using aspirin to treat flu or chicken pox. Likewise, FDA will take steps to inform teenagers - who often treat themselves -- of the possible link between aspirin and Reye syndrome. PAGENO="0384" 378 Third, I am contacting media leaders throughout the country asking them to use every possible resource to help broadcast the message. I am telegraphing the presidents of the three television networks as well as the American Newspaper Publishers Association, the National Association of Broadcasters, the Association of Independent Television Stations, and the National Cable Television Association. I will also send letters to the owners of newspapers as well as television and radio stations throughout the country. I will re-emphasize the importance of the public service announcements we've already supplied to them. And I will urge them to take additional steps to convey this important message: for example, special news coverage, new public service announcements, messages specially designed to reach teenage audiences, or other appropriate steps. Finally, I will ask the makers of aspirin products to take two steps voluntarily: first, to immediately remove any labels which recommend that aspirin products be used to treat flu or chicken pox in children or teenagers; and second, to further label all aspirin products to indicate that there is a possible association between the use of aspirin and the onset of Reye syndrome in children and teenagers, and that aspirin products should not be used in those cases unless a physician is first consulted. I would ask the industry to voluntarily retain this expanded labelling until the results of the full-scale CDC study have been reported and thoroughly analyzed. I want to emphasize that this step does not mean that aspirin is unsafe for other uses. Aspirin is, in fact, a tremendously valuable and effective analgesic and anti-inflammatory drug that has, will and should continue to be used by tens of millions of Americ~ans safely. But, as with any other drug, it is crucial that aspirin be administered appropriately. I am confident that both aspirin manufacturers and the American media will take the steps needed to ensure the best possible protection for our children. These are useful first steps. I believe they are entirely in the spirit of the recommendations we have received from the National Academy of Sciences' Institute of Medicine. In addition, the data now available in the pilot study will be reviewed further with great care, as will all independent comments and recommendations, to determine whether further steps may be warranted. PAGENO="0385" 379 HHS U.S. D~PARTMCNT O~ HCALTH AND HUMAN SERVICES FOR IMMEDIATE RELEASE Claire del Real -- (202) 245-6343 Jan. 23, 1985 HHS Secretary Margaret M. Heckler announced today that the nation's major aspirin manufacturers have agreed to her call for voluntary action concerning the rare but serious Reye syndrome. A new program by the manufacturers will include television announcements, s'ore posters and label changes and warnings regarding the rare but serious Reye syndrome. Secretary Heckler had called for such voluntary action Jan. 9 and today applauded the Aspirin Foundation of America for "its prompt and responsible action, which will be getting the message to Americans within a week." The program was worked out in a series of meetings between the foundation and the Food and Drug Administration over the past two weeks. The Secretary's request for information and labeling was made following a review by the Institute of Medicine of the National Academy of Sciences of a pilot study supporting a link between use of aspirin to treat childhood flu and chicken pox and the subsequent development of Reye syndrome. Public service announcements and store posters and signs will be distributed next week by the manufacturers' sale representatives and the Advertising Council, Secretary Heckler said. She asked the media and store managers to use the materials widely, "because we will rely on these materials to notify people buying aspirin products with the old labels -- or already having such products in their homes." Some of the label changes and warnings may be in place as early as this summer, and will thus appear well in advance of the next winter's flu and chicken pox seasons. Warning stickers on store shelves will appear in some areas as early as this week. The posters and radio-TV public service announcements say, in part: "A rare but serious childhood disease called Reye syndrome may develop in children who have chicken pox or flu. Although the cause of Reye syndrome is not known, some studies suggest a possible association with medicines containing salicylate or aspirin. So it is prudent to consult a doctor before giving these medicines to children and teenagers with chicken pox or flu." The posters and announcements also note that Reye can occur without a link to medications. The materials list the symptoms -- lethargy, belligerence or excessive vomiting -- and recommend quick medical help. The labeling changes are twofold: --Suggestions for use in flu will be deleted from the labels of children's aspirin. -- The following warning will be added to labels of aspirin-containing products for adults as well as children: "Consult a physician before giving this medicine to children, including teenagers, with chicken pox or flu." Reye syndrome is a rare condition, with only several hundred reported cases a year. Last year there were 190 cases reported. But 20-30 percent of reported cases are fatal, and many of the surviving youngsters suffer brain damage. -MORE- 52-266 O-85---13 PAGENO="0386" 380 Pour state studies initially made possible associations between Reye and aspirin's use for childhood chicken pox and flu. A larger federal study to confirm or negate the link will continue through next winter's flu and chicken pox seasons. A pilot for this larger epidemiological case review found 96 percent of cases had the common thread of aspirin use for flu-like illnesses or chicken pox. After a review, the Institute of Medicine of the National Academy of Sciences advised that the federal government should alert parents and physicians now and not await the full study's results. The institute recommended that the full study continue, however. A task force of Public Health Service employees is overseeing the study. First to respond to the new information was Plough Inc. of Memphis, Tenn., manufacturer of St. Joseph products. for children. Plough is making label changes and is placing stickers on products already produced but not yet distributed. The Aspirin Foundation represents such major aspirin manufacturers and distributors as Sterling, Bristol-Myers, Miles, Burroughs Wellcome, Merrell Dow and Procter & Gamble. Retailers such as Giant Foods, with offices in the Washington area, plan their own posters and shelf signs on Reye syndrome and aspirin in the nonprescription drug sections of their pharmacies and food stores. FDA has been working with these retailers. Giant Foods plans to have their posters in place tomorrow. Secretary Heckler emphasized that warnings on Reye syndrome ~do not mean aspirin is unsafe for other uses. Aspirin is, in fact, a tremendously valuable and effective analgesic and anti-inflammatory drug that has, will and should continue to be used by tens of millions of Americans safely. But as with any other drug it is crucial that aspirin be administered appropriately." HI' PAGENO="0387" 381 FDA ,.Ru < J34\J)[J~, FOOD AND DRUG ADMINISTRATION U.S Department of Health and Human Services Public Health Service 5600 Fishers Lane Rockvile, Maryland 20857 FDA Talk Papers are prepared by else Offlee ci Public Affairs to guide FDA personnel in responding with consistency and accuracy to questions from the public on subjects c(current interest Talk Papers are subject to change as move information becomes available. Talk Papers are not intended for general distribution outside FDA. but all information in them a public, and full tests are releasable upon request. T85-7 Bill Grigg Jan. 25, 1985 (301) 443-4177 RECENT ACTIONS ON REYE SYNDROIcE/ASPIRIN LINK The FDA has held a series of meetings to carry forth HHS Secretary Margaret M. Heckler's Jan. 9 call for voluntary labeling changes on aspirin products. The changes were requested to reflect a recent federal pilot study supporting earlier state studies linking aspirin's use in teen and childhood flu and chicken pox to the subsequent development of the rare but serious Reye syndrome (see Talk Paper T85-3). Secretary Heckler announced the results of these meetings -- agreement with the major manufacturers for label changes, store posters and radio-TV announcements -- on Jan. 23. The following may help answer questions on the warning labels and broadcast announcements pledged: The labeling agreed to by members of the Aspirin Foundation of America -- such major manufacturers as Sterling, Bristol-Myers, Miles and Burroughs Wellcome, Squibb, Whitehall and Procter & Gamble -- and found acceptable by FDA will add to the warning section of the labels: "Contact a physician before giving this medicine to children, including teenagers, with chicken pox or flu." In addition, recornendations for use in flu will be removed from children's products. Als~as part of the agreement, the Aspirin Foundation has produced 60- and 30-second TV and radio public service announcements to be distributed to the media in the next few days. The shorter version says: "A rare but serious childhood disease called Reye Syndrome may develop in children and teenagers who have chicken pox or flu. Although the cause of Reye Syndrome is not known, some studies suggest a possible association with medicines containing salicylate or aspirin. So, it is prudent to consult a doctor before giving these medicines to children or teenagers with chicken pox or flu.' The longer version adds to the above: "Remember, Reye Syndrome occurs even in children and teenagers who take other medicines or no medicines. It's important to be aware of the early signs and symptoms. If your child shows unusual behavior, such as severe tiredness, belligerence, or excessive vomiting after appearing to recover from chicken pox or flu, get medical help imediately. Give no medications.' Plough Inc. of Memphis, Tenn., maker of St. Joseph aspirin and non- aspirin products for children, is not a member of the Aspirin Foundation but was the first to announce it would comply with the Secretary's request (even though company officials said they did not feel aspirin had been established as a cause of Reye syndrome). Its program is different from the foundation members. The corporation met with FDA Jan. 15 and later announced that it: -MORE- PAGENO="0388" 382 -- would begin next week to print packages for its aspirin-containing products with changes suggested by the Secretary and FDA in the labeling, eliminating any recommendation for use in childhood or teen flu or chicken pox, and adding a warning against such use, with an explanation of Reye syndrome; and -- was adding warning stickers on the boxes of aspirin products already produced but still under its control. Consumers may begin to see the stickers soon. The stickers say, "Consult doctor before use in children or teenagers with flu or chicken pox." The Plough label warning will say: "WARNING: Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin may increase the risk of developing this disease. Consult doctor before use in children or teenagers with flu or chicken pox." Plough will also insert in packages information to read: "The symptoms of Reye Syndrome can include persistent vomiting, sleepiness and lethargy; violent headaches; unusual behavior, including disorientation, combativeness and delirium. If any of these symptoms occur, especially following chicken pox or flu, call doctor immediately, even if your child has not taken any medication. REYE SYNDROME IS SERIOUS, SO EARLY DETECTION AND TREATMENT ARE VITAL." FDA Commissioner Frank E. Young wrote Plough commending the company's speed and cooperation. Giant Foods and other retailers have contacted FDA about producing their own posters and shelf labeling. The Giant materials will be in all of the chain's food and drug stores tomorrow, Jan. 26. The main poster says, "The U.S. Food and Drug Administration recommends that parents check with a doctor before giving aspirin or products containing aspirin to children or teenagers who have the flu or flu-like symptoms or chicken pox." Below the posters, Giant is attaching to the shelves tear-off literature giving more details about the warning and about Reye syndrome. FDA has reviewed the wording used by Giant and supports it. FDA has conducted public education campaigns cautioning about the use of aspirin in childhood flu and chicken pox for three winters and is now updating those materials. Since the pilot and last year's case reports indicate about half the cases of Reye syndrome to be in teens and children over 10, who may self-medicate, the campaign will shift emphasis toward this older group. A new radio announcement and a column for weekly newspapers is being given priority. Secretary Heckler has sent letters, on the pilot study to pediatricians and family doctors, as well as to newspapers and broadcast outlets. PAGENO="0389" 383 INDUSTRY INITIATIVES OTHER THAN ASPIRIN FOUNDATION ON REYE SYNDROME WARNINGS cc~s Waigreen Drug Stores Letter Walgreen/Lampkin Dated March 11, 1985 Mamorandum, Reye Syndrome Signs Waigreens News Flash, Reye Syndrome Signs Dated February 4, 1985 Reye Syndrome Sign Giant Feod Reye Syndrome Warning Poster Consumer Leaflets Thrift Drug Company Letter Thrift/Lampkin Dated March U, 1985 Thrift Drug Bulletin Dated February 1, 1985 Reye Syndrome Warning Poster Peoples Drug Stores Bulletin on Reye Syndrome Sign Osco Drug Stores Letter Osco/Lampkin Dated March 8, 1985 Daily General Bulletin on Aspirin Warning Signs "Shelf Talker" on Reye Syndrome Safeway Stores, Incorporated Letter Safeway/Lampkin Dated March 8, 1985 Inter-Office Coninunication, Reye Syndrome Food Marketing Institute American Pharmaceutical Association Apharmacy Weekly Dated February 1, 1985 Reye Syndrome Warning Poster Plough, Incorporated Letter Schering-Plough/Lampkin Dated March 12, 1985 Labeling for St. Joseph Cold Tablets for Children Package Insert Labeling for St. Joseph Cold Tablets for Children Package Insert Labeling for St. Joseph Aspirin for Chi1drej~ Package Insert Bottle Label for St. Joseph Aspirin for Children Bottle Label for St. Joseph Cold Tablets for Children PAGENO="0390" 384 Walgreen Drug Stores 200 Leermond Road Deerfield, Illinois On February 4, 1985, sent out Reye Syndrome warning statment posters and instructions to over 1100 Waigreen Stores. Waigreen also will be sending out bulletins to all store managers requesting an effectiveness check to see if the posters have been displayed and are still in place. Walgreen's will not allow other posters to be placed in their stores. They feel that additional posters will cause clutter on the shelves and confusion to the customer. Walgreen's stated that the State of Illinois had proposed a State law requiring a Reye Syndrome warning statment and poster but this bill has died. PAGENO="0391" 385 Wa~teei~~ Walgreen Co. Corporate Offices 200 Wilmot Road Deerfield, Illinois 60015 March 11, 1985 Win. Lampkin FDA 5640 Nicholson Lane Room 26 Rockville, MD 20852 Dear Mr. Lampkin: Enclosed please find the information that we discussed on the telephone. As I mentioned to you earlier, the Waigreens News Flash was originally sent nationwide to all Waigreen store managers - over 1,050 drug stores. I am in the process of distributing the follow-up memo from Mr. G.S. Kraiss, Senior Vice President of Store Operations, to our Pharmacy Supervisors. As you can tell from the memo, the Pharmacy Supervisors will verify that the Reye's Syndrome notice has been provided to our aspirin buying consumers. Sincerely, Dr~iI1 Jill Leslie Drell Senior Attorney Governmental and Public Affairs JLi~/pr Enclosure PAGENO="0392" 386 W~94~a1cL look Tide: i i "T"T" i i i . Subject: REYE'S Syndrome Signs From: C. S. Kraias To: AU Pharmacy Supervisors Attached is a copy of a Nevaflash that went to all Store Managers requesting the posting of Reye's Syndrome signs in the analgesic depart- ments of our stores. On your next visit to the stores within your District, insure that the signs have been posted in the appropriate locations. Included are extra notices for use in those stores that have lost the original signs sent to them. For additional signs, contact the Governmental and Public Affairs Department. It is very important that our atores provide this notice to buyers of aspirin products. - GSK:btm cc: F. F. Canning V. A. Brunner V. 0. Shank K. C. Atlas K. L. Cudworth K. A. Daniels V. L. Earnest G. C. Eilers .1. B. Karlin P. E. Eanifen V. C. Thien K. K. King All District Managers V. K. Hatfield .1. L. Drell I I ~ ~ PAGENO="0393" tV~z4jr,teei~1~ ~ News Flash Subject REYE `S SYNDROME SIGNS From T. A. Braun - Drug Merchandising Division To All Store Managers Date February 4, 1985 The Aspirin Council, which represents proprietary manufacturers of aspirin and aspirin compounds, has voluntarily agreed to provide consumer information on Reye's Syndrome. This voluntary program will be implemented in all Walgreen stores in the form of signs that will be placed in the analgesic department. Accompanying this letter are two signs, 3 1/2 X 5 1/2, that are to be displayed in the analgesic department and inserted into the appropriate chrome sign holder. THESE SIGNS ARE THE ONLY SIGNS APPROVED FOR DISPLAY IN WALGREEN STORES. It is our recoimnendation that if you have a 12 foot department that two signs be used, and if you have a 9 foot department, one sign should be utilized. Irregardless of department location, the signs are to be placed on the third shelf from the bottom since childrens' products are on this shelf or nearby. They are to remain until further notice. All manufacturers of aspirin products are implementing a warning on their packages and the signs will be removed when all packaging is revised. If there are any further questions concerning this program, please do not hesitate to call me on X312O. Drug Merchandising Division 387 copies: Mr. F. F. Canning Mr. W. D. Cavanaugh Mr. V. A. Brunner Mr. W. C. Thien Mr. C. S. Kraiss Mr. W. H. Hatfield Mr. W. 0. Shank Health Service Representatives Mr. R. C. Atlas Mr. E. H. King Mr. E. L. Cudworth Ms. J. L. Drell Mr. R. A. Daniels Mr. T. L. Mammoser Mr. W. L. Earnest Ms. M. T. Kari Mr. C. C. Eilers Mr. A. F. Tuhy Mr. J. B. Karlin Mr. N. D. Smith Mr. P. E. Hanifen File this N Iash1wjthstore bulletins Fo~O6 Re~1O181 PAGENO="0394" 388 The Shopper's Center CONSUMER INFORMATION "Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin may in* crease the risk of developing this disease. Consult doctor before use in children or teenagers with flu or chicken pox" -Post in analgesic Dept.- PAGENO="0395" 389 Giant Food Landover, MD Giant prepared and sent out 11 inch by 14 inch yellow and red posters and 3 1/2 inch by 3 inch consumer leaflets with the Reye Syndrome warning statement. The posters and slips were sent out on January 22 to approximately 132 stores in Virginia, Maryland and the District. 1 a doctor before giving aspirin OF products containing apirin to child~en or teenagers whO have the flu, flu-like symptoms or óhlcken pox. See shelf sign below. Giant Food Inc. PAGENO="0396" 390 PLEASE TAKE ONE DRUG ALERT Rsye syndroms Recent medical studies show a Nnk between the use of aspirin and a rare, serious and sometimes fatal condition known as Reys Syndrome. This condition can develop when children or teenagers are recovering from the flu, flu-like symptoms, or chicken pox and In many cases have been taking aspirin. UntU more Is known, the U.S. Food and Drug Administration recommends that parents Check with a doctor before giving aspirin or products containing aspirin to children or teenagers who have the flu, flu-Ilk. symptoms, or chicken pox. Se other ~de for sympfoms. Reye Syndrome usually occurs when the child or teenager appears to be recovering from the original Illness and then develops the following symptoms: * Persistent vomiting * Fatigue * ConfusIon and Irritability IF YOUR CHILD DISPLAYS ANY OF THE ABOVE SYMPTOMS, CONSULT YOUR DOCTOR IMMEDIATELY ANNE HARTNETT CONSUMER AFFAIRS SPECIALIST GIANT FOOD INC. P. 0. BOX 1804 WASHINGTON. DC 20013 PHONE (301) 341-4373 PAGENO="0397" 391 Thrift Drug Company Pittsburgh, PA Thrift Drug send out Reye Syndrome warning bulletins and posters in the first week of February to approximately 375 stores. TRUST THRIFT DRUG ,./tt3flW ~ PHYLLIS PATTERSON March 11, 1985 Mr. Lampkin: As requested, please find enclosed the bulletin and sign that was sent to all of our stores regarding the Reyes Snydrome. If I can be of any further assistance, please do not hesitate to contact me. erely, yl Patterson P c Affairs Coord. Attachment PAGENO="0398" 392 ,4Tt Drug Bulletin February 1, 1985 Bulletin No. 2/1 * Mail To All Stores Retain Until February 1, l98~ Copies To IA SECTION I - DRUG DEPARTMENT A. OPERATIONAL 1. Reyes Syndrome Warning In keeping with our company's tradition of working in the best interest of the consumer, we are voluntarily cooperating in warning the public of the potential hazards of using aspirin in children and teenagers with the flu or chicken pox. Attached to this bulletin you will find (2) Warning Signs. One sign must be placed in your Pain Relief Department and the other in the Cough & Cold Department on the top shelf where it is visible to the consumers. 2. Fill Every Prescription Our Mail Order Pharmacy is in need of the following product: Essence of Pepsin manufactured by Lilly. Should you have this item, please notify: Express Pharmacy Services 100 Delta Drive Pittsburgh, PA 15238 Attention: Janet Rukas SECTION II - GENERAL INFORMATION A. OPERATIONAL 1. March Tabloid Items Update The following items are still on division from the servicing Distribution Center indicated. All other items should be in your hands by this date. Check your March Advertising Bulletin for a complete list of all items. ITEM DESCRIPTION ITEM # LANG. ATL. PGH. Happy Ending Books Asst. 968826 X X X Woodtone Plaques 974964 X X X PAGENO="0399" WARNING: REYE'S SYNDROME *REYE'S SYNDROME IS A RARE BUT SERIOUS DISEASE WHICH CAN FOLLOW FLU OR CHICKEN POX IN CHILDREN AND TEEN- AGERS. *WHILE THE CAUSE OF REYE'S* SYNDROME IS UNKNOWN, SOME REPORTS CLAIM ASPIRIN MAY INCREASE THE RISK OF DEVELOPING THIS DISEASE. *CONSULT YOUR DOCTOR BEFORE USING I ASPIRIN IN CHILDREN OR TEENAGERS WITH FLU OR CHICKEN POX. PAGENO="0400" 394 Peoples Drug Stores Alexandria, VA Peoples sent out Reye Syndrome warning bulletins to approximately 330 stores in Maryland, Virginia, West Virginia, Pennsylvania, North Carolina, and the District during the middle of February 1985. - J Bulletin No. TO: Wash. Area Only ____________ Mid-Atlantic Division xxx Mid-West Division ____________ SUBJECT: REYES SYNDROME SIGN Distribution was recently made to all stores on Reyes Syndrome (copy below). Please post this sign in a sign holder in the OTC Section where the aspirin- containing products are located. Any stores not receiving the Reyes Syndrome sign shown below should contact the Advertising Department. We have also been advised that Norrell Services are distributing to stores in the Washington Metro area a similar sign on Reyes Syndrome provided by the Aspirin Foundation. This sign may also be placed in the area of the aspirin- containing products or placed on the wall by the pharmacy drug wrap counter. t4CS:mlt RE YE'S SYNDROME Notice to Parents A rare but serious childhood disease called Reye's Syndrome may develop in children and teenagers who have chicken pox or flu. Although the cause of Reye's Syndrome is not known, some studies suggest a possible association with medicines contaIning Salicylate or Aspirin. So, it Is prudent to consult a doctor before giving these Medicines to children or teenagers with chicken pox or flu. PEO~I~~fl~i?RUG PHARMACY PAGENO="0401" 395 Osco Drug Stores Wheaton, Illinois Osa~ sent out two-sided "Shelf Talkers." ~ielf Talker is a two-sided bufletin printed with Reye Syndrome warning statments. Osco sent these shelf talkers to a~roximately 330 stores during the last week of January 1985. OscoDrua SubsidIary of Jewel Companie~ ln~ EXPRESS MAIL March 8, 1985 WRITER'S DIRECT LINE (312)887-5237 ExecutIve Offics l8l8SwiftDr)ve Oak Brook IllinoIs 60521 (312) 887- Food and Drug Administration Room 326 5640 Nicholson Lane Rockvifle, MD 20852 Attention: Mr. Willias Lampkin Re: Reye Syndrome Dear Mr. Lenpkin: The enclosed materials are being sent in response to your telephone conversation today with Ms. Paula Dahlquist of our company. You will note that the memo sent to the Osco Drug Stores referenced a sign statement which eventually was changed. The sign enclosed contains the actual statement used. If you have any further questions regarding this, please contact me. Very truly yours, OSCO UG, INC. Vice President and General Counsel - LAM: 1mg: 1 79X4 Copy to: P. Dahlquist PAGENO="0402" 396 DAILY GENERAL BULLETIN 1k Zfl" ~ AU. $T0A$ PAGE N STORE ~ ~$TA'~U71OU 0GB DAN TO: ALL STORES FROM: SEROMIECKI SUBJECT: ASPIRIN WARNING SIGNS Within the next week, all stores will receive three aspirin warning signs with their ad signing package. These signs will state, `Consult doctor before giving aspirin to children or teenagers with flu or chicken pox.' These signs will be printed on both sides and should be put into the special sign clips that hold then perpendicular to the shelf. Please place these sl~s In front of the following Items In the analgesic section - St. Joseph Aspirin For Children, Bufferin Tablets Regular Strength 165's and Osco Thin Coated Aspirin Tablets 300's. In the near future all aspirin products will provide the following type label, `Warning: Reye Syndrome Is a rare but serious disease which can follow flu or chicken pox In children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin ~y Increase the risk of developing this disease. Consult doctor before use In children or teenagers with flu or chicken pox.' Additionally, children's products will contain an insert which will give the symptoms of Reye Syndrome.and the vital Importance of early detection and treatment. This Information will read: `The symptoms of Reye Syndrome can include persistent vomiting, sleepiness and lethargy, violent headaches, unusual behavior, including disorientation, cothatlveness and dellrliai. If any of these symptoms occur, especially following chicken pox or flu, call doctor imediately, even If your child has not taken any medication. REYE SYNDROME IS SERIOUS, SO EARLY DETECTION AND TREAThENT ARE VITAL.' Aspirin is, In fact, a tremendously valuable and effective analgesic and antl-lnflamator~ drug that has, will and should continue to be used by tens of millions of Americans safel~ But as with any other drug, It Is crucial that aspirin be administered appropriately. 02570C ~ READ REACT TOSS PAGENO="0403" 397 PAGENO="0404" 398 Safeway Stores, Incorporated Oakland, California Sent a bulletin dated January 30, 1985 to their 17 independent United States retail divisions requesting that they post Reye Syndrome warning statements in the pharmacy section by the children's aspirin. Safeway had no idea as to how many divisions actually posted the signs but will collect the information and relay it to us next week (week of March 18-22). - Eoecutiue Offices (C~ SAFEWAY P( ~ STORES INCORPORATED 201 Fourth St reef. Oakland, CA 94660 March 8, 1985 Mr. William Lampkin Food & Drug Administration 5640 Nicholson Lane #326 Rockville, MD 20852 Dear Mr. Lampkin: Per your telephone request I am attaching a copy of the bulletin that I issued to our 17 independent U.S. retail divisions. As I mentioned, I do not have information on which of our divisions actually used it, but I am trying to collect that information now and will call you next week. Unfortunately, our Washington, D.C. division did not use the signs and our San Francisco division has no samples available since all their signs are posted. Maybe the Food Marketing Institute will be able to obtain a sample sign. I hope the attached is helpful. Thanks for calling. Sincerely, C~fo Felicia del Campo, Manager Public Affairs Department FdC:pat 016 6U PAGENO="0405" 399 4 TO Robert E. INTER-OF Bradford FICE COMMUNIC FROM ATION~?J~~ FeliCia de Campo for U.S. Public Relations Mgrs . LOCATION Public Affairs Dept. Manager LOCAT ION DATE January 30, 1985 SUBJECT REYE SYNDROME The Aspirin Foundation released information last week to the media concerning their proposed labeling on children's aspirin. They also mentioned that supermarket retail outlets would be provided with shelf stickers and labels to cover the time period before new container labels appeared on the shelves. You may want to post signs in your pharmacy sections by the children's aspirin. If you do post the signs, you should not forget any aspirin displays in the baby section, also. The aspirin package warnings will read as follows: `Reye syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin may increase the risk of developing this disease. Consult doctor before use in children or teenagers with flu or chicken pox. If you do elect to use signs, your wording should coincide with the above which has been developed by the aspirin industry. FDC: jas/0091U Attach. cc: P. DiGrazia Everything you want from a stote % and a little bit more F Ho. 45$ (~io. 4-5*) PAGENO="0406" 400 Food Marketing Institute Food Marketing Institute is an organization which serves food stores in the United States. Safeway is one of their largest customers. The Institute has not developed any Reye Syndrome warning posters of their own but they have been contacted by the Aspirin Foundation to distribute their posters. As of March 8, 1985, the Institute has not received the posters from the Aspirin Foundation. They indicated that once the posters have been received that they will be distributed by the Institute to their member organizations. PAGENO="0407" 401 American Pharmaceutical Association (APhA) Washington, D.C. APhA inserted a warning poster approximately 17 inches by 11 inches in their weekly newsletter dated February 1, 1985. The newsletter was mailed on January 25, 1985 to over 36,000 pharmacists. A smaller version of the same poster was reproduced and printed in the March 1985 issue of the APhA Journal which was mailed to over 50,000 members on March 3, 1985. APha also received a request from Long's Drug Stores in Walnut Creek, CA, for 400 extra copies of the APhA poster. PAGENO="0408" 402 February 1,1985 apharmacy 15 weekly © Dear Pharmacist: In the words of the National Academy of Sciences' Institute of Medicine (IOM), a pilot study done by the Centers for Disease Con- trol shows "a strong association between the Reye syndrome and the use of aspirin." The IOM committee added, "considering that data from previous studies also show an association of use of aspi- rin and Reye syndrome. . steps should be taken to protect the public health before the full study is completed." What the investigation had shown was that 97% of Reye's syndrome cases had received some sort of salicylates during a bout of the flu or chicken pox, whereas only slightly more than half of a group of control children, with similar antecedent illnesses, had gone on to develop Reye's. Statistically, this meant that the use of aspirin.in these illnesses in children or teen-agers involved a 12-26 greater risk than notgiving aspirin (depending on which statistical model was assumed). Therefore, APhA has prepared a poster to warn parents about this possible danger. We urge pharmacists to display it prominently, at least for the duration of the flu season, as a public health service to your patients. PAGENO="0409" 403 Themessageprintedbelowshouldberensovedandplaced na prominentposltlon Inyour pharmacyasa publkhealth servicetoyourpatients. Permission to reproducetheir message is granted. ~u~o A study by the Federal government's Centers for Disease Control has found a strong association between the use of aspirin in children with flu orchicken pox and the development of the potentially fatal illness Reye's Syndrome. Symptoms of Reye's Syndrome include vomiting, fever, lethargy, and convulsions. The symptoms generally appear as the child seems to begetting better. * Do not use aspirin for children or teenagers with the flu or chicken pox without first consulting a physician. * If symptoms of Reye's Syndrome appear, immediate medical attention is required. For additional information, consult your pharmacist. The American Pharmaceutical Association The national professionalsociety of pharmacists PAGENO="0410" 404 Shering Plough, Incorporated Memphis, ¶L~J Stopped shipping unstickered product on January 9, 1985. Started stickering children's aspirin on January 9, 1985. Stickered all existing inventory in warehouses. Stickered product available for shipoent late January 1985. All products manufactured after January 9,. 1985 have Reye's Syndrome warning statement. All products which contained an insert has the Reye Syndrome warning statement printed on the insert. Firm has no plans for unstickered product on market. Firm plans no market withdrawal. Firm has not prepared public service announcements. Firm will not give projection on when remaining unstickered stock on market will be exhausted. PAGENO="0411" 405 ~ Schering-Plough Schering-Plough Corporation Telephone 901/320-2011 3030 Jackson Avenue Telex 53861 P. o. Box 377 Memphis, TN 38151-0001 U.S.A. March 12, 1985 SENT BY FEDERAL EXPRESS Mr. William Lampkin Office of Compliance Food and Drug Administration 5640 Nicholson Lane Room 326 Rockville, MD 20852 Dear Mr. Lampkin: Pursuant to your request, enclosed are representative samples (2 each) of Plough aspirin-containing products bearing either a sticker or printed warning label concerning Reye Syndrome. They are as follows: AVAILABLE FOR BRAND LOT WARNING SHIPMENT 1. St. Joseph 4HlOl Stickered late January Aspirin for 1985 Children 2. St. Joseph 4G279 Printed early March Aspirin for 1985 Children 1. St. Joseph 4C177 Stickered late January Cold Tablets 1985 for Children 2. St. Joseph 4C178 Printed early March Cold Tablets 1985 for Children Please note that the cartons bearing the printed warning also contain a package insert with a printed, detailed statement regarding Reye Syndrome. January 9, 1985, the very day Secretary Heckler requested aspirin manufacturers to comply with the voluntary program, Plough immediately stopped shipment of such products from our warehouses and distribution centers pursuant to oral instructions to appropriate personnel. These instructions were confirmed in writing the next day. Since that date, Plough has shipped no aspirin-containing product without a Reye Syndrome warning. It is our pleasure to cooperate with the Agency and we hope that the enclosed information is beneficial. Respectfully yours, Gary ~7Wi1kerson Legal Director PAGENO="0412" PAGENO="0413" 1! F 1 PAGENO="0414" PAGENO="0415" 0 LU 0 * 0 * Lt~ PAGENO="0416" 0 PAGENO="0417" h 1111111 k~ ~ n a PAGENO="0418" 412 PAGENO="0419" 413 Mr. WAXMAN. Before I recognize my colleagues, I just want to say that what I think the administration did was to take precau- tions not to offend the aspirin industry, and in doing that, I think you did a disservice to the American people, and children particu- larly, who may come down with Reye's Syndrome. I know you don't like to fight with any of the industry groups. I know it is better to do things voluntarily than to have to require it. But when you rely on the good will of people who have a profit to make and a product to sell, they are going to be more interested in that profit, and if you are going to let them be more interested in it, they are going to take advantage of you. And I think they already have, because I don't think what you have agreed to is going to reach the American people. Even your own statistics indicate that I don't think there is much of a hope even in the next flu season that people are going to be aware of this danger, and that they should, when it comes to a child, avoid the use of aspirin for one of the most common symptoms for which we are all conditioned to think aspirin is appropriate. Mr. Wyden. Mr. WYDEN. Thank you, Mr. Chairman. Dr. Young, you do not look like a callous man to me. Dr. YOUNG. I hope not. Mr. WYDEN. But the effects of these actions in my view are very, very callous. I see a huge gap between the concerns that you have professed to have in this area, concerns everybody shares, and the actions that the Department has actually taken. I wanted to start my questioning by asking you to read the Plough label out loud, if you would. Dr. YOUNG. Surely. The label that I showed you here is the one that was put on in regard to the immediate withholding of ship- ment at that time, and I will also read the label changes to give you the complete portion. Mr. WYDEN. Read the long-term label, not the short-term one. Dr. YOUNG. Fine, let me just get it here for you. Warning: Reye's Syndrome is a rare but serious disease which can follow flu or chickenpox in children and teenagers. While the cause of Reye's Syndrome is un- known, some reports claim aspirin may increase the risk of developing this disease. Consult doctor before use in children or teenagers with flu or chickenpox. The symptoms of Reye's Syndrome can include persistent vomiting; sleepiness and lethargy; violent headaches; unusual behavior, including disorientation, combative- ness and delirium. If any of these symptoms occur, especially following chickenpox or flu, call your doctor immediately, even if your child has not taken any medica- tion. REYE'S SYNDROME IS SERIOUS, SO EARLY DETECTION AND TREAT- MENT ARE VITAL. Mr. WYDEN. Doctor, that strikes the subcommittee as a strong, dramatic label. Dr. YOUNG. Yes, it does, and I worked in a number of meetings with a wide variety of industry, and I am pleased to see that label. Mr. WYDEN. Why wouldn't that be preferable in terms of policy than the one that you agreed to with the Aspirin Foundation? You agreed to a substantially weaker one with the Aspirin Foundation. Why wouldn't the stronger label have been preferable to protect the public? Dr. YOUNG. This is an excellent question. We made widely-known the Plough decision, and we fully discussed this with each of the PAGENO="0420" 414 corporations and the Aspirin Foundation, and any of the others that came to see us, or that we invited in. We feel that if we are maintaining a voluntary effort, it is not for us to prescribe the exact makeup of the label, but to encourage, in the sense of voluntarism those types of labeling activities. We feel that that is an excellent label. We are still in the early phases of the voluntary efforts. Mr. WYDEN. I want to yield to the chairman in just a second, but Plough is just a small percentage of the aspirin market? Dr. YOUNG. That is correct. Mr. WYDEN. And they have developed something that would really help the public. And yet, whether it was because you didn't want to rock the boat or because you were looking at obscure scien- tific arguments, you wouldn't go with something that really would help the public. I think that is unfortunate. I think that the public needed that kind of strong, aggressive action. You know, I hear a lot from various administration spokes- persons about being pro-family and taking profamily positions on the issues. Well, here is a chance where the administration could have done something that really would help the families of this country, and you let them down. I think that the country is owed more than that. The chairman wanted me to yield, and I have another question or two. Mr. WAXMAN. You have got two values here, doing things volun- tarily and doing what is necessary to protect the public health. You think the label on this children's aspirin is more calculated to pro- tect the public health. Why do you think voluntarism is so important? Aren't you en- trusted not with doing things voluntarily with the industry, but doing what is helpful to protect the public from dangers? Dr. YOUNG. Mr. Chairman, that is exactly why I listed the two points in the order that I did. I think that the first issue to be em- phasized is that the information that we are working on at this point is not completely definitive, and therefore, though not defini- tive, as a physician and public health official, I feel that we must, still in the face of uncertainty, bring as much information as we possibly can to the American public. That is why the actions were undertaken. Mr. WAXMAN. But you don't have to be definitive in your state- ment. You don't have to say taking aspirin absolutely will cause Reye's Syndrome. You can say, taking aspirin has been determined by the Institute of Medicine, the Centers for Disease Control, every scientific organization including the American Academy of Pediat- rics, may cause Reye's Syndrome. Isn't that sufficient, a responsible warning that you could order? Dr. YOUNG. This is exactly what we have done in our public edu- cation, and as you would see on the tape, I have tried to make very clear these type associations, and these types of warnings to the American public, and I still contend that warning labels on pack- ages are only one of many parts. Mr. WAXMAN. I know, but you are throwing away one of the most important ways to reach people at the time when they are PAGENO="0421" 415 about to use the product that may kill their kids. It seems to me you are throwing away an effective vehicle to communicate, be- cause you don't want to offend the aspirin industry, and I am just astounded by that. Mr. Bates. Mr. WYDEN. Could I ask one more question, Mr. Chairman? Mr. WAXMAN. Certainly. Mr. WYDEN. Dr. Young, let me read to you from a letter from the FDA dated February 22, 1985. It has got a Dear Consumer at the top. I quote: The purpose of this letter is to alert you to the link between Reye's Syndrome and the use of aspirin-containing products as treatment of children and teenagers with flu or chickenpox. It goes on to say: A pilot study recently completed at the Department substantially strengthens ear- lier evidence of the association between the use of aspirin-containing drugs and the development of Reye's Syndrome. While the results of the pilot study are only pre- liminary, we are making them public because of their clear importance to protect- ing the health of children and teenagers. Now, it seems inconsistent at best to hear you make these kinds of strong statements on the one hand, and then to look at the con- clusion of this letter, which states that the Surgeon General advise, and I quote here, "People should consult their physician before using aspirin for children with chickenpox or flu." It is inconsistent at best, and you are going to confuse some people. I can't figure out why you want to have it both ways. At one point, you are trying to tell people it is very serious. At the other point, you tell them people ought to consult a physi- cian before using aspirin. Again, it is symptomatic in my view of this kind of "don't rock the boat" way of thinking. You are taking very cautious steps, when in fact what the public really needs is aggressive action along the lines of the plough label or something similar. How do you think this campaign is going to work if you send out those kinds of messages, which at best are confusing, and show that you want to have it both ways. How is that going to help to get your message across? Dr. YOUNG. We don't want to have it both ways, and we want to articulate clearly. Mr. WYDEN. Does that letter do that? Dr. YOUNG. I think the point of the letter, or where I would in- terpret it as not doing it is that we wanted to point out what the facts were as we knew them today. We wanted to add the addition- al point of replaying the Surgeon General's message, and point out that he advised in all cases involving children, including teenagers, a physician should be consulted before using aspirin in cases of flu or chickenpox. I think that is pretty clearly the same message. Mr. WYDEN. I just tell you my reading of that letter is a very strong warning in the beginning, a completely different message at the end. Here we need a clear, direct, educational campaign. PAGENO="0422" 416 All our witnesses have said this, and they represent a variety of different professions. You aren't performing that function. I think you have already written off this year's flu season. I don't see any evidence that what you are doing today is going to mean we have got a good plan in place for next year's flu season, and I think it is too bad. Thank you, Mr. Chairman. Mr. WAXMAN. Thank you. Mr. Bates. Mr. BATES. Thank you, Mr. Chairman. I appreciate the chance to participate in this hearing, and particularly to ask the person charged with this responsibility of carrying out the warning of Americans of the possible association between aspirin and Reye's Syndrome. I have been trying to talk to someone who maybe has a different point of view, because most of the panelists that we have heard today are very concerned, and feel very strongly. And the impression I got is that the warning would be a good idea. Just to clarify the record, do you support Congressman Wax- man's legislation? Dr. YOUNG. I do not believe that legislation is necessary at this time. Mr. BATES. Why? Dr. YOUNG. I think that we are very early in the understanding of two points. First of all, I would like to, in response to Mr. Wyden's question, give the sequence of the educational materials, and I will introduce this for the record. On January 9, 1985, there was a statement by the Secretary; January 11, the CDC Morbidity and Mortality Weekly Report; Jan- uary 11, 1985, the Secretary's telegram to TV executives; January 17, the Secretary's letter to the general managers of radio stations; the 23rd of January, letters to editors; the 23rd of January, Miller's letter from FDA to the Public Service Directors with 30- and 60- second radio spots; the 28th of January, the letter of the Secretary to hospital administrators; the 28th of January, the Secretary's let- ters to doctors; the 28th of January, the Commissioner's letter to the testing council; the 28th of January, the Commissioner's letter to store managers, the variety of newspaper articles in English and Spanish that were sent forward as columns; in February, on the 8th, Myers' letter to drug registrants; and the 11th of March, the poster that you see there. Those are the educational activities. In regards to the data, we did not expect the pilot study to come forward with the degree of association that it revealed. We felt that the pilot study was designed to see if the definitive study would be correct. When the code was broken, we were surprised by the association and felt that it was not appropriate, even though the flu season had started, to do nothing. It would be wrong to do nothing, and therefore, we studied whether the data was available to go with a mandatory labeling at this time. We concluded not at this point, and therefore, embarked upon the information that I just read to you, sir. You can see our educa- tional campaign and how we have worked very vigorously. PAGENO="0423" 417 As I mentioned earlier, the saccharin labeling only added a little bit to the total program, and I felt, as an educator, that the first thing to do was rapidly get the information out to the American public. [Testimony resumes on p. 457.] [The information follows:] PAGENO="0424" 418 REYE SYNDROME PUBLIC EDUCATION MATERIALS January 9, 1985 - Statement by Secretary Margaret M. Heckler January 11, 1985 - CDC Morbidity and Mortality Weekly Report January 11, 1985 - Secretary Telegram to TV Executives etc., with list of addressees January 17, 1985 - Secretary letter to General Managers of Radio and TV Stations January 23, 1985 - Secretary letter to Editors January 23, 1985 - Miller letter to Public Service Directors with 30-second and 60-second Radio spots Undated - Radio Station PSA comment card January 28, 1985 - Secretary letter to Hospital Administrators January 28, 1985 - Secretary letter to Doctors January 28, 1985 - Commissioner letter to The Advertising Council January 28, 1985 - Commissioner letter to Store Managers February/March - Newspaper column English version February/March - Newspaper column - Spanish version March 8, 1985 - Meyer letter to Drug Establishment Registrants March 11, 1985 - Miller letter to School and Colleges with Poster PAGENO="0425" I 419 / ThSSSC*(TAAY OF P$ti TN AND N(~AN $5NVIU~S WAN*NSTON.DC. ~S* JAN 91985 Statement by Margaret N. Heckler Secretary of Health and Human Services Nothing is more important to Americans than the health and safety of their children and, as Secretary of Health and Human Services, I feel a special responsibility to protect the health of our nation's children during their most vulnerable years. That is why I ordered special steps to resolve the scientific dispute when some early studies showed an association between Reye syndrome and the use of aspirin for children suffering from chicken pox, influenza and flu-like illnesses. That is also why I instructed the Food and Drug Administration to pursue a vigorous public education campaign to ensure that parents were made aware of the possible link. In particular, I ordered the Centers for Disease Control a year ago to undertake a new study of aspirin and Reye syndr~. The study had two parts - a one-year pilot study followed by a full-scale investigation. The Centers for Disease Control have now completed the pilot study. This study is not completely conclusive - but its findings do show an association between the use of aspirin and the onset of Reye syndrome in children and teenagers. These results make it urgent that CDC vigorously pursue the full- scale study. That work was begun last month and is now fully underway. In the meantime, I strongly urge parents to follow the advice of the Surgeon General: in all cases involying children, including teenagers, a physician should be consulted before using aspirin in cases of flu or chicken pox. It is significant that fewer children are now being struck by Rey. syndrome - 190 known cases in the year ending November 1984 - while reported cases in previous years were as high as 548 (in 1980). Hut this does not mean we can be complacent. The disease is deadly, with a fatality rate of 26 percent last year. In addition, those who suffer from the disease are increasingly older children and teenagers, as wall as young children: According to the pilot study, some 50 percent of all cases were in those over age 10, and 15 percent were in those aged 15 and older. In order to ensure that all children continue to be given the fullest protection, even while we await final scientific conclusions, I am today taking four additional steps: First, I amoz~dering CDC to release the pilot study immediately, and I am instructing that it also be published as soon as possible in CDC's journal Morbidity and Mortality Weekly Report. This information along with other scientific evidence will appear ii~ a refereed scientific journal. Second, I am asking the Food and Drug Administration to extend and expand its public education efforts -- parents must understand the need to consult a physician before using aspirin to treat flu or chicken pox. Likewise, FDA will take steps to inform teenagers - who often treat themselves -- of the possible link between aspirin and Reye syndrome. PAGENO="0426" 420 Third, I am contacting media leaders throughout the country asking them to use every possible resource to help broadcast the message. I am telegraphing the presidents of the three television networks as well as the American Newspaper Publishers Association, the National Association of Broadcasters, the Association of Independent Television Stations, and the National Cable Television Association. I will also' send letters to the owners of newspapers as well as television and radio stations throughout the country. I will re~enphasize the importance of the public service announcements we've already supplied to them. And I will urge them to take additional steps to convey this important message: for example, special news coverage, new public service announcements, messages specially designed to reach teenage audiences, or other appropriate steps. Finally, I will ask the makers of aspirin products to take two steps voluntarily: first, to immediately remove any labels which recommend that aspirin products be used to treat flu or chicken pox in children or teenagers; and second, to further label all aspirin products to indicate that there is a possible association between the use of aspirin and the onset of Reye syndrome in children and teenagers, and that aspirin products should ~ be used in those cases unless a physician is first consulted. I would ask the industry to voluntarily retain this expanded labelling until the results of the full~scale CDC study have been reported and thoroughly analyzed. I want to emphasize that this step does not mean that aspirin is unsafe for other uses. Aspirin is, in fact, a tremendously valuable and effective analgesic and anti'inflammatory drug that has, will and should continue to be used by tens of millions of Americans safely. But, as with any other drug, it is crucial that aspirin be administered appropriately. I am confident that both aspirin manufacturers and the American media will take the steps needed to ensure the best possible protection for our children. These are useful first steps. I believe they are entirely in the spirit of the recommendations we have received from the National Academy of Sciences' Institute of Medicine. In addition, the data now available in the pilot study will be reviewed further with great care, as will all independent comments and recommendations, to determine whether further steps may be warranted. PAGENO="0427" 421 CB~4TB~$ FOR DSEASE CONTROL M~NP MORBIDITY AND MORTALITY WEEKLY REPORT Reye Syndrome - United States, 1984 For the 1984 surveillance year,' 190 cases of Reye syndrome (RS) meeting CDC's case definitiont were reported. Although delayed reports will increase the number of cases for 1984 somewhat, the 1984 total is presently among the lowest annual totals reported through the National Reye Syndrome Surveillance System (NRSSS) since its initiation in December 1973 (Table 1). `For the purposes of surveillance, Reye syndrome years extend from December 1 to November 30 (i.e. the 1984 year runs from December 1, 1983. to November. 30, 1984). The data for 1984 are preliminary and include cases reported as of January 8, 1985. tThe CDC case definition is (1) acute noninflammatory encephalopathy documented by the clinical pic- ture of alteration in the level of consciousness and, if available, a record of cerebrospinal fluid containing eight teukocytes or less per mm3, or histologic sections of the brain demonstrating cerebral edema with- out perivascular or meningeal inflammation; (2) fatty metamorphosis of the liver diagnosed by either biopsy or autopsy or a threefold or greater rise in the levels of either the SGOT, SGPT, or serum ammo- nia; and (3) no known more reasonable explanation for the cerebral or hepatic abnormalities. PAGENO="0428" 422 Cases were reported from 42 states. The sex and race distributions were similar to previ- ous years. Of patients for whom this information was reported, 51% were male; 94%, white; 3%, black; and 3%, of Asian or American Indian extraction. Most AS patients were school-aged children; 38% were 10-14 years of age; 29%, 0-4 years of age; 18%, 5-9 years of age; 13%, 15-19 years of age; and 2%, 20 years of age or older. For 179 (94%) of the patients, a prodromal illness occurring within 2 weeks before the onset of vomiting or neurologic symptoms of AS was reported. This prodromal illness was characterized by respiratory symptâms (76%), varicella exanthem (15%), diarrhea without re- spiratory symptoms (2%), or other signs and symptoms, including fever alone (7%). Most patients were hospitalized in the first 6 months of the surveillance year (Figure 1). This winter and spring seasonal distribution primarily reflected the incidence of respiratory virus infections among children, particularly influenza types A(H1 NI) and B, the predominant influenza isolates during 1984. In addition, the small number of varicella-associated AS pa- tients were hospitalized primarily during this period. The largest percentages of patients were admitted to hospitals in the three precomatose stages of AS: stage I-38%; stage 11-36%; or stage 0-8% (1). Of these, 56% progressed to coma. The short-term outcomes were reported for 173 (91%) of the AS patients; 45 died, for a case-fatality ratio of 26%. Editorial Note: The NRSSS is useful in providing crude annual comparisons of AS activity, al- though the number of cases reported is recognized to be an underestimate of the true inci- dence of AS. During 1982-1984. the annual incidence of AS was the lowest reported since the initiation of national surveillance. The incidence of AS in previous years has reflected, at least in part, the intensity and/or type of influenza activity. However, the influenza activity in 1984 appeared to be much greater than in the 2 previous years. with widespread school out- breaks of both influenza types A(H1 Ni) and B (2). When analyzed by 10-year age groups, the decline in reported cases from 1981 to 1984 is accounted for by a consistent decline in the number of cases reported each year among children under 10 years of age. No such decrease has occurred in the number of patients 10-19 years of age; in 1984, the number of cases reported in this age group increased, con- sistent with the increased influenza activity. Varicella-associated AS cases show an even larger decline (from 77 in 1981 to 26 in 1984) in the number of cases reported each year among children under 10 years of age. However, annual varicella activity in the United States remained relatively stable during this period. The TABLE 1. ~icldence of Reys syndrome, by year - thilted States, 1974 and 1977-1984 ye- (D.c. 1- Nov 30) Major Influenza activity No. cases kicidence' Death/caset ratio (%) 1974~ B 379 0.58 157/379(41) 1977 B 454 0.71 156/373 (42) 1978 A(H3N2),(H1NI) 237 0.37 66/225 (29) 1979 A(H1N1) 389 0.62 113/349 (32) 1980 B 548 0.88 114/516(22) 1981 A(H3N2),(H1N1) 313 0.49 89/296 (30) 1982 B 222 0.35 73/208 (35) 1983 1984 A(H3N2).(H1N1) A(H1N1),B 198 1901 0.32 0.30 57/181 (31) 45/173(28) Cases/100.000 population under 18 years of age. tW1th known outcome. §For the period December 15. 1 973-June 10, 1974. 1Preliminary count; reported cases as of January 8. 1985. PAGENO="0429" 423 reasons for the decline in incidence among children under 10 years of age is unclear, although it does not appear to be solely the result of annual differences in the incidence of either in- fluenza or varicella. One possible, explanation for the reduced incidence among children under 10 years of age is that there has been a decline in the use of salicylates among younger children in recent years. In 1982, the Surgeon General of the Public Health Service (PHS) advised against giving sa- licylates and salicylate-containing medicati,,,-c to children with influenza and chickenpox (3). This advice was based on the review of results of case-control studies that showed a statisti- cally significant association of AS with the ingestion of salicylates during the antecedent ill- ness (4-6). Because of concerns regarding methodologic issues and the limitations of these studies, the Secretary of Health and Human Services appointed a PHS Task Force comprised of members of the National Institutes of Health, Food and Drug Administration, and CDC to design and implement a new epidemiologic study concerning the nature of the possible rela- tionship between AS and medications. A pilot study was conducted between February and May 1984 to determine the study feasibility and establish methodology. The pilot study included 29 AS cases and 143 controls consisting of children admitted to the same hospital (lP) or emergency room (ER), attending the same school, or identified by random-digit dialing (ADD). Ninety-seven percent of case children were reported to have received salicylates during the respiratory or chickenpox illness before a clinically defined onset of AS, compared with 28% (ER), 23% (P), 59% (school), and 55% (ADD) at any time during their matched illnesses. The risk defined in the pilot study was comparable to or greater than that determined in the previous studies. The Institute of Medi- cine (lOM). National Academy of Sciences, served to advise and critique the protocol, monitor the study progress, and review study analysis and results. Following a review of the data cot- FIGURE 1. Reye syndrome cases, by month of onset - United States, December 1, 1 983-November 30, 1984 60 50 40 0 Nonvaric.II. prodrom* 30 ~ Varicells prodrome U 20 10 0 r~fl DEC JAN FEB MAR APR MAYJUN JUL AUG SEP OCT NOV 1533 1934 ONSET PAGENO="0430" 424 lection methodology in July 1984 and the data analysis In December 1984, the tOM. on Janu- ary 8, stated: 1. The PHS Task Force should proceed with the full study. 2. Results of the pilot study should be released promptly to the public end to scientists for review and analysis. 3. Analysis of the pilot study data reveals a strong association between the Reye syn- drome and the use of aspirin; considering data from previous studies also show an association of use of aspirin and Reye syndrome, the Committee recommends that steps should be taken to protect the public health before the full study is completed. 4. Although it is impossible to know with certainty whether the release of the pilot study data will harm the full study, the Committee suspects the effects of the attendant pub- licity will be no more damaging than the current climate of public opinion, which ap- pears not to have impeded conduct of the pilot study. A report of the pilot study is currently being prepared for publication. In view of these prelimi- nary findings, physicians, parents, and older children who self-medicate should continue to be advised of the probable increased risk of RS associated with the use of salicylates for child- ren, including teenagers, with influenza-like illness or chickenpox. Reported by Div of Viral Diseases, Center for Infectious Diseases, CDC; the Reye Syndrome Task Force, consisting of members from U.S. Food and Drug Administration, National Institutes of Health. Office of theAssistant Secretary of Health, and CDC. References 1. Hurwitz ES, Nelson DB, Davis C, Morens D, Schonbergar IS, National Surveillance for Reye syn- drome: a five-year review. Pediatrics 1 982;70:895-900. 2. CDC. Influenza-United States, 1983-1984 season. MMWR 1 984;33:41 7-8. 3. CDC. Surgeon General's advisory on the use of salicylates and Reye syndrome. MMWR 1982;31 :289-90. 4. Starko KM. Ray CG, Dominguez LB. Stromberg WL Wodall DF. Reye's syndrome and salicylate use. Pediatrics 1 980;66:859-64. 5. Waldman RJ, Halt WN, McGee H, Van Amburg G: Aspirin as a risk factor in Reye's syndrome. JAMA 1 982;247:3089-94. 6. Halpin TJ. Holtzhauer FT. Campbell RJ, et al: Reye's syndrome and medication use. JAMA 1 982;248:687-91 PAGENO="0431" 425 January 11, 1985 Telegram to:. W. Frederick Pierce, thief Executive Officer Mer1~an Broadcasting Coaianles, Inc. 1330 Avenue of the Americas lew York, NY 10019 I am writing to ask your help in reaching the Americanpeople with an 1n~ortant message concerning the health of our children.. A pilot study recently completed for the Departh~ent of Health and Hianan Services materially strengthens earlier evidence suggesting that children and teenagers who take aspirin~containing medicines during a bout of flu or chicken pox are at increased risk of developing Re)e syndrome, a rare disease that causes death in 20 to 30 percent of its victims. While the results of the pilot study are only preliminary, I believe it is important that parents, children, teenagers and the health care coninunity be made aware of this evidence and be urged to obtain medical advice before using aspirin to treat the symptoms of flu or chicken pox. Here are the salient facts that have been provided to us: The Institute of Medicine of the National Academy of Sciences has carefully analyzed the results of a pilot study conducted b, the U. S. Public Health Service involving 29 children and teenagers who developed Reye syndrome following a case of flu or chicken pox and 143 other children (controls) who had flu or chicken pox but did not develop Reye syndrome. The study Shuwed that 28 of the children, br 96 percent of those who developed Reye syndrome, had recently taken or been given aspirin. Fewer than half of the controls (those who did not have Reye syndrome) had had aspirin or an asp1rin~conta1ning drug during their illness. It is also significant that those who suffer from the disease are increasingly older children and teenagers as well as young children; according to the pilot study some 50 percent of all cases were in those over age 10 and 15 percent were in those aged 15 and older. This finding does not prove that aspirin causes Reye syndrome or that aspirin is not a safe and effective drug for other purposes. It does, however, strengthen existing evidence suggesting an association between aspirin and Reye syndrome. We have reason to believe that the public educatiorrcampaign conducted for the past several years by the Public Health Service has helped to reduce the number of cases of Reye syndrome, particularly in young children who receive medication from their parents. The increase in Reye cases among older children and teenagers may result from their tendency for self treatment at the onset of flu symptoms. Therefore, it is necessary to redouble our efforts to Inform the public of this health risk, and I am asking for your help in doing that. PAGENO="0432" 426 Radio, television, and print media public service announcanents have beers distributed throughout the country to inform the American people thout the possible association of aspirin and Reye s~idrone. I urge )VU to make use of these announcenents-to give than the widest possible circulation and to cooperate In publicizing the known facts about this situation. It ~uld be particularly helpful for additional eophasis to be placed on public service announcenents durThg progranning that has a target audience of older children and teenagers. In a separate mailing, I en sending you additional information that can be used to get this important health message to the American people. In the meantime, however, please help us by giving this preliminary message the wide distribution it clearly warrants. Thank you for your assistance. Merger N. Heckler Secretary Department of Health and Human Services Washington, DC PAGENO="0433" 427 Frederick Pierce, Chief Izeciative Officer Amarican Broadcasting Coi~,anies, Inc. 1330 Ave. of the Americas 1ev York, BY 10019 Grant A. tinker, Chief Executive Officer National Broadcasting Co. 30 lockefeller Plaza 1ev York, BY 10020 Thomas B. Wyman, Chief EzecuticS Officer CBS, Inc. 51 West 52nd St. New York, 1! 10019 National Association of Broadcasters Edward 0. Pritts, President and CBO 1771 N St., N.W. Washington, D.C. 20036 National Cable TV Association James P. Mooney, President 1724 Massachusetts Ave., LW. Washington, D.C. 20036 Association of Independent TV Stations Inc. Herman N. Land, President 1200 18th St., 1.1. Suite 502 Washington, D.C. 20036 American Newspaper Publisher! Associatioj~ Jerry Friedheim, President 11600 Sunrise Valley Dr. Reston, VA 22091 PAGENO="0434" 428 mz SEC~ETA*Y O~ $tALTh *110 llt~*N a~viczs .~Ø~STO~O~ asvsi JAN 17 ~85 ~Dear General Manager: I am writing to ask your help in reaching the American people with an important message concerning the health of our children. A pilot study recently completed for the Department of Health and Human Services materially strengthens earlier evidence suggesting that children and teenagers who take aspirin-containing medicines during a bout of flu or chicken pox are at increased risk of developing Reye syndrome, a rare disease that causes death in 20 to 30 percent of its victims. While the results of the pilot study are only preliminary, I believe it is important that parents, children, teenagers and the health care community be made aware øf this evidence and be urged to obtain medical advice before using aspirin to treat the symptoms of flu or chicken pox. Here are the salient facts that have been provided to us: The Institute of Medicine of the National Academy of Sciences has carefully analyzed the results of a pilot study conducted by the U.S. Public Health Service involving 29 children and teenagers who developed Reye syndrome following a case of flu or chicken pox and 143 other children (controls) who had flu or chicken pox but did not develop Reye syndrome. The study showed that 28 of the children, or 96 percent of those who developed Reye syndrome, had recently taken or been given aspirin. Fewer than half of the controls (those who did not have Reye syndrome) had had aspirin or an aspirin-containing drug during their illness. It is also significant that those who suffer from the disease are increasingly older children and teenagers as well as young children; according to the pilot study some 50 percent of all cases were in those over age 10 and 15 percent were in those aged 15 and older. This finding does not prove that aspirin causes Reye syndrome or that aspirin is not a safe and effective drug for other purposes. It does, however, strengthen existing evidence suggesting an association between aspirin and Reye syndrome. We have reason to believe that the public education campaign conducted for the past several years by the Public Health Service has helped to reduce the number of cases of Reye syndrome, particularly in young children who receive medication from their parents. The increase in Reye cases among older children and teenagers nay result from their tendency for self-treatment at the onset of flu symptoms. Therefore, it is necessary to redouble our efforts to inform the public of this health risk, and I am asking for your help in doing that. PAGENO="0435" 429 Page 2 General Managers Radio, television, and print edia public service announcanents bays been distributed throughout the country to Inform the ~mer1cw people about the possible association of aspirin and Re)e syndrome. I urge you to make use of these announcenents~..to give than the widest possible circulation and to cooperate in publicizing the known facts about this situation. It ~uld be particularly helpful.for additional emphasis to be placed on public service announcements during prograimning that has a target audience of older children and teenagers. In a separate mailing, I an sending you additional information that can be used to get this important health message to the American people. In the meantime, however, please help us by giving this preliminary message the wide distribution it clearly warrants. Thank you for your assistance. Sincerely, 1~ ~ Margarf N. Heckler SecretI~ry PAGENO="0436" 430 T~~$5CUTA*V OF NIA%.ThNID HUMAN *mvicu M~HSNST~.OC. *I `JAN 23 ~35 Dear Uitorz I am writing to ask your help in reaching tbe~Americ*fl people with on important message concerning the hóalth of our children. A pilot study recently completed for the Department of ~ea1th and Human Services materially strengthens earlier evidence suggesting that children and teenagers who take aspirin~containthg medicines during a bout of flu or chicken pox are at increased risk of developing Reye syndrome, a rare disease that causes death in 20 to 30 percent of its victims. While the results of the pilot study are only preliminary, I believe it is important that parents, children, teenagers and the health care community be made aware of this evidence and be urged to obtain medical advice before using aspirin to treat the symptoms of flu or chicken pox. Here are the salient facts that have been provided to us: The Institute of Medicine of the Wational Academy of Sciences has carefully analyzed the results of a pilot study conducted by the U.S. Public Health Service involving 29 children and teenagers who developed Reye syndrome following a case of flu or chicken pox and 143 other children (control!) who had flu or chicken pox but did mmt develop Reye syndrome. The study showed that 28 of the children, or 96 percent of tlfo!ewho developed Reye syndrome, had recently taken or been given aepirin. Fewer than half of the controls (those who did not have Reye syndrome) had had aspirin or an aspirin~cOntaining drug during their illness. It is also significant that those who suffer from the disease are increasingly older children and teenagers as well as young children; according to the pilot study some 50 percent of all cases were in those over, age 10 and 15 ~ercent were in those aged 15 and older. This finding does not prove that aspirin causes ReyeayndrOme or that aspirin, is not a safe and effective drug for other purposes. It does, howeyer, strengthen existing evidence suggesting an association between aspirin and Reye syndrome. We have reason to believe ~bat the public education campaign conducted for the past severaijears by the public Health Service has helped to reduce the number of cases of Reye syndrome, particularly in young children who receivd medication from their parents. The increase in Reye cases among older children and teenagers may result from their tendency for self-treatment at the onset of flu symptoms. Therefore, it i5 necessary to redouble our efforts to inform the public of this health risk, and I am asking for your help in doing that. PAGENO="0437" 431 Radio, television, and print media public service announcements have been distributed throughout the meuntry to inform the American people about the possible association of aspirin and Reye syndroime. I urge you to make use of these announcements....to give than the widest possible circulation and to cooperate in publicizing the known facts about this situation. It would be particularly helpful for additional emphasis to be placed on public service announcements during programming that has a target audience of older children and teenagers. In a separate mailing, I am sending you additional information that can be used to get this in~ortant health message to the American people. In the meantime, however, please help us by giving this preliminary message the wide distribution it clearly warrants. Thank you for your assistance. Sincerely, 14argaj~t N. Heckler Secretary PAGENO="0438" 432 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville MD 20857 January 23, 1985 Dear Public Service Director: A new scientific study has strengthened existing evidence linking the use of aspirin to treat flu or chicken pox and the development of a rare but dangerous condition known as Reye syndrome. Because of that new evidence, the Food and Drug Administration has prepared the accompanying public service announcements to urge people not to use aspirin or aspirin-containing products for flu or chicken pox. The new evidence was in a pilot study done for the U.S. Public Health Service. Of 29 Reye syndrome cases studied, 28 had been treated with aspirin. It has long been realized that Reye syndrome, which is fatal in about one out of four cases, strikes mostly children. However, the new study indicated that teenagers up to the age of 19 are also likely victims, and the 60-second taped spot provided is aimed directly at the teen listener. Also provided is copy for a 30-second spot. We hope you are able to use them. By broadcasting them, you may help to avert tragedy. Sincerely, Roger W. Miller Director Communications Staff Food and Drug Administration PAGENO="0439" 433 DEPARTMENT OF HEALTH & HUMAN SERVICES PuMa Health Service Food and Drug Administration Rockville MD 20857 Teenagers/Aspirin/Reye syndrome :60 Radio PSA (The voice in parentheses is that of a teenage girl.) Young people often get the flu. (So do adults.) Sometimes a rare but dangerous condition called Reye syndrome develops from the flu or chicken pox. (Thank goodness it's only sometimes.) Children, including teenagers, are most often the victims of Reye syndrome. (That's not fair!) Reye syndrome usually occurs just when the child seems to be recovering. (How weird!) The symptoms of. Reye include persistent vomiting, fatigue, confusion and belligerence. (Sounds bad. Can it be prevented?) The cause of Reye syndrome is unknown but studies suggest a link between the development of Reye and the use of aspirin. (So shouldn't I take ~ medicine?) It's a good idea to check with a doctor before treating the flu or chicken pox with aspirin or any product containing aspirin. (But how will I get well?) Flu and chicken pox are usually self-limiting. Time will cure them. Take it easy. Get plenty of rest. (Oh, I'm really good at that.) A message from the U.S. Department of Health and Human Services. PAGENO="0440" 434 DEPARTMENT OF HEALTH & H~MAN SERVICES Public Health Sertoce Food and Drug Administration Rockville MD 20857 Reye syndrome PSA 30-seconds HERE S SOME ADVICE WE WANT TO PASS ALONG TO YOU FROM THE U. S. SURGEON GENERAL ABOUT REYE SYNDROME AND THE USE OF ASPIRIN. REYE SYNDROME IS A RARE BUT DANGEROUS CONDITION THAT MAY DEVELOP FROM FLU OR CHICKEN POX. IT OFTEN STRIKES JUST WHEN AN INDIVIDUAL APPEARS TO BE RECOVERING. CHILDREN, INCLUDING TEENAGERS, ARE MOST OFTEN THE VICTIMS. STUDIES SUGGEST A LINK BETWEEN THE USE OF ASPIRIN TO TREAT THESE ILLNESSES AND THE DEVELOPMENT OF REYE SYNDROME. SO, THE SURGEON GENERAL URGES YOU TO CHECK WITH YOUR DOCTOR BEFORE USING ASPIRIN OR PRODUCTS THAT CONTAIN ASPIRIN TO TREAT FLU OR CHICKEN POX. Contact: Louise Patterson Office of Communications, HFW-40 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (301) 443-3210 PAGENO="0441" 435 Your PSA's have been rcelved In ________ condition. I PLANNED USE: (IA? a ~ ~ COMMENTS: NAME:___________ TffL~ P ~ CALL LIRS: J(~1t') ~... ! ~ `AM____ FM____ ADDRESSe ~ t«='7 CI1Y: ~ STATE.~ (4 PAGENO="0442" 436 THE SECRETARV OF HEALTH AND HUMAN SERVICES Dear Hospital Administrator: Results obtained in the pilot phase of a case-control study conducted by the U.S. Public Health Service provide strengthened evidence of an association between aspirin and Reye syndrome. Enclosed with this letter is detailed information about the study methodology and findings and about steps which I have called for to protect children and teenagers, the groups most clearly at risk. I am providing this information to you and your colleagues so that you can be familiar with these recent findings and take appropriate action to reduce the risk of Reye syndrome. As you know, on the basis of earlier studies, the U.S. Public Health Service has for the past several years conducted an education campaign to alert the public to the symptoms of Reye syndrome and to call attention to preliminary findings suggesting that the use of aspirin-containing drugs to treat flu-like illnesses or chicken pox in children appears to be associated with increased risk of developing Reye syndrome. The pilot study described in the enclosed MNWR article strengthens the evidence for such an association and clearly warrants increased efforts to warn the public -- parents, teenagers, and health care providers -- of the potential risk involved in using aspirin-containing drugs to treat childhood chicken pox or flu. We have taken steps to bring this information to the attention- of the American people. Some of those steps are outlined in the enclosed statement I issued on January 9. In addition, I hope that you and your colleagues will carefully consider the implications of these new Reye syndrome findings and join in translating them into improved protection against this serious disease. Your cooperation will be deeply appreciated. Sincerely, i~ Margar~M. Heckler Secret'ary Enclosures PAGENO="0443" 437 Tht$~CRCTAsV o~ .~Aa.m NiB iS.N*N VNV$ctS y. ~ ama JAN 28 1985 Dear Doctars Results obtained in the pilot phase of a case-control study conducted by the U.S. Public Health Service provide strengthened evidence of an association between aspirin and Reye syndrome. Enclosed with this letter is detailed information about the study methodology and findings and about steps which I have called for to protect children and teenagers, the groups most clearly at risk. I am providing this information to you and your colleagues so that you can be familiar with these recent findings and take appropriate action to reduce the risk of Reye syndrome. As you know, on the basis of earlier studies, the U.S. Public Health Service has for the past several years conducted an education campaign to alert the public to the symptoms of Rsye syndrome and to call attention to preliminary findings suggesting that the use of aspirin-containing drugs to treat flu-like illnesses or chicken pox in children appears to be associated with increased risk of developing Reye syndrome. The pilot study described in the enclosed *IWR article strengthens the evidence for such an association and clearly warrants increased efforts to warn the public -- parents, teenagers, and health care providers of the potential risk invoJ~ved in using aspirin-containing drugi to treat childhood chicken pox or flu. We have taken steps to bring this information to the attention of the American people. Some of those steps are outlined in the enclosed statement I issued on January 9. In addition, I hope that you and your colleagues will caref~ully consider the implications of these new Reye syndrome findings and join in translating them into improved protection against this serious disease. Your cooperation will be deeply appreciated. Sincerely, Marg~t H. Heckler Secr~tary Enclosures PAGENO="0444" 438 DEPARTMENT OF HEALTH & HUMAN SERVICES PIM~ *4Mth $sivics - Food and Dw~ Admi~strodon Rodmil, MD 20357 January 28, 1985 The Advertising Council 1730 Rhode Island Avenue, N.W. Washington, D.C. 20036 Dear Sirs: The Food and Drug A&ninistration has reviewed public service announcements prepared by the major aspirin manufacturers with the cooperation of the Advertising Council. These materials are responsible and clear. They have the support of F~. They were prepared in response to the request of U.S. Health and Human Services Secretary Margaret P1. Heckler. Store posters and announcements are also being distributed. Thank you for your work in distributing these public service announcements. trust that the broadcast media will air these vital messages promptly, during this flu season. Sincerely, FrankE.Y , Comissioner of Fo and ugs PAGENO="0445" 439 ( DEPARTMENTOF HEALTh & HUMAN SECVICES H~Ic I~iaI SaMoa Feed and Drug AdmW~medon m~~vIP. MD 30557 January 28, 1985 Dear Store Manager: The Food and Drug Ackninistration has reviewed posters and buBetin board announcements prepared by the major aspirin manufacturers with the cooperation of the Advertising Council. These materials are responsible and clear and have F1's support. They have been prepared in response to a request of U.S. Health and Human Services Secretary Margaret H. Heckler. Television and radio announcements are also being distributed. Sincerely, Comissloner of Fo and ugs PAGENO="0446" 440 FOR IMMEDIATE RELEASE William Grlgg Feb. - March 1985 (301) 443-3285 In the midst of the flu season, important new information has become available about the development In teens and children with flu -~ of Reye syndrome, a rare but serious condition that kIlls 20 to 30 percent of Its young victims and leaves many survivors brain damaged. The new information comes from a U.S. Public Health Service pilot study of a possible link seen in four earlier state studies between the use of aspirin in treating flu or chicken pox and an Increased risk of Reye syndrome. The Institute of Medicine of the National Academy of Sciences has reviewed the pilot study and found Nstrong supportw for the link. Although personnel from the Food and Drug Administration, the National Institutes of Health and the Centers for Disease Control will contiune the study through next winter, the Institute of Medicine advised that the federal government not wait to inform and protect the public. As a result, Health and Human Services Secretary Margaret M. Heckler has asked manufacturers to remove any~recommended use in flu and chicken pox from aspirin-containing products aimed at children -- and to add a warning to all aspirin-containing products against use for flu and chicken pox in children and teens. The pilot study looked at the histories of drug treatments and other factors of 29 young people who got Rey~ syndrome last year. Use of aspirin for flu or chicken pox symptoms was the common thread shown in 28 of the 29 MORE PAGENO="0447" 441 REYE/ASPIRIt4 page 2. (whereas ordinarily less than half the young people with flu or chicken pox would be expected to take aspirin.) U.S. Surgeon General C. Everett Koop, M.D., has said that most childhood illnesses are self-limiting and ususally don't require any medication at all. Doctors often suggest that a child with fever simply be made comfortable with cool compresses. Of course, physicians continue to find aspirin Useful and safe for adult, teen and childhood arthritis and other conditions. Reye syndrome is a rare condition a few hundred cases a year. It was named in 1963 for an Australian pathoiogist who described it as a swelling of the brain, combined with liver malfunction and blood chemistry disorders leading In most cases to death. Improved recognition and early treatment of the disease has helped reduce the death rate, but still about one out of four reported cases are fatal. It is crucial to take action quickly if Reye's symptoms occur whether or not aspirin or an aspirin-containing product has been used. The first sign is generally persistent vomiting. The young person may be sleepy and lethargic, but still responsive. Within half a day, he or she can become disoriented, combative and delirious. Untreated, the teenager or child can go into a coma and die. Thus, Reye is a medical emergency. A child with Reye syndrome symptoms must be taken immediately to a hospital, where blood andbody fluids can be monitored and a respirator used if breathing fails. Surgery may be needed, in some cases, to relieve pressure on the swoflen brain. Therefore, act promptly If you suspect Reye syndrome. ft.,' PAGENO="0448" 442 Feb.-March 1985 Reye Ahora que estamos en piena ~poca de ia influenza, nueva e iinportante inforrnaci6n se ha dado a conocer acerca del desarroilo del s~ndrome de Reye, una condicic~n poco comun pero muy seria que ocasiona la muerte del 20 al 30 por ciento de Bus v~ctimas -~ ni~os y adolescentes -- y serios daftos en el cerebro de los que ia sobrevi yen. La nueva informaci6n fue el resuitado de un estudio lievado a cabo por el Servicio P6blico de Salud de los Estados Unidos, sobre la posibilidad observada en cuatro estudios preliminares -- de una asociacic~n entre el uso de la aspirina para el tratamiento de influenza o varicela y un auinento en el riesgo de contraer ci s~ndrome de Reye. El Instituto del4edicina de la Academia Nacional de Ciencias, despu~s de analizar el estudio mencionado, ha liegado a la conclusic~n de que existe una "marcada posibilidad" de que la mencionada asociaci~n entre la aspirina y ci srndrome de Reye sea una realidad. Aunque ci personal de la Adininistracic~n de Drogas y Alimentos, (FDA), los Institutos Nacionales de Salud (NIH) y los Centros de Control de Enfermedades (CDC) continuar~n el estudio durante ci prccximo invierno, ci Instituto de Medicina ha aconsejado al gobierno federal no esperar para informar y proteger ai pi~biico. Como resuitado, Margaret M. Heckier, Secretariadei Departamento de Salud y Seryicios Humanos, ha pedido a los PAGENO="0449" 443 laboratorios manufactureros de drogas, abstenerse de recomendar el uso de medicarnentos para el tratamiento de influenza y varicelas que contengan aspirina, y m~s bien a~adir una advertencia que prevenga ci uso de tales productos en niftos y adolescentes. El estudio principal examinc«= las historias m~dicas, las drogas usadas en los tratamientos, y otros factors de 29 jóvenes vi~ctixnas del sindrome de Reye durante el aflo pasado. El uso de la aspirina contra los sintomas de influenza o varicela, fué ci factor predominante en 28 de los 29 casos. El Cirujano General de Los Estados Unidos, C. Everett Koop, M.D., ha manifestado que la mayori'a de las enfermedades en los niftos generalmente son leves, y no requieren medicamentos. Los in~dicos usuaimente sugieren tratar un caso de fiebre conuin con compresas de agua fr~a; desde luego, ellos contintcan recetando aspirina a ni~os y adultos para aliviar otras dolencias, tales. como la artritis. El s«=ndrome de Reye as una condici6n ~oco com~n -- unos pocos casos se presentan cada a~o. Fue llamado Reye, como ci pat~iogo Australiano que en 1963 10 describio como una infiaTnacidn del cerebro, en combinaciä'n con defectos en ci funcionamiento del h(gado y desc~rdenes en la composici6n qu«=mica de la sangre, generalmente resultando en la muerte. Diagnc~sticos acertados y r~pido tratamiento m~dico de ~sta condici6n han ayudado a reducir la mortalidad, pero todavia, uno de cada cuatro casos reportados es fatal. 52-266 0-85-15 PAGENO="0450" 444 Es de decisiva. importancia actuar con rapidez, ~i los srntomas del s«=ndrome de Reye se presentan -- haya el paciente o no tornado aspirina o algi~n otro medicamente conteniendo aspirina. Generalmente, el primer scntoma es un v6mito persistente. El nifto aparenta estar so?~oliento y letárgico, pero todav~a responde. En pocas horas, puede encontrarse desorientado, agresivo o delirante, y de no recibir asistencia m~dica inmedlata, puede entrar en estado de coma y morir. El si'ndrome de Reye es una emergencia médica. Un ni~o enfermo debe ser ilevado inmediatamente a un hospital, en donde la sangre y los fluidos del cuerpo pueden ser observados y corregidos; se puede alli usar un aparato respiratorio si la respiracic~n est~ fallando y Si es necesario, se le puede someter a una operaci~n para disminuh la presi~n del cerebro inflamado. No lo olvide. Act~e con rapidez ante la menor indicaci~n del s«=ndrome de Reye. PAGENO="0451" 445 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville MD 20857 March 8, 1985 Dear Drug Establishment Registrant: On January 9, 1985, the Secretary of the Department of Health and Human Services requested the aspirin industry to undertake a voluntary program to warn parents and teenagers about the possible association between the use of aspirin and the onset of Reye Syndrome. As a consequence, the Conanissioner of Food and Drugs met with representatives of the Aspirin Foundation of America, Inc., and Plough, Inc., at which time both organizations announced they weuld launch voluntary Reye Syndrome precautionary programs. The purpose of this letter is to inform you of the voluntary labeling programs being undertaken by the Aspirin Foundation and Plough, Inc. and to. ascertain whether, and to what extent, your firm intends to join in this nationwide program. As a part of its voluntary program, the Aspirin Foundation has proposed labeling revisions for aspirin and aspirin-containing products, which include: (1) Indications for use in `flu' will be renewed from products packaged only for use in children (pediatric products). (2) All such products will bear the statement: `Warning: Contact a physician before giving this medicine to children, including teenagers, with chicken pox or flu.' Plough, Inc. of Wasrçthis, W, maker of St. Joseph aspirin and non-aspirin products for children, which is not a nner~er of the Aspirin Foundation, has developed its nwn voluntary precautionary program. A part of its program includes th~ labeling revisions for children's products proposed by the Aspirin Foundation with the foll~eing expanded warning statement: PAGENO="0452" 446 "Warning: Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylatas) may increase the risk of developing this disease. Consult a doctor before use in children or teenagers with flu or chicken pox." Plough, Inc. also intends to include in its packages an insert bearing information which identifies the symptoms of Reye Syndrome. The FDA supports these voluntary precautionary programs of the Aspirin Foundation and Plough, Inc. and the labeling revisions proposed by them and urges that they be applied to all aspirin and salicylate-containing drug products intended for use in the treatment of flu or chicken pox, and/or likely to be used by children or teenagers in the treatment of symptoms cosmonly associated with flu or chicken pox (e.g., fever, cough, headache, sore throat, sneezing, nasal congestion, rhinitis). For more information, please refer to the attached HHS Press Releases and FDA TALK PAPER. Should you elect to participate in this voluntary program, we would recoirmend that a warning statement appear on all cartons, container labels, and other printed materials as the first warning for products with multiple warning statements, and that the labeled directions for use refer to the warning statement, such as "For Chicken pox or Flu see Warnings." This is consistent with the agency's position in the advance notice of proposed rulemaking that was issued on December 28, 1982 (47 FR 578~6). In an effort to update our files under the drug listing regulations, we request that you answer the questions on page 3 of this letter: PAGENO="0453" 447 (1) Establishment Name Address City/State/Zip ________ ___________ ( ) (2) Respondent's Name Title Telephone No. (3) Is your firm currently involved in the manufacturing, repackaging, relabeling, and/or distribution of products containing aspirin or salicylates? Yes No If yes, please attach specimens or ~ of each container label, carton label, and accompanying labeling. Mark on each specimen or copy whether the product is manufactured (N), repackaged (NP), relabeled (RL), repackaged and relabeled (RP/RL), or distributed only (D). (4) Does your firm intend to relabel its aspirin or salicylate-containing products in conformance with the voluntary initiatives developed by the Aspirin Foundation or Plough, mc? Yes No ~ot Applicable If yes, please attach specimens or copies of each container label, carton label, and accompanying labeling showing changes to be made. (5) If yes to items 3 and 4, what is your anticipated date to begin using the new labeling? Date__________ (6) If yes to items 3 and 4, what is your anticipated date for such newly labeled products to reach the retail market place? Date_________ Please return using enclosed envelope by 3/29/85 to: Food and Drug Administration HFN-3l2 5600 Fishers Lane Rockville, MD 20857 Atth: Reye Syndrome Labeling PAGENO="0454" 448 As indicated above, we request that, whether or not you decide to participate, you submit one copy of each label, carton label, and accompanying labeling for each aspirin or salicylate-containing product currently manufactured, repackaged, relabeled and/or distributed by you. Should you agree to participate in this program, we ask that you also submit a copy of each label, carton label, and accompanying literature for each such product showing the revisions to be made. With regard to questions 5 and 6, we request that you identify the anticipated dates for using such revised labeling and when products, bearing revised labeling, will reach the retail market place. Please return page 3 of this letter and any pertinent labeling, as requested, using the enclosed envelope, by March 29, 1985. Should you have any questions you may contact Kevin M. Budich, Assistant to the Director, Division of Drug Labeling Compliance, Office of Compliance, Center for Drugs and Biologics at (301) 443-7283. Thank you for your prompt attention in this matter. Sincerely, (7~-~7 /2i Harry M. fr~yer, Jr., M.D. Director Center for Drugs and Biologics Enclosures (3): Secretary's Press Stateirmnt, 1/9/85 tillS Press Release, 1/23/85 FDP~ Talk Paper, 1/25/85 PAGENO="0455" 449 ThE$LCSET**Y OF H(ALTW aso wusas sr.sv.cts Statement by Margaret N. Heckler Secretary of Health and Human Services Nothing is more important to Americans than the health and safety of their children and, as Secretary of Health and Human Services, I feel a special responsibility to protect the health of our nation's children during their most vulnerable years. That is why I ordered special steps to resolve the scientific dispute when some early studies shoved an association between Reye syndrome and the use of aspirin for children suffering from chicken pox, influenza and flu-like illnesses. That is also why I instructed the Food and Drug Administration to pursue a vigorous public education campaign to ensure that parents were made aware of the possible link. In particular, I ordered the Centers for Disease Control a year ago to undertake a new study of aspirin and Reye syndrome. The study had two parts - a one-year pilot study followed by a full-scale investigation. The Centers for Disease Control have now completed the pilot study. This study is not completely con~lusive - but its findings do show an association between the use of aspirin and the onset of Reye syndrome in children and teenagers. These results make it urgent that CDC vigorously pursue the full- scale study. That work was begun last month and is now fully underway. In the meantime, I strongly urge parents to follow the advice of the Surgeon General: in all cases involving children, includi~~q teenagers,~_physician should be consulted before using aspirin in cases of flu or chicken pox. It is significant that fewer children are now being struck by Reye syndrome - 190 known cases in the year ending November 1984 - while reported cases in previous years were as high as 548 (in 1980). But this does not mean we can be complacent. The disease is deadly, with a fatality rate of 26 percent last year. In addition, those who suffer from the disease are increasingly older children and teenagers, as wall as young children: According to the pilot study, some 50 percent of all cases were in those over age 10, and 15 percent were in those aged 15 `and older. In order to ensure that all children continue to be given the fullest protection, even while we await final scientific conclusions, I am today taking four additional steps: First, I am ordering CDC to release the pilot study immediately, and I am instructing that it also be published as soon as possible in CDC's journal Morbidity and Mortality Weekly Report. This information along with other scientific evidence will appear in a refereed scientific journal. Second, I am asking the Food and Drug Administration to extend and expand its public education efforts -- parents must understand the need to consult a physician before using aspirin to treat flu or chicken pox. Likewise, FDA will take steps to inform teenagers - who often treat themselves -- of the possible link between aspirin and Reye syndrome. PAGENO="0456" 450 Third, I am contacting media leaders throughout the country asking them to use every possible resource to help broadcast the ssage. I am telegraphing the presidents of the three television networks as well as the American Newspaper Publishers Association, the National Association of Broadcasters, the Association of Independent ?elevisior* Stations, and the National Cable Television Association. I wiU also send letters to the owners of newspapers as well as television and radio stations throughout the country. I will re~emphasize the importance of the public service announcements we've already supplied to them. And I will urge them to take additional steps to convey this important message: for example, special news coverage, new public service announcements, messages specially designed to reach teenage audiences, or other appr~riate steps. Finally, I will ask the makers of aspirin products to take two steps voluntarily: first, to immediately remove any labels which recommend that aspirin products be used to treat flu or chicken pox in children or teenagers; and second, to further label all aspirin products to indicate that there is a possible association between the use of aspirin and the onset of Reye syndrome in children and teenagers, and that aspirin products should not be used in those cases unless a physician is first consulted. I would ask the industry to voluntarily retain this expanded labelling until the results of the ful]~-scale cDC study have been reported and thoroughly analyzed. I want to emphasize that this step does not mean that aspirin is unsafe for other uses. Aspirin is, in fact, a tremendously valuable and effective analgesic and anti~inflammatory drug that has, will and should continue to be used by tens of millions of Americans safely. But, as with any other drug, it is crucial that aspirin be administered appropriately. I am confident that both aspirin manufacturers and the American media will take the steps needed to ensure the best possible protection for our children. These are useful first steps. I believe they are entirely in the spirit of the recommendations we have received from the National Academy of Sciences' Institute of Medicine. In addition, the data now available in the pilot study will be reviewed further with great care, as will all independent comments and recommendations, to determine whether further steps may be wArranted. PAGENO="0457" 451 HHS ~ U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES FOR IMMEDIATE RELEASE Claire del Real -- (202) 245-6343 Jan. 23, 1985 HHS Secretary Margaret M. Heckler announced today that the nation's major aspirin manufacturers have agreed to her call for voluntary action concerning the rare but serious Reye syndrome. A new program by the manufacturers will include television announcements, store posters and label changes and warnings regarding the rare but serious Reye syndrome. Secretary Heckler had called for such voluntary action Jan. 9 and today applauded the Aspirin Foundation of America for Uits prompt and responsible action, which will be getting the message to Americans within a week. U The program was worked out in a series of meetings between the foundation and the Food and Drug Administration over the past two weeks. The Secretary's request for information and labeling was made following a review by the Institute of Medicine of the National Academy of Sciences of a pilot study supporting a link between use of aspirin to treat childhood flu and chicken pox and the subsequent development of Reye syndrome. Public service announcements and store posters and signs will be distributed next week by the manufacturers' sale representatives and the Advertising Council, Secretary Heckler said. She asked the media and store managers to use the materials widely, because we will rely on these materials to notify people buying aspirin products with the old labels -- or already having such products in their homes. U Some of the label changes and warnings may be in place as early as this summer, and will thus appear well in advance of the next winter's flu and chicken pox seasons. Warning stickers on store shelves will appear in some areas as early as this week. The posters and radio-TV public service announcements say, in part: UA rare but serious childhood disease called Reye syndrome may develop in children who have chicken pox or flu. Although the cause of Reye syndrome is not known, some studies suggest a possible association with medicines containing ealicylate or aspirin. So it is prudent to consult a doctor before giving these medicines to children and teenagers with chicken pox or flu. U / The posters and announcements also note that Reye can occur without a link to medications. The materials list the symptoms -- lethargy, belligerence or excessive vomiting -- and recommend quick medical help~ The labeling changes are twofold: --Suggestions for use in flu will be deleted from the labels of children's aspirin. -- The following warning will be added to labels of aspirin-containing products for adults as well as children: UConsult a physician before giving this medicine to children, including teenagers, with chicken pox or flu. U Reye syndrome is a rare condition, with only several hundred reported cases a year. Last year there were 190 cases reported. But 20-30 percent of reported cases are fatal, and many of the surviving youngsters suffer brain damage. -MORE- PAGENO="0458" 452 Four state studies initially made possible associations between Reye and aspirin's use for childhood chicken pox and flu. A larger federal study to confirm or negate the link will continue through next winter's flu and chicken pox seasons. A pilot for this larger epidemiological case review found 96 percent of cases had the common thread of aspirin use for flu-like illnesses or chicken pox. After a review, the Institute of Medicine of the National Academy of Sciences advised that the federal government should alert parents and physicians now and not await the full study's results. The institute recommended that the full study continue, however. A task force of Public Health Service employees is overseeing the study. First to respond to the new information was Plough Inc. of Memphis, Tenn., manufacturer of St. Joseph products for children. Plough is making label changes and is placing stickers on products already produced but not yet distributed. The Aspirin Foundation represents such major aspirin manufacturers and distributors as Sterling, Bristol-Myers, Miles, Burroughs Wellcome, Merrell Dow and Procter & Gamble. Retailers such as Giant Foods, with offices in the Washington area, plan their own posters and shelf signs on Reye syndrome and aspirin in the nonprescription drug sections of their pharmacies and food stores. FDA has been working with these retailers. Giant Foods plans to have their posters in place tomorrow. Secretary Heckler emphasized that warnings on Reye syndrome "do not mean aspirin is unsafe for other uses. Aspirin is, in fact, a tremendously valuable and effective analgesic and anti-inflammatory drug that has, will and should continue to be used by tens of millions of Americans safely. But as with any other drug it is crucial that aspirin be administered appropriately." tilt PAGENO="0459" 453 FDA `PjJ ( E~AJ'E1~ FOOD AND DRUG ADMINISTRATION U.S. Department of Health and Human Seivices Public Health Service 5600 Fishen Lane Rockvile, Maryland 20857 FDA Talk Papers are prepared by the Office ci Public Affairs to guide FDA personnel in responding with consistency and accuracy to questions from the public on subjects of current interest. Talk Papers are subject to change as more information becomes available. Talk Papers are not intended for general distribution onnide FDA, but all information in them I, public, and full tests are releasable upon request. 185-7 Bill Grigg Jan. 25, 1985 (301) 443-4177 RECENT ACTIONS ON REVE SYNDROIE/ASPIRIN LINK The FDA has held a series of meetings to carry forth HHS Secretary Margaret N. Heckler's Jan. 9 call for voluntary labeling changes on aspirin products. The changes were requested to reflect a recent federal pilot study supporting earlier state studies linking aspirin's use in teen and childhood flu and chicken pox to the subsequent development of the rare but serious Reye syndrome (see Talk Paper T85-3). Secretary Heckler announced the results of these meetings -- agreement with the major manufacturers for label changes, store posters and radio-TV announcements -- on Jan. 23. The following may help answer questions on the warning labels and broadcast announcements pledged: The labeling agreed to by members of the Aspirin Foundation of America -- such major manufacturers as Sterling, Bristol-Myers, Miles and Burroughs Wellcome, Squibb, Whitehall and Procter & Gamble -- and found acceptable by FDA will add to the warning section of the labels: `Contact a physician before giving this medicine to children, including teenagers, with chicken pox or flu.' In addition, reconmendations for use in flu will be removed from children's products. Also as part of the agreement, the Aspirin Foundation has produced 60- and 30-second TV and radio public service announcements to be distributed to the media In the next few days. The shorter version says: `A rare but serious childhood disease called Reye Syndrome may develop In children and teenagers who have chicken pox or flu. Although the cause of Reye Syndrome Is not known, some studies suggest a possible association with medicines containing salicylate or aspirin. So, it Is prudent to consult a doctor before giving these medicines to children or teenagers with chicken pox or flu.' The longer version adds to the above: `Remember, Reye Syndrome occurs even in children and teenagers who take other medicines or no medicines. It's important to be aware of the early signs and symptoms. If your child shows unusual behavior, such as severe tiredness, belligerence, or excessive vomiting after appearing to recover from chicken pox or flu, get medical help Immediately. Give no medications.' Plough Inc. of Memphis, Tenn., maker of St. Joseph aspirin and non- aspirin products for children, is not a member of the Aspirin Foundation but was the first to announce it would comply with the Secretary's request (even though company officials said they'did not feel aspirin had been established as a cause of Reye syndrome). Its program is different from the foundation members. The corporation met with FDA Jan. 15 and later announced that it: -MORE- PAGENO="0460" 454 -- would begin next week to print packages for its aspirin-containing products with changes suggested by the Secretary and FDA in the labeling, eliminating any recommendation for use in childhood or teen flu or chicken pox, and adding a warning against such use, with an explanation of Reye syndrome; and -- was adding warning stickers on the boxes of aspirin products already produced but still under its control. Consumers may begin to see the stickers soon. The stickers say, `Consult doctor before use in children or teenagers with flu or chicken pox." The Plough label warning will say: "WARNING: Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin may increase the risk of developing this disease. Consult doctor before use in children or teenagers with flu or chicken pox." Plough will also insert in packages information to read: "The symptoms of Reye Syndrome can include persistent vomiting, sleepiness and lethargy; violent headaches; unusual behavior, including disorientation, combativeness and delirium. If any of these symptoms occur, especially following chicken pox or flu, call doctor immediately, even if your child has not taken any medication. REYE SYNDROME IS SERIOUS, SO EARLY DETECTION AND TREATMENT ARE VITAL." FDA Commissioner Frank E. Young wrote Plough commending the company's speed and cooperation. Giant Foods and other retailers have contacted FDA about producing their own posters and shelf labeling. The Giant materials will be in all of the chain's food and drug stores tomorrow, Jan. 26. The main poster says, "The U.S. Food and Drug Administration recommends that parents~ check with a doctor before giving aspirin or products containing aspirin to thildren or teenagers who have the flu or flu-like symptoms or chicken pox." Below the posters, Giant is attaching to the shelves tear-off literature giving more details about the warning and about Reye syndrome. FDA has reviewed the wording used by Giant and supports it. FDA has conducted public education campaigns cautioning about the use of aspirin in childhood flu and chicken pox for thre~ winters and is now updating those materials. Since the pilot and last year's case reports indicate about half the cases of Reye syndrome to be in teens and children over 10, who may self-medicate, the campaign will shift emphasis toward this older group. A new radio announcement and a column for weekly newspapers is being given priority. Secretary Heckler has sent letters on the pilot study to pediatricians and family doctors, as well as to newspapers and broadcast outlets. PAGENO="0461" 455 DEPARTMENT OF HEALTH & HUMAN SERVICES Pubbc Health Service Food and Drug Administration Rockville MD 20857 March 11, 1985 Dear Madam or Sir: The flu is a common ailment, and usually self-limiting -- particularly for children. Not 80 common and not so easy' to treat is Reye syndrome, which may develop in children who, have had the flu or chicken pox. Reye syndrome can result in brain damage and is fatal in about one case out of four. Some scientists have suspected that Reye syndrome develops mainly in children who have been treated with aspirin when they have had those illnesses. Recently, a U.S. Public Health Service study confirmed evidence linking Reye syndrome with the use of aspirin. Equally significant was that the study found a number of Reye syndrome cases among teenagers. Previously, it had been thought that the disease was found almost exclusively in children under 16. The Public Health Service, through the Food and Drug Administration, is taking a number of steps to warn teenagers about the suspected association between Reye syndrome and aspirin. Messages, such as the enclosed poster, are aimed directly at these youths, many of whom do their own medicating. When Reye syndrome strikes, fast action is required to forestall its dire consequences. But the fastest action is to prevent its occurrence. This poster is designed to make that point. We hope you find a suitable place to display it. Roger W. Miller Director Communications Staff PAGENO="0462" 456 R~for Flu c~ Chicken Pox: Kindness Be good to yourself when you'vegot the fluorchicken pox. Take it easy. Get plenty of rest. Viral illnesses such as these are usually self~limiting. Time will cure them. Check with yourdocsorahoutusing medications to treat flu or chicken pox. For children-including teenagers-medications such as aspirin and aspirincontaining products may not be a good idea. A rare but dangemuscnnditioncalled Reye syndrome may develop in young people just when they appear to be re covering. Studies suggest a link between the development of Rcye and the use of aspirin to treat the flu or chicken pox. So, treat yourself tight when you've got the flu! cs. DepavxrvsnfHeslth riot Hsxas Snxim * PvblicHnfth Srswr * Fssdrod DxgAdicixi,msiss * Scot) rot Lair. Rsdi,itk. Md. 2)057 * HHSPnblicaisv No. (ODA)t5.0)49 PAGENO="0463" 457 Mr. BATES. Thank you. Let me just follow that logic that the legislation is not needed. Evidently, we live in an imperfect world. Dr. YOUNG. Yes, sir. Mr. BATES. Science is constantly changing our facts or knowledge about the effects of drugs or other medicines, so there is a margin of error. Dr. YOUNG. Yes. Mr. BATES. And if we err, which way do we err? Do we err on the side of the public, or do we err on the side of the aspirin manufac- turers? Let me ask you, because I think this is the fundamental ques- tion, and you could say you are being cautious in one sense, but you also said that you are not being cautious in another sense. Dr. YOUNG. Sure. Mr. BATES. So I would ask this question: Do we have any evi- dence to suggest that children or adolescents or adults have died from not taking aspirin? In other words, does aspirin prevent death in flu or something that someone may have? Would aspirin keep them alive? Dr. YOUNG. It is very clear, as stated by Dr. Wolfe and the testi- mony from the American Academy of Pediatrics, that we do over- medicate. I think that is unquestionable in many cases. Many of these infectious diseases, particularly nonbacterial, will resolve spontaneously. In the event that one has a very high fever, and the fever is not brought down either by antipyretics or cooling, a young child, particularly a young child could die, I must have to say, in my own case, when my fever hit 105, 105.5, my wife got ap- prehensive, and I was equally apprehensive. One has, in the case of high fever, a chance of having complica- tions of death due to the fever itself, and in that circumstance, as- pirin and salicylates and other antipyretics are designed primarily to lower fever. In those cases where fever is not lowered, death could occur. It must also be stated that there are other ways of low- ering fever besides aspirin, and even besides drugs. Cool bath is one. Mr. BATES. And is there any indication or any evidence at all to demonstrate that there is an association between aspirin and Reye's Syndrome? Dr. YOUNG. I think there is an association with aspirin and Reye's Syndrome, as shown in the variety of studies, and I have said that clearly on both TV and the other media that are there. We do not know the exact etiology or the magnitude. There is a very tight link. But there are other factors; we felt at this time there was not sufficient information to warrant mandatory label- ing, but felt because of the association that a very vigorous pro- gram should not only be instituted, but we must monitor how effec- tive it is. Mr. BATES. So, you do think that whether it is mandatory or vol- untary, that at this time a vigorous public education program is warranted? Dr. YOUNG. Absolutely. Mr. BATES. And the posters-I personally would like 300 of those today delivered to my office. PAGENO="0464" 458 Dr. YOUNG. Would you please, Joe, arrange for that? Mr. BATES. And I intend to take your letter, which I think was a strongly worded letter, and include it in my next newsletter. Dr. YOUNG. How many copies would you like, sir? Mr. BATES. I will have it reprinted. I will start with one copy. Have you done any television, public service announcements? Dr. YOUNG. Yes; could I please show the public--- Mr. WAXMAN. We are not really going to have time. I don't know how long this thing is, but let's just have questions now. Dr. YOUNG. Fine. I do have that, and if you would like? Mr. BATES. I would like copies of that. Dr. YOUNG. I could provide you with a reel that you might be able to send out to your constituents as well, and we will provide that. Joe, will you please be sure that that is available to the Con- gressman, and we will have a reel that will be sent. If you would like, we can provide the radio announcement that went out as well. Mr. BATES. Send 50 of those. [The following material was submitted for the record:] PAGENO="0465" 459 DEPARTMENT OF HEALTH & HUMANSERVICES Pubbc Health Service Food end Drug Administration Rockvilhe MD 20857 Rbye syndrome PSA 30-seconds HERE' S SOME ADVICE WE WANT TO PASS ALONG TO YOU FROM THE U.S. SURGEON GENERAL ABOUT REYE SYNDROME ~ND TEE USE OP ASPIRIN. REYE SYNDROME IS A RARE BUT DANGEROUS CONDITION THAT MAY DEVELOP PROM FLU OR CHICKEN POX. IT OFTEN STRIKES JUST WHEN AN INDIVIDUAL APPEARS TO BE RECOVERING. CHILOREN, INCLUDING TEENAGERS, ARE MOST OFTEN THE VICTIMS. STUDIES SUGGEST A LINK BETWEEN THE USE OP ASPIRIN TO TREAT THESE ILLNESSES AND THE DEVELOPMENT OF REYE SYNDROME. SO, THE SURGEON GENERAL URGES YOU TO CHECK WITH YOUR DOCTOR BEFORE USING ASPIRIN OR PRODUCTS THAT CONTAIN ASPIRIN TO TREAT FLU OR CHICKEN POX. Contact: Louise Patterson Office of Communications, HFW-40 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (301) 443-3210 PAGENO="0466" 460 DEPARTMENT OF HEALTH & HUMAN SERVICES Pubic Health Food and Drug Ad sat at on Rockvilla MD 20857 Teenagers/Aspirin/Reye syndrome :60 Radio PSA (The voice in parentheses is that of a teenage girl.) Young people often get the flu. (So do adults.) - Sometimes a rare but dangerous condition called Reye syndrome develops from the flu or chicken pox. (Thank goodness it's only sometimes.) Children, including teenagers, are most often the victims of Reye syndrome. (That's not fair!) Reye syndrome usually occurs just when the child seems to be recovering. (Bow weird!) The symptoms of Reye include persistent vomiting, fatigue, confusion and belligerence. (Sounds bad. Can it be prevented?) The cause of Reye syndrome is unknown but studies suggest a link between the development of Reye and the use of aspirin. (So shouldn't I take any medicine?) It's a good idea to check with a doctor before treating the flu or chicken pox with aspirin or any product containing aspirin. (But how will I get well?) Flu and chicken pox are usually self-limiting. Time will cure them. Take it easy. Get plenty of rest. (Oh, I'm really good at that.) A message from the U.S. Department of Health and Human Services. PAGENO="0467" 461 Mr. WYDEN. Would the gentleman yield? Mr. BATES. Yes. Mr. WYDEN. I think you asked a very good question. I would like to know, is there any evidence that anyone has died or suffered se- rious injury as a result of not taking aspirin? Dr. YOUNG. There is evidence that people have died or suffered serious injury from not having their temperature lowered, and the primary focus of aspirin in its use is to lower temperature. A second area is the anti-inflammatory actions that are there, and that is trivial. By and large, one does not die of inflammatory reactions that would be prevented by aspirin, but the lowering of temperature and the subjective relief of symptoms has been what the drug has been used for, amongst other purposes. Mr. WYDEN. But we have already been talking about the alterna- tives, and I don't want to have it on my conscience that aspirin stock went down as a result of this hearing, but I think we do want to make it clear that there is no evidence that anybody has died or suffered serious injury as a result of not taking aspirin. I haven't heard anything to the contrary. Dr. YOUNG. Just so your conscience is clear, the sales on aspirin have gone down between 1980 and 1983 by 72 percent. It might not go down by another 72 percent as a result of today's hearing, so I think we have already seen a big drop, and that is one of the em- phases that I made in my testimony, to indicate that the campaign has been working. Mr. WYDEN. I don't want to prolong this, and you have been very patient. We know that some of that reduction is due to the fact that there is evidence that people who take aspirin may have stom- ach problems and the like, isn't that correct? Dr. YOUNG. I think there is a variety of factors contributing. I wouldn't want to claim any one. Mr. WYDEN. I appreciate that. Mr. WAXMAN. In your calculations as to how best to inform the public, did you figure that there are thousands of people, I don't know how many, maybe tens of thousands, buying aspirin bottles right now, with all the information that you warn people about, that will say, "Use aspirin for flu and chickenpox"? Dr. YOUNG. We tried to deal with that, Mr. Chairman. I think that is the most troubling problem that we faced. We felt that the best way to get this out, actually, is the public media, the media that we see here, television, the evening media broadcasts and the radio and newspapers. Mr. WAXMAN. Have you purchased any media on television, radio or the newspapers? Dr. YOUNG. We have sent out a newspaper ad. We have already sent out the radio-and of the 6,600 stations that were contacted, 1,000 have played this. Mr. WAXMAN. These are all public service announcements? Dr. YOUNG. Yes, sir. Mr. WAxM~. That are played during the time they play public service announcements, and we all know what time that is? Dr. YOUNG. Sometimes it is 2 in the morning. Mr. WAx~.N. Usually not the same time the advertisements are on to take aspirin? PAGENO="0468" 462 Dr. YOUNG. But I think the prime-time coverage that we got with the announcement of the Secretary and the prime-time coverage by radio and newspapers in the announcement was very effective. Mr. WAXMAN. Dr. Young, I have already expressed my position to you. I hope you will rethink your position. Let me just ask you this: You are the head of the Food and Drug Administration, you are Commissioner of the Food and Drug Ad- ministration. You are a physician, aren't you? Dr. YOUNG. Yes, sir. Mr. WAXMAN. If I asked your advice as a patient, should I give my children aspirin or let my children have aspirin for flu or chickenpox, what would you tell me? Dr. YOUNG. My advice would be similar to that of the American Academy of Pediatrics. I would say that at this time, although there is not an absolutely proven association between aspirin and Reye's Syndrome, that it would be prudent to take all precautions and to not use that. Mr. WAXMAN. You feel comfortable making that statement, don't you? Dr. YOUNG. Yes. Mr. WAXMAN. Wouldn't you feel comfortable having that on a label? Dr. YOUNG. I think we depart there, sir. Mr. WAXMAN. Why? Do you think that is an inaccurate state- ment, that factually it is irresponsible to make? Dr. YOUNG. No. I think that at this point, that we can accom- plish this in the current flu season with a voluntary educational program, and to get the information in place for next flu season. Mr. WAXMAN. Thank you very much for being with us. We ap- preciate your testimony. We will look forward to working with you, because I think legislation is going to be necessary. Dr. YOUNG. I certainly appreciate, sir, your genuine concern, and I know that it is heartfelt, and I look forward to working with you on this. Mr. WAXMAN. We will now call forward Dr. Joseph White, presi- dent of the Aspirin Foundation; James Cope of the Proprietary As- sociation; and Neil Chayet, Committee on the Care of Children. Gentlemen, we want to welcome you to this hearing. We have your prepared statements, which we will place in the record in their entirety. What we would like to ask you to do is to summarize your state- ments in no more than 5 minutes. Dr. White, why don't we start with you? STATEMENTS OF JOSEPH M. WHITE, M.D., PRESIDENT, ASPIRIN FOUNDATION OF AMERICA, ACCOMPANIED BY R. BRUCE DICK- SON, COUNSEL; JAMES D. COPE, PRESIDENT, THE PROPRIE- TARY ASSOCIATION; AND NEIL L. CHAYET, LEGAL COUNSEL, COMMITTEE ON THE CARE OF CHILDREN Dr. WHITE. Good morning, Mr. Chairman, and members of the subcommittee. I am Dr. Joseph M. White, I am a physician, phar- macologist. I am appearing before you today as president of the As- pirin Foundation of America. PAGENO="0469" 463 With me is R. Bruce Dickson, the counsel to the foundation. The Aspirin Foundation is a trade association of the aspirin in- dustry. Its members include all producers of bulk aspirin and all the major producers of finished aspirin products in the United States. I appreciate this opportunity, and I would like, first, to ask you to consider just two things. First, I urge you to listen to the scien- tific data. It is important in this situation, because Reye's is such a terrible condition. It has occurred in many children who have never been given as- pirin, and it is a danger that if we think we have solved the prob- lem, and it really isn't solved, that this terrible disease will go on, and we will have to start out all over again and reinstitute the search for what is the real cause. In addition t~ that, the voluntary program is in it~ early stages and has been quite successful. It is unfair at this time to say volun- tary programs will never work because we just learned that this one is working well. Some parts of that program, as a matter of fact, went in the mail just last night, so that we have to wait until that filters out, and there are a lot of stories people have about postal deliveries and so forth these days, that tell us that we have to give the distribution channels a chance to deal with it, and we think that even the early indications that we have now are that there is an upward trend in the awareness of the American public. It was said sometime back as being around 50 percent of mothers were aware of aspirin as being possibly associated with Reye's syn- drome. We have data just available now that indicates that that is ap- proaching 80 percent now. So the combined effort of what the Sur- geon General is doing, what the Public Health Service is doing, what the members of the industry are doing, is actually beginning to have an effect. Mr. WAXMAN. Would you repeat that percentage again? I want to see if I understand it. Dr. WHITE. Seventy-nine as we now read it. Mr. WAXMAN. Seventy-nine percent? Dr. WHITE. Are now aware, that is mothers who have children between the age of 2 and 15, that was the category that happened to be questioned, and that 79 percent of them were aware of Reye's syndrome and the possibility that aspirin had something to do with it. Mr. WAXMAN. Who did this study? Dr. WHITE. I can get you those names. Mr. WAXMAN. I would like the names and the study for the record. Dr. WHITE. Yes, we will be glad to supply it. [Testimony resumed on p. 489.] [The following material was submitted for the record:] PAGENO="0470" 464 PAUL. HASTINGS. JANOFSKY & WALKER April 10, 1985 The Honorable Henry A. Waxman Chairman House Energy and Commerce Subcommittee on Health and the Environment House Office Building, Annex 1 300 New ~Tersey Avenue, S.E. Washington, D.C. 20515 RE: H.R. 1381 Dear Mr. Chairman: Enclosed herewith are materials requested during the hearing on the above-referenced bill on March 15, 1985. Speci- fically, the materials include: o Reye Syndrome Awareness Research -- * Final Report (March 28, 1985) o Supplementary Report on Aspirin Foundation Voluntary Reye Syndrome Pre- cautionary Program (April 10, 1985) If you or any member of the Subcommittee has any questions about the enclosed, please do not hesitate to call. * Respectfully submitted, R. Bruce Dickson Counsel to the Aspirin Foundation of America RBD : cs Enclosures PAGENO="0471" 465 REYE SYNDRCI4E AWARENESS RESEARCH F~NAL REPORT PURPOSE AM) METH0DOL~Y Purpose The purpose of this research was to determine relative awareness of Reye Syndrome associated with aspirin along with three other "child oriented" product/safety Issues. This information was obtained to ascertain the impact of the aspirin industry's current effort to Inform the public of the potential danger of children or teenagers using aspirin with flu or chicken pox combined wit~. prior publicity about the issue from other sources. Methodology This research was conducted among 300 women with at least one child between 2-15 years of age. These interviews were done via telephone using a national probability sample. All interviews were conducted between March 11-13, 1985. A total of 210 natIonally dispersed sampling points were utilized to complete the final sample. The presentation of the four Issues evaluated was rotated to avoid position bias. The cost of tttis study was $4,850. Research Supplier The fieldwork for this research was conducted by Joseph Ramos Inc. Joseph Ramos Inc. 114 East 32rd Street New York, New.York 10016 (212) 685-5101 Method Of Analysis While the major issue of concern is "aspirin being associated with Reye Syndrome," awareness of three other "child oriented" product/safety issues was obtained to provide a basis for comparison: "asbestos being associated with health problems in schools," "adult safety belts in cars being unsafe for children," and "children's toys being unsafe." The final report reviews awareness of each Issue by the total sample of 300 women with at least one child between 2-15 years of age. In addition, awareness levels for each issue have been reviewed by the following sample characteristics: PAGENO="0472" 466 Total Sample: 300 Women Ag~ of Respondent: 18-34 (139) 35+ (157) Education: Completed High School or Less (140) Some College or More (157) Total Number QLQhild~ren: 2-7 Years Old (172) 8-15 Years Old (195) One Child Householdn: 2-7 Years Old (58) 8-15 Years Old (77) Note: Not all respondents were willing to respond to the age question (4- no response). Also, three respondents attended "business or special school" but were not included in the two educational attainment groups. PAGENO="0473" 467 cc*iciusicti Overall1 mothers appear to be relatively familiar with the association QL ~spir1n and Reye Syndro~. Specifically: * About 8 out of 10 respondents indicated that they were familiar with the asplrin/Reye Syndrome Issue (79%). This compares favorably with the indicated levels of awareness for the other three "child oriented" product/safety issues included in the survey: Adult safety belts in cars being unsafe for children: 63% Asbestos being associated with health problems in schools: 85% Children~s toys being unsafe: 95% * Among the respondent sub-groups examined, familiarity with the asplrin/Reye Syndrome issue did vary somewhat - from 75% to 83%. However, awareness of the other three issues also varied across sub-groups: Adult safety belts in cars being unsafe for children: 60-75% Asbestos being associated with health problems in schools: 81-90% Childrèn's toys being unsafe: 92-98% Among each of the sub-groups, asplrin/Reye Syndrome awareness was within the range of awareness of the other three issues. PAGENO="0474" 468 SUMMARY OF FIt1)INGS 1. Overall Awareness Leve1~ Respondents were quite familiar with the four "child oriented" product/safety issues included In this study. The issue which respondents were ]~.ost familiar with was "adult safety belts in cars being unsafe for children" (63%). "ChIldren's toys being unsafe" (95%) obtained the highest awareness level followed by "asbestos being associated with health problems in schools" (85%) and aspririn being associated with Reye Syndrome" (79%). AWARENESS OF SELECT "CHILD ORIENTED!~ PRODUCTJSAFETY ISSL1E~ Total Awareness Base: (Women With a Child 2-15) (300) I "Have You Ever Heard or Read Anything About".... Childt~en's Toys Being Unsafe 95 Asbestos Being Associated With Health Problems In Schools 85 Aspirin Being Associated with Reye Syndrome 79 Adult Safety Belts In Cars Being Unsafe For ChIldren 63 2. ~.sr.eness Levels By Select Sample Characteristics A. ~g~: Women "35+" years of age were more likely than women "18-34" years of age to be aware of three "child oriented" product/safety issues: Age Groups ("35+" vs. "18-34") 3.5± Pt. DIHI. Asbestos Being Associated With Health Problems In Schools 81% 89% +8 Aspirin Being Associated With Reye Syndrome 75% 82% +7 Children's Toys Being Unsafe 92% 98% +6 PAGENO="0475" 469 Women "18-34" years of age, however, were somewhat more aware of "adult safety belts in cars being unsafe for children" ("18-34," 66% and "35+," 60% -- +6 points). B. Education: Women who had a "some college or more" level of education were more likely to be aware of two "child oriented" product/safety issues: Educational Attainment "Some College +" vs. "High School Or Less") High School Some OrJess College Pt. Diff. Asbestos Being Associated With Health Problems In Schools 81% 90% +9 Aspirin Being Associated With Reye Syndrome 75% 83% +8 Awareness levels show minimal differences by education attainment levels for the remaining two issues. C. Ageof Children: The 300 mothers in this research had a total of 367 children -- 172 "2-7" years old and 195 "8-15" years old. Women with a child "~-15" were more aware of "asbestos being associated with health problems in schools" than mothers with a child " 2-7" (89% versus 82%, respectively). No other issue had a meaningful difference in awareness by age of child. Among those households with only one child, those households with one child "8-15" years old were more aware than households with one child "2-7" years old of "adult safety belts in cars being unsafe for children" (75% vs. 62%, respectively). No other "child oriented" product/safety Issue had a meaningful difference by age of child among one child households. (Please note the following table for additional details.) PAGENO="0476" `Have You Ever Beard Or Head Anything About'.... Ø~fl~so's Sbys Being Unsafe 95 Asbestos Being Associated With Health Problese In Scbools 85 Aspirin Being Associated With Haye Syndrc~ 79 Adult Hafety Belts In Cars Being Unsafe For Children 63 470 A~8362E83 LEVELS ~ SELEC'F ~1HSR thildren Sbtal Me High Sch. Hens AnyThild_ Une Child 83. Base: (Intel Hespordents) 6eo~1i Or Less Oalleoe± 21 91~ ...2~1 9.15 (300) (139) (157) (140) (157) (172) (195) (58) (77) % C t ~ I I I I 92 98 94 96 95 97 98 96 81 89 81 90 82 89 86 90 75 82 75 83 79 81 78 75 66 60 61 - 65 62 62 62 75 PAGENO="0477" 471 JOSEPH RAMOS INC. 114 East 32nd Street Job # 0395 New York, New York March, 1985 PUBLIC ISSUES STUDY Hello my maine is ________________________ from JRI Research, a national marketing research~ganizatjon. We ar~conducting a survey on public issues and I'd like to ask you a few questions. 1. Are you the female head of the household? Yes 1 No 2.......+(ASK TO SPEAK TO FEMALE HEAD OF HOUSEHOLD) 2. Do you have any children from two to fifteen years of age? Yes 1 No 2.....~(TERMINATE) 3. We would like to ask you about the following health issues. (START AT ~XtdW ITEM). START HERE: Have you ever heard or read anything about asbestos being associated with health problems in schools? Yes 1 No 2 Have you ever heard or read anything about adult safety belts in cars being unsafe for children? Yes 1 No 2 ~ Have you ever heard or read any~thing about aspirin being associated with Reye Syndrome? Yes 1 No 2 Have you ever heard or read anything about childrens' toys being unsafe? Yes 1 No 2 PAGENO="0478" 472 4, And just for statistical purposes, what is your age? (DO NOT READ LIST) 18-24 1 25-34 2 35-49 3 50-64 4 65 plus 5 5. What was the last grade of school you completed? (DO NOT READ LIST). Grade school or less.. .1 Some high school 2 Completed high school. .3 Some college 4 Completed college 5 Post graduate 6 Business or special school 7 6. How many children do you have in the following age groups? (READ LIST, RECORD NUMBER BELOW). 2 to 4 years 5 to 7 years 8 to 10 years 11 to 13 years 14 to 15 years Thank you for your cooperation. RESPONDENT'S ~ZAMP.. CITY: AREA CODE:________________ INTERVIEWER: TIME STARTED: DATE: STATE: ZIP:_______ TELEPHONE NUMBER: . - TIME ENDED:___________________ PAGENO="0479" JOSEPH RAMOS, INC. TABLE- 1 QUESTIOH- 3 PUBLIC ISSUES STUDY HO. 0395 MARCH, 1985 HEARD OF OR READ ABOUT ASBESTOS BEING ASSOCIATED WITH HEALTH PROBLEMS IN SCHOOLS CHILDREN EDUCATION * I CHILD IH HOUSEHOLD COMPLE- TED ANY ANY 1 CHILD 1 CHILD A 0 E HIGH SOME CHILD CHILD OHLY OHLY SCHOOL COLLEGE 2-7 8-15 2-7 8-15 TOTAL 18-34 35 + OR LESS OR MORE YEARS YEARS YEARS YEARS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 YES 256 112 140 113 141 141 173 50 69 85.3 80.6 89.2 80.7 89.8 82.0 88.7 86.2 89.6 NO 44 27 17 27 16 31 22 ~ 8 14.7 19.4 10.8 19.3 10.2 18.0 11.3 13.8 10.4 DON'T KNOW/NO ANSWER PAGENO="0480" JOSEPH RINDS, INC. TABLE- 2 QUESTION- 3 PUBLI.C IS'~JES STUDY NO. 0395 `RCH, 1985 HEARD OF OR READ ABOUT ADULT SAFETY BELTS BEING UNSAFE FOR CHILDREN CHILDREN EDUCATION * 1 CHILD IN HOUSEHOLD COMPLE- TED ANY ANY 1 CHILD 1 CHILD A 0 E HIGH SOME CHILD CHILD OHLY ONLY SCHOOL COLLEGE 2-7 815 2-7 8-15 TOTAL 18-34 33 + OR LESS OR MORE YEARS YEARS YEARS YEARS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 YES 189 92 94 86 102 106 121 36 58 63.0 66.2 59.9 61.4 65.0 61.6 62.1 62.1 75.3 NO 111 47 63 54 55 66 74 22 19 37.0 33.8 40.1 38.6 35.0 38.4 37.9 37.9 24.7 DON'T KNOW/NO ANSWER PAGENO="0481" Ii JOSEPH RAMOS, INC. TABLE- 3 QUESTION- 3 PUBLIC ISSUES STUDY NO. 0395 MARCH, 1985 HEARD OF OR READ ABOUT ASPIRIN BEING ASSOCIATED WITH REYE SYNDROME CHILDREN EDUCATION 1 CHILD IN HOUSEHOLD COMPLE- TED ANY ANY 1 CHILD 1 CHILD A G E HIGH SOME CHILD CHILD ONLY ONLY SCHOOL COLLEGE 2-7 8-IS 2-7 8-15 -TOTAL 18-34 35 + OR LESS OR MORE YEARS YEARS YEARS YEARS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 YES 236 104 128 105 130 136 157 45 58 78.7 74.8 81.5 75.0 82.8 79.1 80.5 77.6 75.3 NO 64 35 29 35 27 36 38 13 19 -.1 21.3 25.2 18.5 25.0 17.2 20.9 19.5 22.4 24.7 Cli DON'T KNOW/NO ANSWER PAGENO="0482" JOSEPH RAMOS, INC. TABLE- 4 QUESTION- 3 PIBLIC ISSUES STUDY HO. 0395 MARCH, 1985 HEARD OF OR READ ABOUT CHILDREN'S TOYS BEING UNSAFE CHILDREN EDUCATION 1 CHILD IN HOUSEHOLD - COMPLE- TED ANY ANY 1 CHILD 1 CHILD A 0 E HIGH SOME CHILD CHILD ONLY ONLY SCHOOL COLLEGE 2-7 8-15 2-7 8-15 TOTAL 18-34 35 + OR LESS OR MORE YEARS YEARS YEARS YEARS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 YES 286 128 154 132 151 163 189 57 74 95.3 92.1 98.1 94.3 96.2 94.8 96.9 98.3 96.1 NO 14 11 3 8 6 9 6 1 3 4.7 7.9 1.9 5.7 3.8 5.2 3.1 1.7 3.9 DON'T KNOW/HO ANSWER PAGENO="0483" JOSEPH RAMOS, INC. TABLE- 5 QUEStION- 4 PUBLIC ISSUES STUDY NO. 0395 MARCH, 1985 AGE CHILDREN EDUCATION 1 CHILD IN ` HOUSEHOLD COMPI E- TED ANY ANY 1 CHILD 1 CHILD A G E HIGH SOME CHILD CHILD ONLY ONLY SCHOOL COLLEGE 2-7 8-15 2-7 8-15 TOTAL 18-34 35 + OR LESS OR MORE YEARS YEARS YEARS YEARS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 18-24 14 14 10 4 14 10 4.7 10.1 7.1 2.5 8.1 17.2 25-34 125 125 60 64 103 56 35 9 41.7 89.9 42.9 40.8 59.9 28.7 60.3 11.7 35-49 145 145 60 83 50 125 11 58 48.3 92.4 42.9 52.9 29.1 64.1 19.0 75.3 50-64 10 10 7 3 3 8 2 7 3.3 6.4 5.0 1.9 1.7 4.1 3.4 9.1 65PLUS 2 2 1 1 1 2 .7 1.3 .7 .6 .6 1.0 NOANSWER 4 2 2 1 4 3 1.3 1.4 1.3 .6 2.1 3.9 MEAN... 36.42 28.64 43.31 36.01 36.77 33.18 39.26 31.35 41.90 STANDARD 8.29 2.56 4.75 9.01 7.61 7.81 7.48 8.05 6.34 DEVIATION STANDARD .48 .22 .38 .77 .61 .60 .54 1.06 .74 ERROR PAGENO="0484" JOSEPH RAMOS, INC. TABLE- 6 QUESTION- 5 PUBLIC ISSUES STUDY NO. *3~5 MARCH, 1985 EDUCATION EDUCATION 1 CHILD IN HOUSEHOLD COMPLE- TED ANY ANY 1 CHILD 1 CHILD A 0 E HIGH SOME CHILD CHILD ONLY ONLY SCHOOL COLLEGE 2-7 8-15 2-7 8-15 TOTAL 18-34 35 + OR LESS OR MORE YEARS YEARS YEARS YEARS 300 139 157 140 157 172 195 58 77 110.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 8 3 5 8 4 6 3 2.7 2.2 3.2 5.7 2.3 3.1 3.9 28 13 14 28 9.3 9.4 8.9 20.0 104 54 49 104 34.7 38.8 31.2 74.3 69 32 36 23.0 23.0 22.9 63 32 30 21.0 23.0 19.1 25 4 21 8.3 2.9 13.4 3 1 2 1.0 .7 1.3 CHILDREN BASE-TOTAL RESPONDENTS GRADE SCHOOL OR LESS SOME HIGH SCHOOL COMPLETED HIGH SCHOOL SOME COLLEGE COMPLETED COLLEGE POST GRADUATE BUSINESS OR SPECIAL SCHOOL 17 17 8 8 9.9 8.7 13.8 10.4 60 67 20 26 34.9 34.4 34.5 33.8 69 43 47 14 16 43.9 25.0 24.1 24.1 20.8 63 35 36 15 15 40.1 20.3 18.5 25.9 19.5 25 11 20 1 8 15.9 6.4 10.3 1.7 10.4 2 2 1 1.2 1.0 1.3 NO ANSWER PAGENO="0485" JOSEPH RAMOS, INC. TABLE- 7 QUESTIOH- 6 PUBLIC ISSUES STUDY HO. 0395 MARCH, 1985 NUMBER OF CHILDREN IN FOLLOWING AGE GROUP 2 - 4 YEARS CHILDREN * EDUCATION 1 CHILD IN ` HOUSEHOLD CO1PLE- TED ANY ANY 1 CHILD 1 CHILD A 0 E HIGH SOME CHILD CHILD ONLY ONLY SCHOOL COLLEGE 2-7 8-15 2-7 8-15 TOTAL 18-34 35 + OR LESS OR FIORE YEARS YEARS YEARS YEARS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100~0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 NONE * 176 47 125 85 89 50 157 17 77 58.7 33.8 79.6 60.7 56.7 29.1 80.5 29.3 100.0 1 105 75 30 45 60 105 33 41 35.0 54.0 19.1 32.1 36.2 61.0 16.9 70.7 2 14 13 1 8 5 14 3 4.7 9.4 .6 5.7 3.2 8.1 1.5 3 * 3 2 1 2 1 3 2 1.0 1.4 .6 1.4 .6 1.7 1.0 4 5. 7 OR MORE NO AHSLJER 2 2 2 .7 1.4 1.3 MEAN... . .48 .78 .22 .48 .47 .83 .23 .71 STANDARD .63 .67 .47 .66 .59 .63 .51 .45 DEVIATION STANDARD .03 .05 .03 .OS .04 .04 .03 .05 ERROR PAGENO="0486" ~IOSEPH RAPIDS, INC. TABLE- 8 QUESTION- 6 PUBLIC ISSUES STUDY NO. 0395 MARCH, 1985 NUMBER OF CHILDREN IN FOLLOWING AGE GROUP 5 -7 YEARS CH IL DR EN EDUCATION - - 1 CHILD IN HOUSEHOLD COMPLE- TED ANY ANY 1 CHILD 1 CHILD A 0 E HIGH SOME CHILD CHILD ONLY ONLY SCHOOL COLLEGE 2-7 8-15 2-7 8-15 TOTAL 18-34 35 + OR LESS OR MORE YEARS YEARS YEARS YEARS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 NONE 203 76 124 95 106 77 152 41 77 67.7 54.7 79.0 67.9 67.5 44.8 77.9 70.7 100.0 1 81 55 25 39 41 81. 36 17 27.0 39.6 15.9 27.9 26.1 47.1 18.5 29.3 2 13 5 8 6 7 13 6 4.3 3.6 5.1 4.3 4.5 7.6 3.1 3 1 1 1 1 1 .3 .7 .6 .6 .5 4 S 6 7 OR MORE NOANSWER 2 2 2 .7 1.4 1.3 MEAN... .37 .50 .26 .36 .37 .64 .26 .29 STANDARD .58 .60 .54 .56 .60 .64 .53 .45 DEVIATION STANDARD .03 .05 .04 .04 .04 .04 .03 .06 ERROR PAGENO="0487" JOSEPH RAMOS, INC. TABLE- 9 QUESTION- 6 PUBLIC ISSUES STUDY HO. 0395 MARCH, 1905 NUMBER OF CHILDREN IN FOLI.OWING AGE GROUP 8 - 10 YEARS CH IL DR EN EDUCATION 1 CHILD IN ` HOUSEHOLD COHPLE- TED ANY ANY 1 CHILD 1 CHILD A G E HIGH SOME CHILD CHILD ONLY DIlLY SCHOOL COLLEGE 2-7 8-15 2-7 8-15 TOTAL 18-34 35 + OR LESS OR MORE YEARS YEARS YEARS YEI~RS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 HONE 206 100 103 97 107 126 103 58 61 68.7 71.9 65.6 69.3 68.2 73.3 52.8 100.0 79.2 1 83 33 49 41 41 40 83 16 27.7 23.7 31.2 29.3 26.1 23.3 42.6 20.8 2 9 4 5 2 7 6 9 3.0 2.9 3.2 1.4 4.5 3.5 4.6 7 OR MORE NO ANSWER 2 2 2 - .7 1.4 1.3 MEAN...* .34 .30 .38 .32 .35 .30 .52 .21 STANDARD .53 .51 .54 .49 .56 ~53 .58 .40 DEVIATION STANDARD .03 .04 .04 .04 .04 .04 .04 .04 ERROR PAGENO="0488" JOSEPH RAPIDS, INC. TABLE- 10 QUESTIOH- 6 PUBLIC ISSUES STUDY NO. 0395 MARCH, 1985 NUMBER OF CHILDREN IN FOLLOWING AGE GROUP 11 - 13 YEARS CHILDREN EDUCATION 1 CHILD IN ` HOUSEHOLD COMPLE- TED ANY ANY 1 CHILD 1 CHILD A G E HIGH SOME CHILD CHILD ONLY ONLY SCHOOL COLLEGE 2-7 8-15 2-7 8-15 TOTAL 18-34 35 + OR LESS OR MORE YEARS YEARS YEARS YEARS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 NONE 206 114 90 102 101 148 103 58 46 68.7 82.0 57.3 72.9 64.3 86.0 52.8 100.0 59.7 1 81 19 61 29 52 22 81 31 27.0 13.7 38.9 20.7 33.1 12.8 41.5 40.3 2 9 2 6 7 2 1 9 3.0 1.4 3.8 5.0 1.3 .6 4.6 3 2 2 2 1 2 .7 1.4 1.4 .6 1.0 4. 5 7 OR MORE NO ANSWER 2 2 2 .7 1.4 1.3 MEAN... .35 .21 .46 .35 .36 .16 .54 .40 STANDARD .57 .53 .57 .64 .50 .42 .63 .49 DEVIATION STANDARD .03 .04 .04 .05 .04 .03 .04 .05 ERROR PAGENO="0489" JOSEPH RAMOS, INC. TABLE- 11 QUESTION- 6 PUBLIC ISSUES STUDY NO. 0395 MARCH, 1935 NUMBER OF CHILDREN IN FOLLOWING AGE GROUP 14 - 15 YEARS CHILDREN EDUCATION 1 CHILD IN , HOUSEHOLD COMPLE- TED ANY ANY 1 CHILD 1 CHILD A 0 E HIGH SOME CHILD CHILD ONLY ONLY SCHOOL COLLEGE 2-7 8-15 2-7 8-15 TOTAL 18-34 35 + OR LESS OR MORE YEARS YEARS YEARS YEARS BASE-TOTAL 300 139 157 140 157 172 195 58 77 RESPONDENTS 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 NONE 223 127 94 105 117 153 120 58 47 74.3 91.4 59.9 75.0 74.5 89.0 61.5 100.0 61.0 1 72 10 60 33 37 18 .72 30 24.0 7.2 38.2 23.6 23.6 10.5 36.9 39.0 2 3 3 2 1 1 3 1.0 1.9 1.4 .6 .6 1.5 3 4 5 7 OR MORE NO ANSWER 2 2 2 - .7 1.4 1.3 MEAN... : .26 .07 .42 .26 .25 .12 .40 .39 STANDARD .46 .26 .53 .47 .44 .33 .52 .48 DEVIATION STANDARD .02 .02 .04 .04 .03 .02 .03 .05 ERROR . PAGENO="0490" 484 Aspkmn Foundation of America, Inc. 1075 Central Park Avenue. Scarsdale, N.Y. 10583 * (914)725-1492 ASPIRIN FOUNDATION OF AMERICA VOLUNTARY PRECAUTIONARY PROGRAM PROGRESS REPORT April 10, 1985 This Progress Report is being filed with the House Energy and Commerce Subcommittee on Health and the Environment in response to questions raised at the Subcommittee's March 15, 1985 hearing on H.R. 1381, the "Emergency Reye's Syndrome Prevention Act of 1985." The Aspirin Foundation of America has responded to Secretary of Health and Human Services Margaret Heckler's request for voluntary efforts to advise the public about Reye Syndrome with a three-part precautionary program. This program has been undertaken in the absence of scientifically sound data showing a link between aspirin and Reye Syndrome, but in a spirit of coop- eration with the Department of Health and Human Services, while the underlying scientific questions remain unanswered. The program encompasses three elements: label warnings and other label modifications, public service announcements and posters. Substantial progress has been made in each area. A. Label Revisions All members of the Foundation and major producers of private label aspirin either have changed or are in the process of changing their labels. PAGENO="0491" 485 In addition to the label changes discussed in testimony filed with the Subcommittee (2.2.' the new warning and the dele- tion of the flu indication for children's aspirin), producers will also "flag" the new label in accordance with the Proprietary Association guidelines. A large number of label changes are required by the program. One company alone is making approximately 75 discreet label changes. Among the steps being taken is the destruction of old labeling by several companies, in order to expedite the shipment of the new labels. Companies are moving expeditiously to implement the changes. Several producers have already made the modifications. For others the changes are in progress. For some products, shipment with old labels will end in April or May, 1985. Because of shipment and purchasing schedules, some products will be shipped with revised labels in the early fall 1985. By the start of the flu season, however, all new products shipped will bear the new labels. B. Public Service Announce ents The Foundation, with the ~~SS9~ of the American Reye's Syndrome Association, the Reye's Syndrome Society and the National Reye's Syndrome Foundation, produced and distributed two television public service announcements (PSA's) and two radio PSA's. More than 1,000 copies have been distributed to televi- sion and radio stations nationwide. PAGENO="0492" 486 The Foundation has specifically surveyed usage of the television PSA's and found an extremely high success rate. Calls were made to 168 television stations in the top 50 markets. These calls revealed that in every market at least one TV station (and in most cases several) is airing or has plans to air a Reye Syndrome PSA. The following responses were received: TABLE A Actual No. % of Total Responses of Stations Responding Currently airing or plan to air PSAs *120 72% Will review and consider airing 15 9.8% Cannot locate spots (Foundation has re-mailed) 18 11.76% Will not air PSA5 due to controversy 10 6.5% Will not air PSAs due to scheduling load 5 3.27% * Includes 3 stations producing their own version of the PSA5. It is highly unusual to experience a success rate as high as 72% for the airing of PSA5. The Foundation believes that its PSA program, supplementing the already extensive government program, has been remarkably successful. C. Posters To supplement the initial distribution of 100,000 pos- ters, the Foundation used a national information network called PAGENO="0493" 487 Pharm/alert to mail the poster to 60,000 pharmacists on March 9, 1985. In addition, the Foundation mailed the poster to 35,000 supermarkets on March 12, 1985. When combined with posters prepared by FDA and private parties, the Foundation's posters are achieving extremely wide visibility. D. Success of Education Program To measure the success of these ongoing efforts, an independent New York-based research firm conducted a "consumer awareness" survey in early March 1985. A national probability sample of 300 women with at least one child between 2 and 15 years of age was identified. The respondents were interviewed by telephone. The major issue of concern for the study was awareness of "aspirin being associated with Reye Syndrome." However, to provide a basis for comparison, three other issues were presented, with the order of presentation rotating among all four questions. The other issues included: "asbestos being associated with health problems in schools," "adult safety belts in cars being unsafe for children," and "children's toys being unsafe." The following table summarizes the survey results: PAGENO="0494" 488 AWARENESS OF SELECT "CHILD ORIENTED" PRODUCT/SAFETY ISSUES Total Awareness Base: (Women With a Child 2-15) (300) % "Have You Ever Heard or Read Anything About".... Children's Toys Being Unsafe 95 Asbestos Being Associated with Health Problems In Schools 85 Aspirin Being Associated with Reye Syndrome 79 Adult Safety Belts In Cars Being Unsafe For Children 63 It should be apparent that the education program is working well. The 79 percent awareness for aspirin and Reye Syndrome raaks along with other "high visibility" issues, such as asbestos in schools. Clearly, the public is aware of the reported association. Conclusion The purposes of H.R. 1381 -- to obtain warnings on aspirin labels and to educate the public to a possible associa- tion between aspirin and Reye Syndrome -- are already being accomplished. Labels are being revised expeditiously. In the meantime, the public is acquiring widespread general awareness of the possible association. Clearly, H.R. 1381 is unwarranted. Respectfully submitted, THE ASPIRIN FOUNDATION OF AMERICA, INC. By: ~ Jc~'ephfr1. White, .D. P~es ident Of Counsel: R. Bruce Dickson Paul, Hastings, Janofsky & Walker 1050 Thomas Jefferson Street Washington, D.C. 20007 (202) 333-8500 PAGENO="0495" 489 Mr. WAXMAN. Excuse me for interrupting. Dr. WHITE. But I think that this is a valuable thing. The reason why we started a three-pronged program is because we are con- cerned that not any one of them might be sufficient, and I think that the Commissioner shares that concern, that not everybody reads the label on the bottle every time one picks it up. There are also many other warnings that are very important, and we wouldn't want to totally eclipse that, so maybe they need to be kept in some level of equality. In the meantime, you can isolate attention to Reye's Syndrome by going through the public service announcements and going through posters at the point of sale. The advantage of the public service announcements is that PSA's get right to the person who is going to make the choice and make the decision, and if you get them to hear and get them to under- stand it, they will make an intelligent choice. The advantage of the poster is it is at the point of sale. It is at the point of sale, and it is in big print instead of somebody having to stand and read through all the fine print that might be on vari- ous packages. We also would like to indicate that there are a number of people who need to take aspirin. The question was raised, just don't give aspirin to children. Children who suffer from juvenile rheumatoid arthritis take as- pirin and they take it in high quantities, and they have to take it for many, many years. It is interesting to know that those children have no more Reye's Syndrome than any other children. The other thing that has happened is that the flaws `in all of the previous studies that have been done, all were found in the raw data, and how that was interpreted and how that was gathered. And we are still concerned that, for example, the pilot study, we have not seen that raw data, so that we have really no way of eval- uating how valid that study might be, and we ask again that we get that opportunity. We also know that this pilot study was meant to be a prelimi- nary study, that they made changes in the study during the oper- ation. It was really a feasibility study to try to learn how to do the major study, and I think that from a scientific point of view that major study is extremely important now, because we really need to know whether there is a connection. And if there is, to deal with it appropriately. If there is not a connection, then we know we have to go back and try to find out what the connection might be, with something else or perhaps this is a spontaneous event in these children. It is interesting, too, that the original position of the Institute of Medicine, who is the monitoring committee, specifically said that the pilot study will in no way be interpreted as being conclusive evidence, and that the chairman of that committee, whose name has already been mentioned here today, Dr. Floyd Denney, advised the FDA that the pilot study did not provide a basis for mandatory labeling. PAGENO="0496" 490 They do not feel that they have learned what they need to learn in order to demand that a mandatory labeling procedure be carried out. Because mandatory labeling was not supported, Secretary Heck- ler called for voluntary action. This call for voluntary action was a surprise to us, too, and I thought it was interesting that every member agreed to do it. There was hardly a hesitation. It went to the management and they were back again immediately, saying yes, go see the people, see what they want, and see what we can do to answer their questions. And we feel that we have done that. We have a three-phase pro- gram. We have gone to public service announcements, we have gone to postering, and we have instituted the label changing. We were not asked, there was not to be a recall. We were not asked to reach the shelf. The way to reach the shelf is to put the poster in the store, and the way to reach even beyond that is to put the public service announcements in the ears and eyes of the con- sumers, so that they have the message already. You don't have to depend on their getting it by chance. During the past week we have made another effort beyond the original posters. In the original poster program, 100,000 of them were sent out through various channels. Just the other day, there were 95,000 more posters sent out directly to pharmacists and to food stores. And one of the things we did was to take advantage of an organi- zation which is called Pharmalert, and ohe of the things which they do is to call attention to the pharmacist when there is some- thing that he needs to know to advise the customers, and so forth, and it says here, on the envelope: "Special Reye's Syndrome Alert From the Aspirin Foundation of America." We had 95,000 of these sent out just the other day, again an indi- cation we have to read this as we go along, and see what the pene- tration is, and what the accomplishment is. I am happy to be here and to have this opportunity to comment. I feel that the scientific justification for passing a law is just not there at this time. We do have a program. We do believe it will work. We hope it will be measured, and an opportunity given to maybe learn better ways of doing it, if there are better ways to do it in the future, and we do ask your support. We volunteer to report to you and give any any additional information you would want to know from what we may gather as time goes by, and as we see this pro- gram actually bloom and come to full fruition. Thank you very much. [Testimony resumes on p. 518.] [The prepared statement of Dr. White follows:] PAGENO="0497" 491 STATE~NT OF JOSEPH M. WHITE, M.D. P RES I DENT ASP IRIN FOUNDATION OF A~ RI CA Good morning Mr. Chairman and members of the Subcommit- tee. My name is Dr. Joseph M. White. I am a physician and a pharmacologist and I am appearing before you today as President of the Aspirin Foundation of America. With me is R. Bruce Dickson, counsel to the Foundation. The Aspirin Foundation is the trade association of the aspirin industry. Its members include all the producers of bulk aspirin and all the major producers of finished aspirin products in the United States. The Foundation was organized several years ago to facilitate and encourage an understanding of the benefits and potential health effects of aspirin based upon sound data and good science. During the past three years, the Foundation has taken a leading role in urging that a sound epidemiology study be con- ducted into the etiology of Reye Syndrome and that regulatory decision-making on this matter, if it is needed, be based upon good science. We are here today to urge this Subcommittee to listen to the scientists, who tell us that there is not sufficient scien- tific justification for mandatory labeling. We are also here to ask you to take a fair look at the voluntary industry program and to give it a reasonable chance to accomplish its objectives before passing judgment. Mplrln In Perspective To put this matter in the proper perspective, the Sub- committee must first consider the background of aspirin use. PAGENO="0498" 492 Since the late 19th century, or for over one hundred years, acetylsalicylic acid, which acquired the trade nane ~aspirin,~ has become widely used to reduce fever and to relieve pain and inflammation. Aspirin is now by far the most widely used over- the-counter medication ingredient in the United States and in the world. Nearly 19 billion dosage units are sold annually.-21 The efficacy of aspirin has been soundly established through its long history of use. As an antipyretic, aspirin has no equal in terms of its many years of safe and effective use around the world. The Internal Analgesic Monograph cited forty- three studies showing the effectiveness of aspirin in reducing pain. It noted that aspirin is often used as the standard against which new drugs are compared for efficacy. With regard to safety, the Internal Analgesic Panel stated: [A]spirin is the most widely used single drug in the United States. The Panel believes that in light of this extensive use and long mar- keting history and the relatively low mci- *dence of serious toxic effects associated with short term use of presently recommended doses, the safety of aspirin has been well-estab-- lished for the majority of the ~opulation and the risk benefit ratio is low."...1 1/ Establishment of a Monograph for OTC Internal Analgesic, - Antipyretic and Antirhetm~atic Products ("Internal Analgesic Monograph"), 42 . ~ 35346, 35382 (July 8, 1977). ~J Id. at 35383. PAGENO="0499" 493 Before considering legislation, then, the Subcommittee must recognize the impressive record that aspirin has created through its long and widespread use as a safe and effective drug for the relief of pain and inflammation and the reduction of fever. SUMMARY OF ASPIRIN FOUNDATION'S POSITION ON H.R. 1381 The Aspirin Foundation opposes H.R. 1381. The bill is without scientific support, and, in view of the ccmprehensive efforts of the Secretary of Health and Hwnan Services, the Food and Drug Administation, Reye Syndrane parents groups, the news media and the Aspirin Foundation, it is entirely unnecessary. First, H.R. 1381 must be viewed in the context of our current knowledge of Reye Syndrane and medications. While the bill is purported to be based upon several Reye Syndrane studies, in fact it was prompted by the preliminary field work (the ~pilot~ study) performed in prepara- tion for the upcoming national Reye Syndrome study. Thus, we really do not yet have any scientific data upon which to base mandatory regulation. PAGENO="0500" 494 -- Second, in view of the limited nature of the available information, the Secre- tary's call for voluntary action was the most appropriate and the most expeditious way to obtain label warnings and an * industry-sponsored public education program without first having to complete a comprehensive epidemiology study. As you know, the industry responded promptly to the Secretary's callfor voluntary action. -- Third, the voluntary precautionary pro- gram represents a responsible industry effort to minimize possible risk while the underlying question of a possible medication link with Reye Syndrome is being studied, and in fact goes well beyond what could have been mandated if sufficient data existed. -- Fourth, the proposed legislation would result in a warning statement that is seriously false and misleading, that will scare the public away fran a valuable PAGENO="0501" 495 medication and that will lead parents to ignore the early symptoms of Reye Syn- drane. A. There is Insufficient Scientific Justification for Mandatory Label Warnings. At the present time, there are no sound epidemiology studies which provide evidence linking aspirin use for chicken pox or flu with Reye Syndrome. Early state surveys, which were etmunarized by the American Academy of Pediatrics Redbook Commit- tee, were severely discredited by scientists from P~, academia, the medical community, and industry. Because of the flaws in those surveys, the Secretary of Health and Htznan Services decided to conduct a new, comprehensive study. That new study was pre- ceded by preliminary methodologic research, which has now been completed and which cannot possibly provide a basis for the conclusion that aspirin is in fact associated with Reye Syndrome. 1. The early state surveys were flawed. Reye Syndrome is an extremely rare childhood condition that can follow chicken pox or influenza. Because of its low incidence, possible causes can be identified only through the case-control method of epidemiologic research. Case-control studies are extremely difficult to design and, if not properly planned, can produce an ~association" that is merely a function of the study design. Such a ~false association" will, of course, PAGENO="0502" 496 be repeated in any subsequent study that incorporates the faulty design. The early state surveys were challenged because of design flaws that could have caused the reported aspirin associa- tion. FDA scientists reviewed the raw data from the state sur- veys and identified serious flaws in each survey. They rejected nearly all of the data because of basic flaws commonly found in poorly designed case-control studies. FDA recently summarized its view of the state surveys and their many flaws in a document filed in federal court. It stated: ~The uncertainty about the adequacy of the four epidemiologiCal studies on Reye Syndrome is reflected not only in the dis- agreement among prominent and qualified experts, but also in the scientific studies themselves. While the agency emphasizes that it does not consider all of the studies to be scientifically invalid, there are deficiencies in the design and implementation of the studies that lessen the confidence that can be placed in the results of the studies. These prominent deficiencies include the following: (I) lack of formal protocols defining the study rules; (2) lack of comparability between cases and controls as to time between illness onset and interview; (3) lack of consistent and comparable verif i- cation of medication brand names and recording information from labels; (4) lack of data collection and analysis in such a way as to be confident that the medications were being used for the treatment of the antecedent illness rather than Reye Syndrome; PAGENO="0503" 497 (5) lack of sufficient characterization of the antecedent illnesses to demonstrate that the controls had illnesses of sever- ity comparable to that of the antecedent illnesses in the cases; (6) reliance on school absentee lists to generate matched controls with the conse- quent underrepresentation of pre-school children and chickenpox associated cases (which has peak incidence in late spring and summer); and (7) lack of adequate precision in disease diagnosis to be confident that all cases truly had Reye's Syndrome. The agency is also aware that the reported association between Reye Syndrome and salicy- lat'~s might be explained by the use of salicy- lates for treatment of the symptoms of Reye Syndrome. Although this hypothesis has not been proven, neither has it been ruled out.~ Defendants' Answers to Plaintiffs' Interroga- tories and Document Production Request, ERG V. Young, Civil Action No. 82-1346 (D.D.C., October 30, 1984). The PDP~ list of flaws in the studies is a catalogue of errors, any of which would be grounds for totally rejecting the studies. These flaws did not go unnoticed in the medical commun- ity. In November 1982 the American Academy of Pediatrics trans- mitted the following statement from its Executive Board to the Assistant Secretary for Health: `In June, 1982, the American Academy of Pedi- atrics published a statement by the Committee on Infectious Diseases alerting pediatricians to the possible association of aspirin admin- istration and Reye's Syndrome. We stated them, and continue to believe, that there should be cautious use of any antipyretic medication in the treatment of influenza or chicken pox. However, at the present time, we PAGENO="0504" 498 do not feel that labeling aspirin-containing preparations as being contraindicated in these illnesses is in the best interest of children or the practice of pediatrics. We believe labeling should be delayed until more conclu- sive evidence of the association of aspirin administration and Reye's Syndrome is shown by further investigation. We urge that support be provided as soon as possible for appro- priate investigators, including government agencies, to address this important question." Thus, before the new study was begun, there was vir- tually unanyinous agreement ~nong the scientific and medical experts who reviewed the state surveys: The surveys could not be used to justify mandatory label warnings. 2. The preliminary field work for the new national Reye Syndrome study cannot support mandatory label warnings. Because of the inadequate data base, the Departhent created a Task Force of scientists from the Centers for Disease Control, FDA and the National Institutes of Health ("PBS Task Force") to design and conduct a nation-wide study of Reye Syn- drane and its possible link with medications. To provide over- sight for the study, the Public Health Service engaged the Insti- tute of Medicine ("IOM") of the National Academy of Sciences. tOM created a committee of pediatricians, epidemiologists and other professionals to review the protocol and the results. The PBS Task Force initially proposed to begin the new study in November 1983. The IOM Committee rejected this sugges- tion, however, noting that PAGENO="0505" 499 the task force is not sufficiently prepared to start an epidemiologically sound investi- gation by the suggested November 1983 date. It is recommended that the present proposal and questionnaires be revised and resubmitted for review by this Institute of Medicine committee. When the proposal is final, ~ liminar field work should be undertaken to resolve the uncertainties of study design and feasibility. Only upon completion of the preliminary studies will the task force be prepared to embark on a national study of ~. * * * RGeneral Level of Preparedness It is the committee's judgment that the task force will be unable to begin the study in November 1983 as proposed. The reasons for this conclusion are as follows. There remain a number of unresolved study design issues that call for further exploration and planning by the Task Force. . . . Whether or not outside personnel are recruited to carry out the study, there will need to be a period of training of staff members in the procedures of case ascertainment, control, and interview- ing. The committee recommends strongly that a preliminary, or pilot, study be conducted to determine the feasibility of control selection and data collection and to pre-test the ques tionnaires. It is not conceivable that these activities cm be completed satisfactorily in time for a November 1983 study commencement date.R (An Initial Evaluation of the PES Study of the Reye Syndrome, Institute of Medicine, September 1983, at 10, 24-25; emphasis added.) The IOM Committee thus concluded that preliminary field work .had to be completed before the study could begin. What began in November 1983 was not the new national study that had been proposed. Indeed, that national study did not begin until. this winter. The study that began in November 1983 and that produced the 29 cases cited by proponents of fl.R. 1381 was merely PAGENO="0506" 500 the preliminary field work or feasibility study recommended by TOM prior to the start of the new national study. In its second report, TOM reiterated the need for a separate investigation in preparation for the proposed national study. It stated: "Pilot Study The Task Force has responded appropri- ately to the Committee's earlier suggestion by recognizing the necessity of conducting a p~lot study in preparation for the proposed investigation. The committee's general recom- i~èndation now is that, during the pilot study, the investigators should focus their greatest efforts on establishing the feasibility of the various case ascertainment and control selec- tion mechanisms, and on developing a valid and reliable questionnaire. The principal product of the pilot study should be a report that describes and summarizes the relative strengths and weaknesses of the various options for case detection, control selection, questionnaire administration, and data collec- tion. Such a document will serve as the objective basis for the decisions that are made about the final study protocol." The PHS Study of the Reye Syndrome: Ccmntents on the Revised PHS Protocol, Institute of Medicine, March 1984, at 2-3; esphasis added. In its third report, following the completion of the pilot work, the TOM Committee recommended that the national study be started, importantly with several significant protocol changes. Specifically, the TOM Committee recommended that the study sample be increased to about 250 case-control sets, in order to evaluate various subgroups. (The PBS Study of the Reye Syndrome: Comments on the Revised PBS Protocol as a Result of the Pilot Study, Institute of Msdicifle, September 1984 at 3.) The PAGENO="0507" 501 Committee recommended that that the Task Force derive indices of severity f or three types of prodranal illnesses to ensure that cases and controls are matched in terms of the severity of their illness. The Committee also recommended several other changes and, with regard to the medication results, stated: `It should be emphasized, however, that the pilot study results of comparisons of me~T~a- t[on use between cases and controls will in no way be interpreted as conclusive evidence for or against an etiologic role of medication use on the risk of RS.' (Id. at 10; emphasis added.) Following the release of this report, Westat, the prin- cipal contractor for the PBS study, released its final report on the pilot study. It confirmed the limited purpose for which the pilot work was conducted: `This pilot test was conducted to deter- mine if a larger study to assess the possible relationship between medications and Reye Syndrome was methodologically feasible.' (Reye Syndrome Pilot Study Final Report, Westat, at 13-1.) Finally, in January 1985, the IOM Committee issued its most recent report, which has been cited as the basis for H.R. 1381. While the Cctnmittee recommended that precautionary steps be taken before the full study is completed, it also recognized the limitations in the preliminary study. It stated: `[Ms the committee has noted in previous reports, pilot studies generally are not used f or drawing conclusions but rather for giving direction and assessing the feasibhity of PAGENO="0508" 502 carrying out a larger study. Most important, all objectives of the proposed PBS study have not been met in the pilot effort; important public health questions remain to be con- si dered. "Questions can and will be raised by some observers about the pilot study findings. The pilot study data suffer from changes in met- hods during its conduct and the limitation of a small and geographically limited sample. Data fran the full study are needed to deter- mine if the pilot study findings are reli- able. Because of uncertainties characteristic of observational studies, ideally a number of studies should be available to corroborate scientific findings. More information on RS and use of medication is required to guide both clinical practice and public health measures." (The PBS Study of the Reye Syn- drome: Recommendations Based on a Review of the Pilot Study Data, Institute of Medicine, January 1985, at 3.) Since the release of the IOM January 1985 report, it has been revealed that FDA was advised by Dr. Floyd Denny, Chairman of the tOM Committee, that the pilot data did not provide a basis for mandatory labeling. At the deposition of Dr. Harry Meyer, Director of FDA's Center for Drugs and Biologics, BRG's attorneys asked about an FDA meeting in January 1985 with the American Academy of Pediatrics and Dr. Denny, as a representative of the tOM Committee. Dr. Meyer testified: "So, I was rather suprised when tDr. Denny] then followed that by saying that he wanted to be sure that people knew where he was because he certainly didn't feel that the data was a basis for mandatory labelling. Which is an example of what I give as the ambivalence of the scientific community on this matter." (BRG v. Youj~g, Civil Action No. 82-1346, Dè~sition of HarryM. Meyer, Jr., M.D., February 12, 1985, at 111.) PAGENO="0509" 503 When the pilot study is viewed, as it must be, as merely the preliminary field work in preparation for the national Reye Syndrome study now being commenced by the Public Health Service, it becomes clear that the pilot study cannot be used as the basis for a regulation requiring aspirin label warnings. It should be clear to this Subcommittee that, the preliminary field work also cannot be used as the basis for legislation. B. Because. of the Limited Nature of the Data, the Call for Voluntary Action Was the Only Course Realistically Available to the Secretary. The proposed legislation is premised on the claim that FDA should have regulated, but has neglected to do so. In fact, FDA has cccmtenced a regulatory proceeding to determine whether label warnings should be required.V In conjunction with that proceeding, FDA has concluded that conducting a well-designed study is necessary in order to provide a scientific basis for deciding whetheradoption of mandatory label warning requirements is warranted. In short, a regulation requiring label warnings could not be supported by the current information base. There- fore, voluntary action was the only course realistically available to the Secretary. ~ See 47 Fed. ~g. 57886 (December 28, 1982). In addition, a petitiorEy `~Tii Public Citizen Health Research Group requesting that advertisements for aspirin products be required to contain a warning concerning Reye's Syndrome is currently pending before the Federal Trade Ccmmission. The FTC staff has indicated it will review the content of current aspirin advertising. PAGENO="0510" 504 A major proponent of H.R. 1381, Health Research Group ("HRG"), filed a lawsuit in 1982 seeking to compel FDA to impose a warning requirement on aspirin. Judge John Garrett Penn, of the United States District Court for the District of Columbia, dismissed the case, stating: [I3t appears that there are sufficient questions so that further consideration of the issue cannot be held to be an unreasonable delay. Moreover, the Secretary is on record that careful and expedited consideration of the issue is necessary. In short, there is sufficient support in the record to conclude~ that a further study is necessary provided it be taken as expeditiously as possible." (HRG V. Haye~, Men. Op. at 5 (D.D.C., March l4, l983T~ HRG appealed the dismissal of its complaint and urged the Court of Appeals to compel FDA to regulate. That court also refused to interfere with FDA's decision, but remanded the case to the district court to evaluate the pace of the agency deci- sional process. The matter is i~w before the district court, which has set a briefing schedule for HRG's promised motion for summary judgment next month. The question whether FDA is obli- gated to require label warnings will soon be presented to the court a second time. The Foundation believes that not only is FDA not under an obligation to regulate, but, more importantly, FDA could not justify such a regulation on the basis of the preliminary work generated to date. Had the agency proposed a regulation on the basis of the preliminary field work, it would undoubtedly have PAGENO="0511" 505 faced objections that such action lacked scientific support. C Indeed, a regulatory finding linking aspirin use and Reye Syn- drone based upon a study whose purpose was limited to determining the feasibility and the best methodology to use in a national study would be subject to attack as arbitrary and capricious. Particularly in view of the advice of the Chairman of the IOM Conmittee that mandatory labeling is not justified, FDA could not have supported such a rule. Clearly, the voluntary route was the most expeditious way for the Secretary to have obtained the label warnings and the industry assistance in a continuing public education program that she wanted. In view of the limited nature of the pilot data, it was entirely appropriate for Secretary Heckler to have called for voluntary action. C. The Voluntary Precautionary Program Renders Legislation Unnecessary Despite the severe limitations in the preliminary data, the Foundation's member companies responded to Secretary Heckler's request with a ccxnprehensive program of label warnings, public service announcements and store posters to supplement the ongoing Reye Syndrane public education program of the Depart- ment. The Aspirin Foundation Reye Syndrome Precautionary Program was designed to help the Department alert the public to the possible association claimed to have been observed in the feasi- bility (pilot) study, while aspirin labels are being revised to include a warning statement. PAGENO="0512" 506 There are two relevant label changes that will be made in aspirin products. First, the "~RNING" section of all aspirin product labels will be revised to add the following: "Consult a physician before giving this medi- cine to children, including teenagers, with chicken pox or flu." Second, the labels of children's aspirin products will be revised to delete all references to flu. These label modifications are designed to ensure that aspirin is used for these conditions only upon the advice of a physician. The new labels will not be designed to proscribe absolutely the use of aspirin or to frighten the public into avoiding the medication. There are certain conditions, such as juvenile rhei.znatoid arthritis, for which the medical consequences of withdrawing or denying aspirin treatment must be fully considered before medical regimens are changed. A physician may believe that the health risks known to arise from the denial of medication outweigh any possible risk of Reye Syndrome. The decision, therefore, to use aspirin in medicating a child or teenager with chicken pox or influenza requires the advice of a physician. As a result of these label changes, it would be in violation of label warnings for the population assumed to be at risk to be given aspirin for chicken pox or flu without the advice of a physician first being sought. PAGENO="0513" 507 The new warnings are entirely consistent with warnings and caution statements that are widely used to reduce other potentially hazardous uses of children's drugs. For example, the risk of aspirin overdose in children is the subject of a caution statement: "For larger or more frequent doses, or for children under 2, consult physician." Members of the Foundation have already begun the process of revising their labels. Art work has been completed or is in process. Materials are being purchased, and actual printing has begun for many products. It is expected that new products will have revised labeling by the next flu season. Because not all aspirin producers are members of the Foundation, a major effort has been undertaken to advise non- members of the voluntary program. The Foundation has mailed information concerning its program to companies who produce virtually all bulk aspirin sold in the United States. As a result, virtually every aspirin producer in the country has been invited to join the program. Because all the major aspirin producers are already taking part in the program, we believe that these other companies will join them. Thus we expect that the entire United States aspirin industry will be included in the labeling program. In addition to the labeling, the Foundation offered to use Its resources to supplement the already extensive public education efforts that have been undertaken by the Food and Drug 52-266 0-85-17 PAGENO="0514" 508 Administration, the Department of Health and Human Services, the Surgeon General, the Centers for Disease Control, the American Academy of Pediatrics, the Reye Syndrome parents organizations and others. While the government's education campaign has been in progress for several years, it was most recently augmented by the following: a January 23, 1985 letter from Secretary Heckler to the general managers of the 6,000 radio and 900 television stations in the country; a January 23, L985 letter from Secretary Heckler to the editors of the 1,750 daily newspapers; a January 23, 1985 letter from FDA to public service directors of the 6,000 radio stations, enclosing two public service announcements; -- a letter from Secretary Heckler to 173,000 physicians and 8,000 hospital admini strators; -- a January 11, 1985 telegram to the major television networks and various tele- vision and newspaper trade associations; PAGENO="0515" 509 -- a January 1985 letter from FDA to the 10,000 weekly newspaper editors, accom- panied by an article. To supplement this extensive public education effort, the industry volunteered to use its contacts with broadcast media and its extensive sales forces in the retail outlets. The Foundation has produced two television public service announce- ments and two radio public service announcements. The following language appears in both sets of announcements: 30 Second Public Service Announcement An important message for parents of children arid teenagers with chicken pox or flu. A rare but serious childhood disease called Reye Syndrome may develop in children and teenagers who have chicken pox or flu. Although the cause of Reye Syndrome is not known, sane studies suggest a possible asso- ciation with medicines containing salicylate or aspirin. So, it is prudent to consult a doctor before giving these medicines to children or teenagers with chicken pox or flu. A public service announcement supported by the American Reye's Syndrome Association, the Reye's Syndrome Society and the National Reye's Syndrome Foundation. 60 Second Public Service Announcement An important message for parents of children and teenagers with chicken pox or flu. A rare but serious childhood diseasecalled Reye Syndrome may develop in children and teenagers who have chicken pox or flu. Although the cause of Reye Syndrome is not known, some studies suggest a possible asso- ci ation with mcdi cines containing salicylate or aspirin. So, it is prudent to consult a PAGENO="0516" 510 doctor before giving these medicines to child- ren or teenagers with chicken pox or flu. Remember, Reye Syndrome occurs even in child- ren and teenagers who take other medicines or no medicines. It's important to be aware of the early signs and symptoms. If your child shows unusual behavior, such as severe tired- ness, belligerence, or excessive vomiting after appearing to recover from chicken pox or flu, get medical help immediately. Give no mcdi cations. A public service announcement supported by the American Reye's Syndrome Association, the Reye's Syndrome Society and the National Reye's Syndrome Foundation. Over a thousand copies of these announcements have been distributed to networks, television stations and radio sta- tions. A letter from Commissioner Frank Young supporting the announcements accompanied the tapes. A copy of the Commis- sioner's letter is attached as Appendix A. The endorsement and support of the three major organizations of parents of Reye Syndrome victims was also obtained to ensure the acceptance and use of the announcements by the media. In addition, the Adver- tising Council issued a Special Supplement to its Bulletin, which wassent as a cover letter with the announcements. A copy of the Special Supplement is attached as Appendix B. Preliminary inquiries to local stations reveal that these materials have already reached 137 of the 198 television stations in the top 50 television markets in the country. A total of 107 of these stations are already airing or planning to PAGENO="0517" 511 air one or more of these Reye Syndrome public service announce- ments.!/ At least one station, and often several stations, in each of the top 50 television markets is currently airing or plans to air these public service announcements. The third element of the Precautionary Program involves the use of the combined sales forces of Foundation members to distribute posters in pharmacies arid food stores, and also to distributors and wholesalers, around the country. The posters contain the same message as the 60 second public service announcements, with the addition of the caption BEYE SYNDRO!'T in bold print. There are two sizes of posters -- 8 1/2 x 11 inches and 5 1/4 x 7 inches. To encourage the use of the posters, the Commissioner has also provided a letter of support for this element of the program. A copy is attached as Appendix C. In the brief time since the campaign began, 100,000 posters, together with copies of Commissioner Young's letter, were distributed to sales forces. The Foundation has found that several large chain stores have designed their own posters arid have therefore not allowed the Foundation's posters to be displayed. Some of these stores, such as Peoples' Drug in the Washington area, have copied the language from the Foundation's posters into a sign bearing the store's logo. Others are distributing the posters internally to each of their stores for display. The corporate office of Dart 4/ This figure includes 3 stations which are producing their own versiOn of the public service announcements. PAGENO="0518" 512 Drug, for example, has distributed the posters to Dart's district managers for delivery to, and posting in, each of Dart's 71 stores. In an effort to increase the use of the Eosters beyond those distributed by sales forces, the Foundation has recently sent additional copies of the poster and Caitinissioner Young's letter, by direct mail to over 60,000 pharmacists and 35,000 food stores, with a wSpecial Notice" cover letter requesting that the poster be displayed pranptly. Member canpany sales staffs have also been asked to redouble their efforts to post the signs in retail stores. We believe that these combined efforts to educate the public to the possible association are i~precedented. Despite the preliminary nature of the pilot study information, the public is being provided with warnings in print and electronic media and in posters within retail outlets. The level of public awareness -- already quite high before the preliminary feasibility work was released will probably soon have reached the saturation point. The public is rapidly becoming fully informed on the possible association. D. H.R. 1381 Would Require a Misleading Statement on Aspirin Products, in ~spirin Advertising and in Stores. The proposed legislation would require that all salicy- late products, advertising and places of sale, bear a prescribed warning statement that is seriously misleading and would result in substantial public confusion. PAGENO="0519" 513 First, the claim that aspirin and other salicylates have been "strongly associated with the developnent of Reye's Syn- drome" cannot be made unless arid until a sound epidemiologic study has been completed. The statement will be interpreted by the public as a statement that aspirin causes Reye Syndrome and that aspirin avoidance will prevent Reye Syndrome. The prelimi- nary feasibility work that has been referred to as the pilot study provides no basis whatsoever to conclude that aspirin use causes Reye Syndrome. As noted above, the IOM Committee stated categorically: "It should be emphasized, however, that the pilot study results of comparisons of medica- tion use between cases arid controls will in no way be interpreted as conclusive evi~ince for ~ against an etiologic role of medication use óii~the risk of PS." P.R. 1381 would use the preliminary feasibility work to support a conclusion that was specifically ruled out by IOM. The warning statement is devoid of scientific support and is therefore seriously misleading. Second, the statement, as well as the very title of the bill, suggests that Reye Syndrome can be prevented by the avoidance of aspirin. Such a representation is grossly unfair and can be dangerous to the population at risk for Reye Syn- drome. It is undisputed that children can develop Reye without having taken aspirin. By suggesting that aspirin avoidance will PAGENO="0520" 514 "prevent" Reye, H.R. 1381 would lead parents who have not used aspirin to the false belief that their children are not at risk for developing Reye. Medical experts agree that prompt diagnosis and treat- ment will save lives and reduce morbidity from Reye Syndrome. Parents must be alert to the symptoms of Reye and be prepared to take quick action. This legislation would remove or diminish the caution that all parents should have when their children have chicken po~c or flu. The resulting false sense of security may result in a return to the high mortality rate that recent educa- tional efforts have reduced. Finally, the warning is also incorrect in referring to "individuals under the age of 21 years" as being at risk for Reye Syndrome. Recent studies have found Reye Syndrome only in children and teenagers. CON~LT~ ION H.R. 1381 must be viewed in light of the limited nature of the available data on Reye Syndrome and in light of the coin- prehensive voluntary relabeling and consisner education program being undertaken by the industry, in cooperation with the Depart- ment of Health and Nissan Services. In that light, the proposed legislation is devoid of scientific justification and would require a misleading warning. The voluntary program, on the other hand, when combined with the extensive efforts of the Depar~nent and others, is clearly the only practical way to communicate a precautionary statement to the public without the necessity of first completing a sound epidemiology study. The voluntary program merits your support. H.R. 1381 is not a viable alternative to that program. I thank the Subcommittee for the opportunity to present the views of the Aspirin Foundation. PAGENO="0521" 515 APPENDIX A DLVARTMI'.I ii~ iii ; TI~ a Ilk %5~\%ERVI(1'. PubhcMeltthSv~.c, coou s~a D.g nc.~ ~ ~n Rock,lIe MD 2080 January 28, 1985 The Advertising Council 1730 Rhode Island Avenue, N.W. Washington, D.C. 20036 Dear Sirs: The Food and Drug Administration has reviewed public service announcements prepared by the major aspirin manufacturers with the cooperation of the Advertising Council. These materials are responsible and clear. They have the support of FDA. They were prepared In response to the request of U.S. Health and Human Services Secretary Margaret M. Heckler. Store posters and announcements are also being distributed. Thank you for your work in distributing these public service announcements. trust that the broadcast media will air these vital messages promptly, dur~np this flu season. Sincerely, Conrissioner of Fo and ugs PAGENO="0522" 516 APPENDIX B v -~ ~ ~ -~ ~S*~V~%~ -~-~ .~ ~ ~ ~ ~ ~4A ~ SUPPLEMENT TO THE ADVERTISING COUNCIL'S JANUARY-FEBRUARY PUBLIC SERVICE ADVERTISING BULLETIN This is to send you information about the Reye Syndrome threat to children and teenagers. The request for Ad Council assistance was received t~o late for inclusion in the January-February, 1985, issue of the Ad Bulletin. Reye Syndrome Aspirin Foundation of America, American Reye's Syndrome Association, Reye's Syndrome Society and National Reye's Syndrome Foundation. Parents of children and teenagers with chicken pox or flu should be alerted that a rare but serious childhood disease could affect both groups. Although the cause of Reye Syndrome is unknown, some studies suggest a possible association with medicines containing salicylate or aspirin. Therefore it is extremely important that parents consult a doctor before giving these medicines to children with chicken pox or influenza. Reye Syndrome can also occur in children and teenagers who take other medicines or no medicines at all. So it's vital that parents are aware of its early signs and symptoms. If a child shows unusual behavior -- severe tirec~ness, belligerence, or excessive vomiting after appearing to recover from chicken pox or influenza -- get medical help immediately. And give no medications. The enclosed spots have been produced by the Aspirin Foundation of America under the joint sponsorship of the American Reye's Syndrome Association, the Reye's Syndrome Society and the National Reye's Syndrome Foundation. They have been reviewed by the U.S. Food and Drug Administration and by the Advertising Council and have the whole-hearted support of both organ- izations. Dr. Frank Young, Commissioner of Food and Drugs, has written the enclosed letter to support urging the broadcast media to "air these vital messages promptly, during this flu season," For further information please contact: Carl Byoir & Associates, Inc., 380 Nadison Avenue, New York, N.Y. 10017 (212) 986-6100. PAGENO="0523" 517 * APPENDIX C DEPARTMENT OF HEALTH & HUMAN SERVICES PuMic HeatthServ~: FoodadD gAd t Rockville MD 20857 January 28, 1986 Dear Store Manager: The Food and Drug A&uinistratiofl has reviewed posters and bulletin board announcements prepared by the major aspirin manufacturers with the cooperation of the Advertising Council. These materials are responsible and clear and have F~'s support. They have been prepared in response to a request of U.S. Health and Human Services Secretary Margaret M. Heckler. Television and radio announcements are also being distributed. Sincerely, Commissioner of Fo and ugs PAGENO="0524" 518 Mr. WAXMAN. Thank you very much, Dr. White. Mr. Cope. STATEMENT OF JAMES D. COPE Mr. COPE. I am Jim Cope of the Proprietary Association. With me is Dan O'Keefe, our senior vice president, general counsel, and secretary. I will abbreviate my written statement, and request if possible that it be included in the record in its entirety. Mr. WAXMAN. All the statements will be in the record. Mr. COPE. Thank you, Mr. Chairman. Our association represents the manufacturers of all over-the- counter medicines, and therefore, we have an interest in this bill. I would like to emphasize at the outset that we share the con- cern that has been expressed by other witnesses about Reyes syn- drome. I will not discuss the scientific issues on Reye's Syndrome, nor will I cover the voluntary efforts of the Aspirin Foundation. The Proprietiary Association has not been involved in those matters, and we defer to the foundation and to the Government on those points. I would like to address some broader issues which the bill raises, specifically, the enactment of legislation at this time which would put warnings in advertising, which is our basic and major concern with the bill. I would like to make four points in my testimony. First is, we really wonder whether congressional action at this stage is neces- sary. We think it may be premature, because there is disagreement among scientists as to this question. There is an important study underway as we have heard this morning, and, of course, it is not yet completed, and there are broad educational programs already underway. The Food and Drug Administration, as you know, is considering the issue, and the Federal Trade Commission is, as well. We be- lieve, as a matter of sound decisionmaking regarding warnings in advertising and labeling, that Government action should be based on generally accepted scientific data. This bill would decide the issue now by legislation. We believe it would be premature for the Congress to act on its own judgment, particularly in an area of honest scientific dispute, while the agen- cies with the expertise-and which have been assigned the respon- sibility by the Congress-are still considering the matter. My second point is that we doubt there is any need for legislated labeling warnings. The aspirin manufacturers agreed to put the warnings on themselves, and there is adequate authority in the Food and Drug Act for the Food and Drug Administration to re- quire label warnings, if and when they are scientifically justified. This bill, however, would require a bracketed or boxed 48-word warning on aspirin and other salicylates, with color-coded symbols and no permitted flexibility. A couple of questions, if I may. Would the prominence and space required for this warning obfuscate other necessary label informa- tion and warnings? And would the use of symbols, required for no PAGENO="0525" 519 other label information, lead consumers to believe that this pro- posed label warning is the only one they should read? A typical aspirin-containing product, a sinus medicine, contains the following warnings, Mr. Chairman: Warning: Individuals with high blood pressure, heart disease, diabetes, thyroid disease, high fever or glaucoma should use only as directed by physician. Do not drive or operate heavy machinery as this preparation may cause drowsiness. Caution: As with any drug, if you are pregnant or nursing a baby, seek the advice of a health professional before using this product. Those are some of the important warnings, in our judgment, which may be superseded and overlooked by the consumer, if this warning is overlaid on them with the force that is proposed. We submit that these questions, and indeed, the issue of impos- ing the special warning is best handled first by the Food and Drug Administration, which it is currently doing. Third, advertising simply cannot do the job this bill would re- quest of it. This bill would require that all advertising, broadcast, print, transit, point of purchase, any and all advertising contain a 48-word warning. It thus fails to take into account the function and limits, and the operative word here is "limits," of product advertising. The function of advertising is three-fold. But before you can get to any of them, you have to do one other thing, and that is, get the attention of consumers, and advertising is not a high-involvement media for consumers. But assuming you can get their attention, it has three functions. First, tell consumers that there is a product on the market for a particular condition, so that in case they have it, they can use the products safely by reading the label; Second, attempt to implant a positive image in the mind of the consumer about that product, and one of its attributes; Third, very importantly, try to impress consumers with the name of the product so that when or if they do have a need for it, they will remember that product. Believe me, this is most difficult to do. We use advertising heavi- ly. We try to improve its effectiveness. We would like to very much, but we find meeting those three simple objectives very, very difficult. There is one other important thing to know about advertising. It is extremely limited as to how much information it can effectively carry. It is a low-involvement medium and it can convey only a limited amount of information. The more information it attempts to convey, the less real infor- mation that is really conveyed, the less real education that goes on. As the information load increases, consumers are inclined to tune it out or to form wrong impressions. Also, if the message is the same for too long, there is a "wear-out" with repetition, and people become bored and no longer pay attention. These are truthful statements, facts about advertising. It is gen- erally agreed by experts in mass communications that broadcasting particularly is an ineffective medium for conveying detailed health information that is directed at a limited segment of the population. Because consumer attentiveness to advertising is low, health mes- PAGENO="0526" 520 sages about specific products may engender confusion and misinfor- mation. Importantly, I think you should know that in a major proceeding before the Federal Trade Commission, which was decided just 8 months ago after consideration of an extensive evidentiary record, the Commission rejected a proposal to require advertisements for OTC antacids, to disclose warning information that FDA has re- quired in antacid labeling. The Commission's decision was unanimous, and it terminated the rulemaking based on a full record demonstrating that the inclusion of label warnings in medicine advertising is unnecessary to protect consumers, will be ineffective in communicating medical informa- tion to the at-risk groups, and will discourage beneficial self-medi- cation with OTC products. Of particular importance this morning, Mr. Chairman, there is ample evidence in that record documenting the point that warn- ings in advertising are not effective in communicating medical in- formation to at-risk groups. The presiding officer who sat through all of those hearings con- cluded that the witnesses have persuasively argued the limitations of the commercial media to make the kind of disclosures under con- sideration, which were warnings in antacid advertising. I would also note one last point, and that is, as a practical matter, it takes about 15 to 20 seconds to say the 48-word warning. Imagine trying to get that 20-second warning in a 20 or 30 or even a 60-second radio advertisement. In our judgment, a far more effective way to communicate this health concern is the way that it is happening-through doctors, pharmacists, nurses, labeling, public service announcements, PTAs, school districts, the press, and other ways. The last point: We question whether there is a need for legislated retail notices. The bill would require every retail establishment selling aspirin to display a notice containing this 48-word warning, and failure to do so would constitute a criminal act. There are literally tens of thousands of retail establishments, bars, restaurants, service stations, motels, hotels which, as a con- venience to the traveling public and others, sell small cartons of as- pirin-containing products. We wonder if it is appropriate to put thousands of small retailers in jeopardy of a criminal violation of the law for failure to display this notice? In conclusion, while we defer to the Aspirin Foundation and Gov- ernment on the science and industry's voluntary programs, we be- lieve that consideration of the need for and details concerning warning requirements, particularly warnings in advertising, is best left in the first instance to the two agencies, FDA and FTC, which have responsibilities and expertise. We ask that the Congress not enact this bill at this time, give it a chance to play out a little more so we can all find out more about Thank you, Mr. Chairman. [Testimony resumes on page 540.] [The prepared statement of Mr. Cope follows:] PAGENO="0527" 521 STATEMENT OF THE PROPRIETARY ASSOCIATION ON H.R. 1381 REQUIRING SPECIAL WARNINGS IN LABELING AND ADVERTISING OF SALICYLATE-CONTAINING PRODUCTS BEFORE THE SUBCOMMiTTEE ON HEALTH AND THE ENVIRONMENT COMMITTEE ON ENERGY AND COMMERCE UNITED STATES HOUSE OF REPRESENTATiVES MARCH 15, 1985 WASHINGTON, D.C. I. INTRODUCTION AND SUMMARY Good morning, Mr. Chairman and Members of the Subcommittee. I am James D. Cope, President of The Proprietary Association. With me this morning is Daniel F. O'Keefe, Jr., Senior Vice President, General Counsel and Secretary of the Association. I will summarize the main points of my written statement, but I ask that it be included in its entirety in the official record. The Proprietary Association, whid~ we call the "PA," is the century-old trade association representing manufacturers and distributors of over-the-counter ("OTC") medicines such as aspirin, cold tablets, cough syrups, and many others, some of which you probably have in your medicine cabinet at home. Some of these products are among the most commonly used consumer products in the United States, such as Bayer Aspirin, Vicks Formula 44e, Anacir~, Bufferint, Contac, Thmse, and Tylenole. PA members, large -and small, account for about 95 percent of the sales of OTC medicines in the United States. PAGENO="0528" 522 Let me emphasize at the outset that we share the concern for children that has been raised with respect to this rare and elusive, but very serious disease called Reye's Syndrome. We do not propose to discuss the scientific issues or the voluntary efforts by the aspirin industry in response to the available information. The Aspirin Foundation, rather than The Proprietary Association, has been involved in both the science and the voluntary program to address the Reye's Syndrome matter. We defer to them on both matters. Our purpose today is to address the broader issues raised by H.R. 1381, specifically, the enactment of legislation which would apply to all salicylate- containing products and would: * Require all labeling of such products to carry a bracketed or boxed 48-word specific warning, flanked by color-coded symt)oIs; * Require all advertisements (print, broadcast, outdoor, transit, and point of purchase) to also contain the 48-word warning; * Require all retail establishments at which such products are sold to display a notice containing the warning; * Require FDA to Issue regulations; ~and PAGENO="0529" 523 Make non-compliance with the bill's requirements a misbranding violation under the Federal Food, Drug, and Cosmetic Act. The Proprietary Association is deeply troubled by the overall thrust of the proposed legislation and the basis upon which it is being considered at this time. We believe that, if adopted, H.R. 1381 would establish an unwise precedent for future regulation of the labeling, advertising, and retail sale of over-the-counter medicines. IL GENERAL BACKGROUND A. The Role of Self-Medication in the Nation's Health Care System OTC drugs are an integral part of the health care system of the United States. These products are composed of ingredients whose pharmacological act ons are well understood and there is a wide margin of safety In their use. Their safety, labeling and effectiveness, including quality control and manufacturing process, is extensively regulated by the U.S. Food and Drug Administration. OTC medicines provide safe and effective treatment for a multitude of ailments, enabling the pthlic to forego time-consuming and expensive doctor visits and the attendant discomfort of delayed treatment. They are Inexpensive and con- veniently available In many thousands of retail outlets - Including food stores, pharmacies, and discount and department stores - everywhere. Self-medication today constitutes an early and ftmdamental level of health care; without self- medication, physicians would be overwhelmed by patients seeking relief for symptoms and ailments that can and should be treated by self-care. Thus. use PAGENO="0530" 524 of OTC drug products for the treatment of conditions capable of lay diagnosis provides an economical and convenient alternative to understandably more costly physician visits. The U.S. Department of Commerce has underscored the significance of OTC medicines in the nation's health care system. A statement, made in 1978 by the Commerce Department, has even more validity today. Self-medication with proprietary drugs is a signif- icant factor in the U.S. health care scheme. Escalating costs of health care create a greater need for low cost self-medication than ever before. Seventy-five percent of all illness and injuries are initially treated through self-care and OTC medication. If only a small percentage of self-treatment was shifted to medical practition- ers, the patient load would disrupt the US. health care system. (U.S. Department of Commerce, U.S. Industrial Outlook 1978, at 131 (January, 1978)] B. Regulation of OTC Medicines Under the Federal Food, Drug, and Cosmetic Act ("FDC Act" or "the Act"), Congress has placed the responsibility of assuring the safety, effectiveness, and truthful labeling of over-the-counter medicines under the primary Jurisdiction of the Food and Drug Administration. Thus,Congress has delegated primarily to FDA the responsibility to make the scientific and policy Judgments necessary to assure the safety, effectiveness, and truthful labeling of over-the-counter medicines and to protect and Inform the putlic with respect to them. Regulation of advertising of OTC medicines I*s been delegated by Congress primarily to the Federal Trade Commission ("FTC") tmder the Federal Trade PAGENO="0531" 525 Commission Act ("FTC Act"). That Act forbids OTC medicine manufacturers from disseminating any false advertisement, defined to mean an advertisement which is misleading in a material respect. This sound division of jurisdiction between the two agencies, with FDA expertise directed primarily to questions of science and FTC expertise directed primarily to questions of consumer understanding of advertising, has been in effect since 1938 and has served the public well. III. CONGRESSIONAL ACTION WOULD BE PREMATURE As we understand the facts, the concern underlying the proposed legislation is that there is evidence that there may be an association between the use of aspirin and the development of Reye's Syndrome. We also understand that there is genuine disagreement among scientists and medical experts regarding the alleged association between the use of aspirin and the development of Reye's Syndrome. Indeed, we understand that the very purpose of a Public Health Service study now under way is to bring the best possible scientific knowledge to bear on the question, and that that task has not yet been completed. It is also our understanding that the Department of Health and Human Services has concluded that the public education programs being sponsored by the Department and the Aspirin Foundation are adequate to meet the public health need while FDA considers the matter. A petition was filed with the FTC on January 16, 1985, by the Public Citizen Health Research Group requesting that agency to require manufacturers of OTC PAGENO="0532" 526 aspirin-containing products to place a warning concerning Reye's Syndrome in all advertisements for such products. To the best of our knowledge, that petition is pending before the agency and no determination has been made that the warning requested by the petition would be justified. We believe that, as a matter of sound decision-making regarding warnings in OTC drug labeling and advertising, government action must be based upon generally accepted scientific data. The proposed legislation would decide the scientific issues now by legislation and prescribe specific warnings that neither agency has thus far seen fit to impose. We believe that it would be premature for Congress to substitute its own judgment, particularly in an area of honest scientific dispute, for that of the agencies with the expertise and the express statutory responsibility for OTC product labeling and advertising and to mandate specific warning language based solely on its own assessment of the health risks presented by a particular product class. If Congress acts now and it is later concluded that there is no association between salicylates and Reye's Syndrome, the legislative requirements would remain in effect though unjustified - a cumbersome and unfair situation. lv. THERE IS NO NEED FOR LEGISLATED LABELING WARNINGS There is adequate legal authority in the present Federal Food, Drug, and Cosmetic Act to require scientifically justified warnings on OTC medicines. However, FDA has not deemed such warnings to be required on the basis of available scientific data. PAGENO="0533" 527 Moreover, as the Subcommittee members are aware, FDA for years has imposed warning requirements on OTCs along with other important information including: (1) the product name; (2) a statement of identity; (3) the conditions which the medicine is designed to treat; (4) directions and dosage instructions; (5) drug interaction precautions, if any; (6) a list of active ingredients and quantities of such ingredients; (7) an expiration date, when needed; (8) the net quantity of contents; and (9) the name and address of the manufacturer, packer or distributor. Thus, the label tells the consumer - in understandable terms - what the product is for, how to use it properly, and cautions which should be exercised in its use. Medicinal products are frequently sold in relatively small packages, thus increasing the need for judicious use of label space to assure that the critical information on labels is seen by the consumer. Consistent with this reality, over the years the FDA has generally taken the position that requirements for OTC label warnings should be limited, to use on specific products when the need for a particular warning has been scientifically demonstrated. Not only would scientifically unsupported warnings divert the attention of the consumer from important label information necessary for proper use by all consumers of the product, such warnings would dilute the significance of other warnings which are scientifically supported and which the consumer therefore needs to know to use the product safely. In addition to causing confusion, unnecessary warnings can needlessly frighten consumers. PAGENO="0534" 528 I H.R. 1381 would require a bracketed or boxed 48-word warning on aspirin and other salicylates, with color-coded signs and symbols and no permitted flexibility. Would the prominence and space required for this warning obfuscate other necessary label information and warnings? And would the use of symbols - required for no other label information - lead consumers to believe that the proposed label warning is the 2~ one they should read? The only information that is really important? We submit that all of these questions and indeed the issue of imposing a special warning on drug labeling in this instance should be considered first and foremost by the FDA, as it Is presently doing. Special legislation is not needed. V. ADVERTISING CANNOT EFFECTWELY CONVEY WARNINGS H.R. 1381 would also require all advertising for salicylate-containing products to carry a 48-word warning. The bill thus fails to recognize the function and limits of product advertising. Its function generally is to Inform potential consumers of the availability of the advertised product in the treatment of a particular ailment, to attempt to implant a positive image in the minds of the consumer about the product and about one of its attributes, and to do so in a way that the consumer will remember the prokict's name when that consumer is In the market to purchase that type of product. Believe me, that Is most difficult to do. There is one other important thing to know about advertising: It is extremely limited in how much information It can effectively contain. PAGENO="0535" 529 Advertising is a low involvement medium which can convey only a limited amount of information. The more information advertising attempts to communicate, the less effective the communication will be. As the information load increases, consumers are more likely to "tune out" or form wrong impressions. Furthermore, advertising "wears out" with repetition and people become bored and no longer pay attention. It is generally agreed by experts in mass communications that broadcast advertising is an ineffective medium for conveying detailed health information that is directed at a limited segment of the population. Because consumer attentiveness to advertising is low, health messages about specific products may engender confusion and misinformation. In addition, consumers who are not at risk may develop a generalized impression that the advertised product is unsafe and should be avoided. As a result, consumers may be discouraged from using OTC medicines - like aspirin - that are safe and effective for most members of the population. The Proprietary Association devoted considerable energy and resources in challenging the imposition of ill-advised warnings on OTC drug advertising in a major proceeding before the Federal Trade Commission. In that proceeding - the "Warnings" TRR after consideration of an extensive evidentiary record, the Federal Trade Commission rejected a proposal to require advertisements for OTC antacids to disclose warning information that FDA has required in antacid labeling.1 The Commission's unanimous decision to terminate this rulemaking was based on a full record demonstrating that the inclusion of label warnings in 1 49 Fed. Reg. 46,156 (November 23, 1984). PAGENO="0536" 530 OTC medicine advertising is unnecessary to protect consumers, will be ineffective in communicating medical information to at-risk groups, and will discourage beneficial self-medication with OTC products. Of particular importance to this Subcommittee's deliberations, there is ample evidence in that record documenting the point that warnings in advertising are not effective in communicating medical information to at-risk groups.2 The Presiding Officer in that proceeding concluded that the witnesses "have persuasively argued the limitations of the commercial media to make the kind of disclosures under consideration [warnings in antacid advertising]."3 These same considerations, we believe, apply to the Reye's Syndrome warning that would be required in salicylate-product advertising under H.R. 1381. It is doubtful whether such a warning will be effective in conveying accurate and meaningful information about Reye's Syndrome to parents of children who may be at risk. At the same time, by singling out salicylate products for a warning in advertising, the proposed legislation could needlessly alarm consumers and discourage use of OTC products that are safe and beneficial. There is extensive evidence that consumers prefer to obtain medical information in a manner that permits a full understanding of its implications and personal relevance rather than receiving such information in product advertising.4 One trusted communication medium is the doctor-patient relationship. Another is public service announcements that more fully describe the medical information 2 Prepared Statement of Michael F. von Gonten and accompanying study, Proposed Trade Regulation Rule Concerning the Advertising for Over-the-Counter Antacids ("Warnings TRR Proceeding"). 3 Report of the Presiding Officer, "Warnings TRR Proceeding," Novem- ber, 1979, at 167. 4 Food and Drug Administration. Consumers and Medication, May 17, 1974, at 60; Prepared Statement of Dr. Louis Lasagna, "Warnings TRR Proceeding". PAGENO="0537" 531 involved and place it in proper perspective. Labeling is another preferred means of obtaining medical information on OTC medicines. By amending the Federal Food, Drug, and Cosmetic Act, H.R. 1381 would make failure to observe the bill's advertising provisions (and regulations issued under it) a violation of that Act. This provision would seriously disrupt the historically recognized jurisdictional distinction between OTC drug advertising and OTC drug labeling. The FDA, as the agency empowered to regulate OTC drug labeling, should be the agency which handles the labeling concerns addressed by this bill. To the extent product advertising issues are involved, the FTC is the proper forum. Thus, insofar as the bill would modify the Federal Food, Drug, and Cosmetic Act to impose a warning requirement for OTC cjrug advertising of specific products, it would encroach on the FTC's authority to consider the need for Information disclosures in OTC medicine advertising. I might note, as a practical point, that it takes 15-20 seconds to read the 48- word warning required by the bill. Im~ine trying to incorporate that into a 20 or 30- - or even a 60- - second radio spot. VI. THERE IS NO NEED FOR LEGISLATED RETAIL NOTICES H.R. 1381 would also require every retail establishment selling aspirin to display a notice containing the warning. Failure to do so would make a retailer guilty of misbranding under the Federal Food, Drug, and Cosmetic Act. A misbranding PAGENO="0538" 532 violation constitutes a criminal offense for which persons can be both fined and imprisoned. Aspirin is one of the most widely available products in America. It is sold in tens of thousands of drugstores, department and variety stores, grocery stores, and discount houses, as well as in small "mom and pop" retail establishments such as gas stations, motels, restaurants and bars. It ~is inappropriate to place thousands of small retailers in jeopardy of a criminal violation of the Federal Food, Drug, and Cosmetic Act for failure to display the notice required by the bill. Thus, we believe that legislation requiring display of retail notices is unneces- sary, unduly burdensome, and unwise. VII. SUMMARY AND CONCLUSION In sum, we believe that consideration of the need for and details concerning warning requirements for particular OTC products is a task best left in the first instance to the two agencies - FDA and FTC - with respective responsibilities for regulating OTC product labeling and advertising. The scientific basis for such requirements is currently under study. The current efforts by the agencies empowered by Congress to protect the public health should be allowed to work their course before legislative action preempts their work. The FDA has the scientific expertise to address these problems and should be able to bring their scientific judgment to bear on the issue in fashioning any further response that may be indicated. The implication and precedent of legislative requirements for warnings in advertising, special warnings in labeling and special notices for retail estab- lishments are such that The Proprietary Association believes that H.R. 1381 is unwise as a matter of policy and urges that it not be enacted. In closing, let me thank the Subcommittee for its time and willingness to receive the views of The Proprietary Association. PAGENO="0539" 533 SUPPLEMENTAL STATEMENT OF THE PROPRIETARY ASSOCIATION ON H.R. 1381 REQUIRING SPECIAL WARNINGS IN LABELING AND ADVERTISING OF SALICYLATE-CONTAINING PRODUCTS BEFORE THE SUBCOMMITTEE ON HEALTH AND THE ENVIRONMENT COMMITTEE ON ENERGY AND COMMERCE UNITED STATES HOUSE OF REPRESENTATIVES APRIL 5, 1985 WASHINGTON, D.C. I. INTRODUCTION The Proprietary Association (EPA' or ~the Associa- tion~) is filing this Supplemental Statement to bring to the Subcommittee's attention certain problems members of our industry have encountered in attempting to examine pertinent data from the Reye Syndrome pilot study. While summary results from that pilot study have been made public, important raw data have not been released in sufficient detail to allow an independent and meaningful scientific evaluation of the pilot findings. We strongly urge that such data be made available promptly for independent review by the scientific community and interested parties. In The Proprietary Association's March 15, 1985 Statement, the Association emphasized that it shared the Subcommittee's concern over the rare, but very serious disease called Reye Syndrome. The PA also pointed out, however, that it is opposed to requiring warnings on over-the-counter (ROTC") medicine labels unless the need for such warnings is justified by generally-accepted scientific data. Because the pertinent PAGENO="0540" 534 scientific data underlying the Reyé Syndrome pilot study has not been made publicly available for independent review, there is no way for the scientific community to determine whether the pilot study offers any support for the suggestion that there exists an association between aspirin usage and the development of Reye Syndrome. Release of these data is particularly impor- tant under these circumstances because the pilot study is the stated basis for the current concern regarding Reye Syndrome. The PA strongly opposes prejudging scientific issues and denying interested parties a meaningful opportunity to examine pertinent data. The OTC industry is vitally interested in determining whether there are indeed reliable and valid data demonstrating an association between aspirin and Reye Syndrome. Without access to such data, however, no such determination can be made--by industry, the scientific community, or by Government. II. BACKGROUND The PA's concern about access to this data from the pilot studies must be viewed against a historical context. While the Association itself has not been involved in past attempts to obtain data from Reye Syndrome studies, we under-* stand from some of our members who have been involved, however, that there is a long history of difficulties in exposing under- lying data on this issue. PAGENO="0541" 535 Following the receipt of allegations that there was an association between aspirin usage and the development of Reye Syndrome, the FDA in February of 1982 established a Working Group to review four state Reye Syndrome studies performed by the Departments of Health of Ohio, Michigan (two studies), and Arizona. Each of the state surveys had been sponsored by the Centers for Disease Control ("CDC~) either with funds dr personnel. However--and distressingly--neither FDA nor CDC were able to obtain copies of the raw data from these studies. Nevertheless, based on summarized results of these data, the Department of Health and Human Services (RHHSW) directed the FDA to promulgate a regulation requiring label warnings for aspirin-containing products. From the time that the Reye Syndrome issue first arose, interested persons had sought unsuccessfully to obtain scientific review of the state surveys, including a thorough and independent examination of underlying data. Although it had the express legal authority to demand underlying data under its contract with Ohio, CDC failed to request the material, and instead determined to rely upon summaries of the studies prepared by the state investigators. CDC also refused to assist in efforts to obtain the release of the underlying data and referred interested persons to the states' Departments of Health. The states, in turn, repeatedly denied or simply ignored requests for access to the underlying data. PAGENO="0542" 536 Given these circumstances, on June 4 and 11, 1982, Plough, Inc. filed lawsuits in Ohio and Michigan, respectively, seeking court orders directing the production of data from the Reye Syndrome studies. Pursuant to these suits, and other independent discovery, the data were ultimately obtained by Plough. Significantly, it was Plough, not the states, which gave the information to CDC and FDA. After review of these data, HHS, on November 18, 1982, reversed its earlier decision and acknowledged that the scien- tific record concerning an alleged association between the use of aspirin and the onset of Reye Syndrome was substantially in dispute, and that new government-supported studies were needed to resolve the controversy. See 47 Fed. Reg. 57,886 (1982) at Docket Ref. 105. It was against the backdrop of these events that HHS created a task force of scientists to design and con- duct a nationwide study of Reye Syndrome and its possible link with medications. The pilot study that began in November 1983 was intended to be the preliminary field work to assist in the development of methodology for a nationwide Reye Syndrome study. III. DATA FROM THE REYE SYNDROME PILOT STUDY SHOULD BE RELEASED TO INTERESTED PARTIES AND THE SCIENTIFIC COMMUNITY SO THAT THEY CAN BE SUBJECTED TO PEER REVIEW. Prior experience regarding Reye Syndrome demonstrates that scientific issues shotild not be prejudged and that data from Reye Syndrome studies should be subjected to public scru- PAGENO="0543" 537 tiny before drawingconclusions. It is therefore of critical importance that data from the Reye Syndrome pilot study be released so that an independent scientific inquiry can be made. In particular, relevant information and key data, including medical records of cases during diagnosis and treat- ment, medical records concerning the underlying illness of cases and controls, and more complete versions of questionnaires used during the actual interviews of cases and controls have not been released to interested parties. Other information from the pilot study has been made available, but only in a Rwhited_outw format with critical information deleted, thereby making meaningful analysis impossible. It is necessary, for example, to have access to the medical records so that, by comparing the preliminary and final diagnosis, it can be determined whether cases actually had Reye Syndrome and when and if they were given aspirin. The principal reason given for withholding this data is that it is necessary to protect the privacy rights of individuals. The PA is always mindful of such rights. But we understand that privacy is not really at issue, since parties interested in examining these data have undertaken to honor the privacy of the individuals involved, and only want an oppor- tunity to analyze these data themselves. Thus, members of the industry have indicated that they are not interested in names, addresses, and telephone numbers of cases, controls, and their physicians. Rather, for example, they seek release of such PAGENO="0544" 538 information as the age and sex of cases and controls in order to determine that cases and controls were adequately matched. The PA, therefore, strongly urges that further data from the Reye Syndrome pilot study be made available to public scrutiny. IV. WITHOUT SUBJECTING THE DATA FROM THE REYE SYNDROME PILOT STUDY TO INDEPENDENT SCIENTIFIC ANALYSIS, IT IS NOT POSSIBLE TO DETERMINE ITS VALIDITY. Under current law, the determination whether a Reye Syndrome warning is required is governed by two provisions of the Federal Food, Drug, and Cosmetic Act (FDC Actw)__section 502(f)(2), which requires adequate warnings against unsafe uses, and s~ection 201(n), which provides that labeling. may be misleading if it fails to reveal material facts about the consequence of using a drug. 21 U.S.C. SS 352(f)(2) & 321(n). Neither of these provisions can be read consistently with the concept underlying H.R. 1381. The legislative history of section 502(f)(2) of the FDC Act makes clear that Congress did not intend to require warnings about speculative or hypothetical risks. During the legislative debate on the bill that eventually became the Act, the sponsor (Senator Copeland) stated that the. provision was directed to wpossible misuse' of drugs, that is, use under conditions or in dosages known to be unsafe. See 81 Cong. Rec. 2,019 (1937). This interpretation of section 502(f)(2) was confirmed in 1951 in testimony on the Durham-Humphrey Amendments PAGENO="0545" 539 enacted that year. See Hearings on H.R. 3298 before the House Interstate and Foreign Commerce Comm., 82d Cong., 1st Sess. 20 (1951) (testimony of Oscar R. Ewing, Administrator of the Federal Security Agency). Similarly, section 201(n) of the Act was not intended to require warnings about every conceivable risk that might arise from use of a drug. This provision applies only to risks for which there is sufficient medical evidence of a significant hazard to meet the statutory test of materiality. Thus, in the preamble to its regulations governing prescription drug label- *ing, the FDA declared that warnings are to be included only wwhen evidence exists on the basis of which experts qualified by scientific training and experience can reasonably conclude that the hazard is associated with the use of the drug.~ 44 Fed. Reg. 37,447 (1979). With the Reye Syndrome pilot study, scientific experts have not yet had the opportunity to make an independent determination as to whether these data are sound. Without release of these data to interested parties, no such scientific determination can be made. V. CONCLUSION Members of the PA are strongly committed to ensuring that all OTC products are safe and that no personal privacy is invaded. Data from the Reye Syndrome pilot study must be released for public scrutiny in order to allow an independent, scientific determination as to whether these data are valid. 52-266 O-85--18 PAGENO="0546" 540 Mr. WAXMAN. Thank you, Mr. Cope. Mr. Chayet? STATEMENT OF NEIL L. CHAYET Mr. CHAYET. Thank you, Mr. Chairman. My name is Neil Chayet, here on behalf of the Committee on the Care of Children. Dr. David Lang was to be with me this morning. He was to take, from your State of California, the Red Eye. He had, unfortunately, a medical emergency within his own family. His wife just gave birth to a child that has recently been in the intensive care unit, and he felt at the last minute he really should not be here. He did send a telegram to you fully supporting this statement, and offering to meet with you as soon as possible. I am particularly sorry he is not here, because he has been in- volved in this from the very beginning. I am very sorry to have to take a position that is contrary to your legislation today, because I believe that you are in very good faith, and that all the people here today, particutarly the parer~~s, have had as much impact on me as anyone else. There is only one problem. The science does not support the warning, period. And it is really a shame, and it is a very difficult position to take. I feel kind of like a voice in the wilderness, but that is the way it is, and nobody can change it. No matter how much is said, no matter how many words are spoken, nothing can change that. Now, there have been two phases to this situation. You have heard them referred to as the "early studies." The "early studies" were disastrous, Mr. Chairman.. Of those studies, three were thrown out by the agencies themselves. Only one survived, and just barely, and when that study was looked at, it wasn't known who took what when. It is as simple as that. It wasn't known what kind of medication was taken. It wasn't known whether the kids in the cases had actually even had Reyes syndrome, cases were excluded. It was a tragedy. But something happened, Mr. Chairman. I want to be sure you understand. Mr. WAXMAN. Please go on. Mr. CHAYET. I understand that, but what I am trying to say is important, and I just would like you to hear me just briefly. Mr. WAXMAN. I am listening to you, and you are recognized for 5 minutes to speak. You can use your 5 minutes any way you wish. Mr. CHAYET. OK. All I am trying to say is that the reason that the Government reversed itself on the initial labeling was not be- cause of industry pressure. It was because the science simply wasn't there, and a mistake was made, that was why the Academy of Pediatrics recommended no relabeling of aspirin at that time, because the science wasn't there. By the way, if there is any doubt about that, I refer you to the document you have in front of you, which I filed. There is a state- ment by the FDA itself, which is a very interesting statement about those early studies. It reads: PAGENO="0547" 541 There is currently uncertainty about whether the reported statistical association between Reyes syndrome and aspirin has any, any reasonable clinical significance. That was the problem, Mr. Chairman. If you read that statement of the Government itself, it just tears to shreds all those early studies. Now, we are in another phase. Of course, in the meantime, an error was made. What may have been the biggest publicity campaign in the histo- ry of this Nation about a drug was launched. How do you call it back when an error has been made? It is a very difficult question, believe me, for everyone. And, what happened in the interim? I hope that what I am about to mention to you didn't happen, but it might very well have. Today is a story of "what-if." Well, what if the following hap- pened? We reviewed the early PSA's released by the Government. We asked the Becker Research Group and First Market Research Group to interview people as impartially as possible. They chose 100 people from a shopping mall. They showed to those people the Government PSA's and then interviewed them, and 40 percent of them believed that aspirin was the sole cause of Reye's syndrome. And 45 percent believed if you didn't give aspirin to your child, you would prevent Reyes syn- drome. The one thing Dr. Wolfe and I, and we all agree on, is that de- layed diagnosis of Reye's syndrome is fatal. Mr. CHAYET. What if somebody saw the Government PSA's and said my child couldn't have Reye's because we. didn't give him aspi- rin, and delayed the diagnosis. What if that led to death? That is why the doctors produced their PSA, because the Government PSA was shown to be misleading. Now, we have the pilot study and I wish I could say to you that there is now credible scientific evidence for the warning, because I would like to at this point say if it were only true, because every- body else is saying it. But it isn't true. Now, we have asked for the raw data of that study-and I have to say the Government has been trying as hard as it can within the constraints of the law to give us the raw data-but we have a prob- lem, because the raw data that we have been given thus far simply doesn't make it. It doesn't measure up, it isn't there, and I refer you to the last tab of my testimony which was received yesterday, which indicates the beginning of what I really hope isn't true, mas- sive, incredible problems with that material. But we don't know yet, and I wonder if I could ask you for some help? We need some help in getting the raw data because what has been passed by the Congress in good faith is apparently making it impossible for us to get it. We asked the Government for it, they said they don't have it. I think they are answering accurately. We asked the private contractor for it. They say we can't give it to you because of the Privacy Act, and the Freedom of Information Act is written into our contract and we can't violate those laws. So, we can't get what we need to review this clinical record. We don't want to identify these poor children or these families, we just want to see if there is credible evidence of hazard. At least thus PAGENO="0548" 542 far, there isn't. This warning is misleading. The science isn't there, and I spent the last 20 years trying to find and work with impar- tial, excellent physicians and scientists, because let's face it, what the real issue is today is credibility. That is the question. When do you warn, and who can you believe, and American people may well be getting fed up with one warning after another that turns out not to be right. That is why I would appeal to you today to help us get the raw data and help us find exactly what the evidence is. I don't think the Institute of Medicine has seen that raw data yet, I don't think the FDA has seen it. I don't know who has seen it. I would like to appeal to you to help us find out so we can all have unanimity here. [Testimony resumes on p. 639.] - [Mr. Chayet's prepared statement follows:] PAGENO="0549" 543 TESTIMONY ON BEHALF OF THE COMMITTEE ON THE CARE OF CHILDREN PRESENTED BY: DAVID J. LANG, M.D. CHAIRMAN, DIVISION OF PEDIATRICS CITY OF HOPE NATIONAL MEDICAL CENTER DUARTE, CALIFORNIA COORDINATING COMMITTEE, CCC AND NEIL L. CHAYET, ESQUIRE GASTON SNOW & ELY BARTLETT BOSTON, MASSACHUSETTS LEGAL COUNSEL, CCC BEFORE THE SUBCOMMITTEE ON HEALTH AND THE ENVIRONMENT OF THE COMMITTEE ON ENERGY AND COMMERCE OF THE HOUSE OF REPRESENTATIVES HONORABLE HENRY A. WA)C'~AN, CHAIRMAN ON H .R. 1381 "THE EMERGENCY REYE * S SVNDROME PREVENTION ACT OF 1985" MARCH 15, 1985 PAGENO="0550" 544 TABLE OF CONTENTS TAB Testimony Statement Correspondence/Article from 1983 re: previous studies on Reye Syndrome - letter to Dockets Management Branch from Alvan R. Feinstein, M.D. - letter to Walter R. Dowdle, Ph.D., Chairman of Reye Syndrome Task Force from Heinz F. Eichenwald, M.D., Chairman of the Committee on the Care of Children Coordinating Committee - letter to Queta Bond, Ph.D. of the Institute of Medicine from Heinz F. Eichenwald, M.D. - article: "NIH, Japanese Studies Fail, to Back Aspirin-Reye's Tie" Scripts from the 1982 public service announcements developed by the Public Health Service and summaries of marketing researching studies of reactions to these announcements by the public developed by Becker Research Corporation at the request of the Committee on the Care of Children 3 Citizen Petition: August 10, 1983 4 Interrogatory 1(a) and responses in reference to the lawsuit of the Public Citizen Health Research Group (Plaintiffs) V Dr. Frank Young, Commissioner of the Food and Drug Administration (Defendants) .5 Statements and correspondence re: the current PHS Study on Reye `Syndrome - summary of statements by Alvan R. Feinstein,M.D. presented at the hearing of the Institute of Medicine on August 6, 1984 - letter to .M. Harry Jennison, M.D., Executive. Director of the American Academyof Pediatrics from Heinz F. Eichenwald, M.D., Chairman of the Committee on the Care of Children Coordinating Committee - Correspondence from Neil L. Chayet, on behalf of the Committee on the Care of Children, to Eugene S.' Hurwitz, M.D. of the CDC and to Mark Novitch, M.D., Thomas Scarlett, Esq., .and to Richard 3. Riseberg, Esq., of the F.D.A 6 Article: "Potentiation of the Toxic Effects of Aceta- minophen in Mice by Concurrent Infection with Influenza B Virus: a Possible.Mechanism for Human Reye's Syndrome?" from Pediatric Research (Vol. 18), No. 2, 1984) Articles: - Boston Globe editorial, November 12, 1984 - articles - February 27, 1985 8 Text of mailgram sent to all television stations on January 17, 1985 on behalf of the Committee on the Care of Children 9 Preliminary analysis of the raw data from the Public Health Services pilot study on Reye Syndrome 10 PAGENO="0551" 545 Mr. Chairman and Subcommittee Members: The Committee on the Care of Children (CCC) is an organiza- tion of approximately 1200 pediatricians from throughout the country. It was formed in the fall of 1982 to address areas of concern to pediatricians and their patients and has spent a great deal of time since its inception reviewing matters re- lated to Reye's Syndrome. The CCC is heade4 by a Coordinating Committee of leading pediatricians from throughout the coun- try. None of the members of the Coordinating Committee, nor any of the members of the full Committee, are paid for any of their efforts with regard to the CCC. From its inception, the CCC indicated that its work in areas which relate to industry would be funded primarily by industry, because of the belief that industry has an obligation to fund arms length efforts to seek the truth with regard to matters of controversy. The CCC believes that there is in fact harmony between the interests of industry in providing products which benefit the health of the public, of the physician who prescribes such products and of the patient who is the ultimate recipient of such products and whose best interests bring all of us here today. On behalf of the CCC, we are pleased to respond to the invitation of Chairman Waxman to testify with regard to HR. 1381, which deals with a matter of great importance to physicians and patients throughout the nation. The position of the CCC with regard to this matter has remained constant and consistent: the public should be warned PAGENO="0552" 546 immediately with regard to any product if such warning is preceded by credible scientific evidence of hazard. (The CCC filed a Citizen Petition, a copy of which is included as Attachment 4, with the Food and Drug Administration in August of 1983 on the generic issue of "When to Warn." The CCC is still awaiting a substantive response to said Petition). As the Subcommittee is no doubt aware, in 1982, the then Secretary of Health and Human Services announced his intention to change the labeling of aspirin containing products and launched a nationwide publicity campaign warning patients of an alleged association between aspirin and "Reye-s Syndrome". The impact on the physicians and patients of this nation was enor- mous, with patients expressing great concern One member of the CCC reported receiving several hundred calls per month from patients inquiring as to how to treat children with high fever. In addition, a physician treating children with rheuma- toid arthritis, of which there are approximately 150,000 throughout the nation, reported that parents and children were refusing aspirin, which is the drug of choice for such cases, (acetaminophen is not effective in treating inflammatory condi- tions) and insisting that other drugs (including experimental drugs) be prescribed. Furthermore, the CCC attempted to ascertain the impact of the government's extensive publicity with regard to this matter and an impartial survey of response to Government television PSAs indicated that 40% of those who viewed such material con- PAGENO="0553" 547 cluded that aspirin was the sole cause of Reyes Syndrome, and 45% actually believed that not giving aspirin to a child could prevent Reye's Syndrome, something which the doctors believe could be extremely dangerous since it could lead a parent to believe that his or her child could not have Reye's Syndrome because he or she had not been given aspirin, leading to the one thing which all agree is extremely dangerous - - delayed diagnosis and treatment of Reye's Syndrome. (Please see Attachment 3.) The problem was that as physicians tried to calm their patients, they also became increasingly concerned that the gov- ernment action was not supported by credible scientific stud- ies. The CCC asked that an impartial review be conducted of the early studies, and it was concluded that they were fatally and fundamentally flawed. (Please see Attachment 2.) In fact, virtually every independent organization or individual scien- tist reviewing the studies that initially gave rise to this controversy has arrived at the same conclusion; the CCC is therefore not an exception, but represents the widely held opinion of these studies. The CCC was not alone in its concern over this matter. In November of 1982, the Executive Board of the American Academy of Pediatrics issued a statement which urged that relabeling be delayed pending further study, and that in the meantime, cau- tion be used with respect to all anti-pyretic medication. Subsequently, the FDA itself in an answer to interrogatories PAGENO="0554" 548 propounded in an action brought by the Health Research Group, stated as follows: "... there is currently uncertainty about whether the report of statistical association between Reye's Syndrome and aspirin has any reasonable clinical signifi- cance. (Please see Attachment 5.) In March of 1983, newly appointed Secretary of Health and Human Services, Margaret Heckler, called for more study of this issue and convened a Public Health Task Force composed of rep- resentatives of the Public Health Service, the FDA and the CDC. The Task Force contracted with the Institute of Medicine of the National Academy of Sciences, which assisted in monitor- ing the development of a protocol and which held a number of public meetings with regard to this matter. At each of these meetings, representatives of the CCC, along with many other organizations, presented comments, noting a number of problems with the intended protocol. Some of the suggestions made by those parties were accepted by those responsible for the study, but others, including a number of suggestions of the Institute of Medicine, were not accepted. The purpose of the pilot study, the results of which were released earlier this year and which may have precipitated the legislation pending before the Subcomttee at this time, was to validate the methodology of the larger intended study, and was not intended to be utilized to provide further evidence of association. In fact, there was concern that premature release of the pilot study might preju- dice attempts to complete an impartial larger study because of PAGENO="0555" 549 the phenomenon of `recall" and "referral" bias based on public- ity. There is no question, however, that serious ethical questions are raised when any study, regardless of its initial purpose, indicates a public health hazard. The question remains, however, whether the pilot study was itself conducted in a manner which gives rise to reliable and credible evidence of a meaningful association between aspirin and Reye's Syndrome. There is increasing concern that there may be ex- tremely serious problems with regard to the data; we were ex- tremely concerned to note recently reported comments by Dr. Floyd Denny, Chairman of the Institute of Medicine Committee named to review and monitor the study. Dr. Denny is quoted as describing the study as "a flawed study, of course" and is fur- ther reported to have stated that the study focused on very small numbers of patients, had very poor geographical distribu- tion and reflected "three or four" changes in the way the interviews were carried out. (Please see Attachment 8.) It is indeed regrettable that we come before you today with no answer to this fundamental question because the raw data with which to answer this question have not been made available to us, or as far as we know, to anyone else. This is not to say that the various government agencies involved have not attempted in recent weeks to make large amounts of data avail- able; the problem is that the data released thus far have raised some extremely serious questions, some of which can only be answered by a review of the clinical records involved. A PAGENO="0556" 550 number of requests for this information have been made, but the response thus far has been that the records are not available under the Freedom of Information Act because the government agencies are not in possession of same (therefore they alleged- ly do not constitute an agency record) and yet, when inquiry is made of the private contractor which carried out the study, the response is that the contract with the government specifically provides that this matter shall be governed by the FOl and Privacy Acts, which are then interpreted as preventing the release of such data -- a kind of `Catch 22' with unfortunate consequences for all. We request in this forum, as we have in virtually every forum open to us, that the doctors be provided with the data they need to review the pilot study; they are ethically and legally bound not to release patient-specific information which could lead to the identification of individ- ual patients. The doctors in no way wish to identify the patients or contact the patients or their families in any way, and it would indeed be paradoxical if the material released thus far were able to be utilized in some way to identify the patients, while doctors who were only interested in validating important research were denied that opportunity. All of the members of the Coordinating Committee of the CCC have acted as trusted consultants to various agencies of the Federal Government and other organizations, including NIH, FDA, the Military, and the National Academy of Sciences. It is com- pletely inappropriate to suggest that these individuals cannot PAGENO="0557" 551 be trusted to protect patients privacy when they do so as a matter of course every day. We are enclosing with this statement the results of a pre- liminary review of the pilot study data, and as can be clearly seen from this material there are many unanswered questions which mandate the availability of further information. (Please see Attachment 10.) It is most important to state that the CCC is not interested in "nit-picking the data, but rather in ascertaining if the present warnings and proposed regulatory action are warranted. (Please see correspondence at Attachment 6.) It is significant and unfortunate that no one from the CDC is present here today (according to the previously announced witness list) to respond to the questions concerning the scientific base for all of the present activity. Furthermore, we have great concern over the manner in which the pilot study results were disclosed; the Institute of Medicine report, based on its December 13, 1984 meeting at which a sum- mary of the data was presented (and for which no meeting trans- cript or tape is available), indicates the importance of peer review of the data. If indeed the study results are fully supportable by the study, and the study is one of which its supporters are proud, why has there been such difficulty in being able to review the statistical and clinical data on which the study is based? It is the usual practice for such studies to be reveiwed by peers prior to publication, and certainly PAGENO="0558" 552 prior to the implementation of any conclusions. This is a normal process that insures scientific accuracy and lack of bias, and without it, no study is recognized as acceptable. Lastly, it is necessary to address one very important guestion of policy. Many have asked, why not warn now, because "what if" the purported association turns out to be true. This is a difficult question, and one to which we have given a great deal of thought. We believe that in the short and long term, the "what if' argument is a dangerous one; "what if" a drug to which millions of people are turned, turns out to be as bad or worse than the original suspect. (Please see Attachment 7 which includes an article referring to acetaminophen and Reye's Syndrome.) "What if" parents believe, based on the strength of the warnings, that the drug is indeed the sole cause of Reye's Syndrome and delay diagnosis and treatment? `What if" the par- ents of children for whom aspirin is the drug of choice (i.e., those with rheumatoid arthritis) refuse to allow aspirin to be used? And what about parents who believe that they have caused harm or death to their child by giving a drug that is in fact not connected with the disease? And lest we forget, this is not the first time the government might be mistaken; the trage- dy surrounding the swine flu vaccine was directly related to a precipitous warning program, which left in its wake no swine flu, but hundreds paralyzed by Guillain-Barre Syndrome. The program was no doubt well-intentioned by those who conceived and implemented it, but the resulting consequences indicate PAGENO="0559" 553 that the "what if" approach to public policy can be fraught with hazard. As for the future, we can only hope that credible evidence can be found to settle this controversy. We therefore believe that it is essential that further studies be carried out. The Yale University School of Medicine has been working in prepar- ing a study that would involve thousands of pediatricians throughout the country. Again, we believe that industry has an obligation to fund arms-length efforts to find the truth and we are confident that such a study will be able to be announced in the near future. Many precautions are being taken to insure the credibility of such a study; in addition to the excellence of Yale University, with its procedures to safequard integrity, the American Academy of Pediatrics has appointed Dr. Sanford Cohen of Wayne State University as a Liaison to the study. Dr. Cohen, in turn, has been asked to chair an Advisory Panel which will include some of the finest epidemiologists and clinicians from throughout the country. In conclusion, for all the reasons noted above, we cannot, at this time, support mandatory labeling of aspirin-containing products. In fact, we believe that the label proposed in H.R. 1381 could well be viewed at this point as resulting in misbranding of said products, based on the scientific evidence available to date. We simply must have credible scientific evidence before proceeding with such a step, and we hope very much that the Subcommittee will assist in securing this evi- dence. Again, we appreciate the invitation providing us the oppor- tunity to be present here today and look forward to working with all parties who have a vital concern for the children of this nation. PAGENO="0560" 554 COMMITTEE ON THE CARE OF CHILDREN COORDINATING COMMITTEE MEMBERS: Chairman, CCC Coordinating Committee: Heinz F. Eichenwald, M.D., a William Buchanan Professor of Pediatrics with the Department of Pediatrics for the University of Texas Southwestern Medical School in Dallas, Texas Members, CCC Coordinating Commitee: John Baum, M.D., the Director of Arthritis and Immunology-MCH Strong Memorial Hospital in Rochester, New York Harvey L. Chernoff, M.D, an Associate Professor of Pediatrics with Tufts University School of Medicine and a Senior Pediatric Cardiologist with the New England Medical Center Hospital in Boston, Massachusetts Joseph F. Fitzgerald, M.D., the Director of the Gastrointestinal Disease Section for The James Whitcomb Riley Hospital for Children in Indiannapolis, Indiana Burton H. Harris, M.D., the Director of the Division of Pediatric Trauma for the New England Medical Center Hospital in Boston, Massachusetts Robert A. Hoekelman, M.D., Professor and Associate Chairman of the Department of Pediatrics for the University of Rochester School of Medicine in Rochester, New York David J. Lang, M.D., the Chairman of the Division of Pediatrics for the City of Hope National Medical Center in Duarte, California James P. Orlowski, M.D., the Assistant Director of the Pediatric and Surgical Intensive Care Unit for the Cleveland Clinic Foundation in Cleveland, Ohio Consultant, CCC Coordinating Committee: Sidney S. Gellis, M.D., the Acting Chief of the Center for Genetic Counseling and Birth Defects Evaluations for the New England Medical Center Hospital in Boston, Massachusetts PAGENO="0561" 555 Yale University I SCHOOL OF 4~rC~E CE'~,l~ L'at 333 Cd..r Sere~ P.O. L'~ LW February 23, 1983 203 4364757 Dcckecs !`.ar.a;amenc Sranch RFA-305 Food and Drug Administration Roan 462 5600 Fishers Lane Rockville, Maryland 20857 Ladies and Gentlemen: The Co=.ittee on the Care of Children has asked me, as a consultant previously un~mvolved in this problem, to review and coent on the epidemiologic studies that purport to show an association between ~eye's Syndrome and Aspirin. These studies are being used as fundamental backgrn~.~zd d.ata for your decision regarding the proposed labelling of aspiria-ccncainiz; products. The three epidemiologic reports are quite well `enown by their sites of ortg~n as the Arizona, Michigan, and Ohio studies. They appeared, respect4veiy in PEDIATRICS 66:859 (Dec.), 1980; in JA~'A 247:3089 (June 11), 1982; and in JAMA 248: 687 (Aug. 13), 1982. After reviewing the published reports of these studies, I conclude that all three of these case-control studies are serIously biased, particularly by the failure to select an appropriate control group. The choice of an appropriate control group is a coon problem in case-control studies, but the trio under review here all share the same major flaw, which renders all three unacceptable as unbiased scientifIc evidence. My reasons for drawing this comclusicn are as fo1~.s In determining the positive or negatIve effects of a pharmaceucIcalagent, the "gold standard" of scientific evidence is a randomized controlled clinical trial. The FDA has played an important and admirable role in helping set thin scientific standard of evaluation and in demanding that the standard be fulfilled when claims are made about the action of pharmaceutical agents. In its usual application, a randomized controlled trial contains at least three operating principles that enhance its scientific quality and that give credibiliry cc, the results: - 1. All patIents entered into the trial must fulfill approprIate criterIa for eligibility. These criteria demand that patients must have suitable therapeutIc indications for the main pharmaceutical agent(s) under study, and must not have contraindications to any of then. 2. The compared agents are assigned with randomization. The purpose of randomization is to ensure that "susceptibility bias" is mac created because certain agents are preferentially aaaigne~ to certain subgroup. of patient~ who are ~re (or less) severely ill than the others, a~d who thereby have worse (or better) prognoses for the outcome event. PAGENO="0562" 556 Dockets MarLagesent Branch February 23, 1983 3. The outco~ event is deternined with "double blind' sethods, The purpose of these nethods is to prevent the outcoce event fron being detected or identified in a nanner that is bfased by the exanloer's knowledge of which treatnent the recipIent received. If we were able to perforn a randosi:ed clinical trial testing whethir aspirIn causes Reye's Syndrnse, we would cosply with all three of these denands: (1) The patients would be children eligible for the trial because they are sick enough to receive aspirin therapy. (2) To ensure that the treatnents are equitably assigned to the nost and least severely ill of these children, they would be randonized tc' receive either aspirin or the cooparative agent (which sight be placebo or acetonincphen). (3) The subsequent diagnosis of Rays's syndroce would be node under double-blind conditions. Since randonized trials cannot feasibly be conducted to deternine the relationship between aspirin and Raye's syndrona, we have been forced to rely on case-control studies. As I pointed out in a recent paper on epideniologic research published in the SEW ENGLAND JOURNAL OF MEDICINE (307:1611 (Dec. 23). 1982), scientific standards need not be abandoned in a case-control study nerely because randoni:ation was not possible. With suitable scientific attention, all three of the cIted principles can be attained or reasonably well approxirated in a case- control study. Nevertheless, all three of the cited princIples seen to have been ositted in all three of the Arizona, Michigan, and OhIo studIes. The consequences of violating the third principle (about double blindIng) are inporrant, but difficult to estinate quantitatively, since the published reports do not describe exactly what happened. It seens clear that the interviewers soliciting data about antecedent aspirin usage were quite aware of which patIents were cases and which ones were controls. It also seens clear that the interviewers were aware that the investigators were testing the hypothesis that aspirin nay cause Reye's Syndrone. In this circun.stance, the opportunity for "ascertainnent bias' is substantial. Without having seen or reviewed the individual fornats that were used by the interviewers, however, and without having checked with the investigators to detersine exactly how the interviews were conducted (and by whon), I cannot detern.ine exactly how nuch bias nay have occurred. Nevertheless, when investigators have deliberately taken adequate scientific precautions to guard against ascertainrent bias (by keeping interviewers unaware of the research hypothesis, etc.), the precautions are usually described when the research is reported. No such precautions are nentioned in these three reporrs. Regardless of the inpact of ascertainment bias, susceptibility bias surely occurred in these studies because the investigators did not establish suitable criteria for eligibility (to satisfy Principle 1) and did not perform suitable satching of clinical severity (to satisfy Principle 2). The investigators clam to have notched the cases and controls on the basis of type of illness (e.g. influenza, varicella) and on the basis of height of fever. Neither ofthase criteria La satisfactory to account for severity of illness. to a ooo_ra0d00~ed stuoy, unless a specific index is used to classify severity of illness (rather than fever alone, anorexia alone, headache alone, etc. or nultivariate C00bLnatiocs of these features), the best way to determine severity of Illness is to ~ik the parent ~ she or he decided to give the child aspirin, acetoninophen, ~ other osdication, or no medication. These reasons for giving or not giving trestnaot constitute the "therapeutic indication" that would be used to deters-ice ~ patients eligibility for s randomized trial of a pharo.sceu:idil agent. The therapeutic existing case-control evidence about the alleged danger of aspirin for Reye'a Syndrome. I believe you would act wisely if you follcwed the prsvious precedent set by the FDA in the reserpine/breast cancer controversy. By delaying any action nov on the labellIng of aspirin-containing products, you can help the FDA maintain its stature, its dedication to high scientific principles, and its useful guidance services to the parents of sick children. Sincerely yours, ~lvsn R. Feinstein Professor of Medicine and Epide~ology Director, Clinical Epidemiology Unit PAGENO="0563" 55? ______________Committee on the Care of Children______________ 50 MIlk Skeet, F'tfteenth Floor, Boston, Ma.ssachu,stts 0~109 * Tdephonr: (617) 4510803 Telex: 95113 Telecopler: (617) 451.~'~) FEDERAL EXPRESS May 6, 1983 Walter R. Dowdle, Ph.D., Chairman Reye Syndrome Task Force Centers for Disease Control 1600 Clifton Road (1-6007) Atlanta, GA 30333 Dear Dr. Dowdle: In response to the April 8, 1983 Notice at Federal Register 48(69) :15331 requesting information regarding the development of a new epidemiologic study to evaluate the possible relationship between the use of medications and Reye Syndrome, the Committee on the Care of Children (`CCC") respectfully requests that you consider our recommendations set forth below. Also, the CCC requests close coordination of the proposed new epidemiologic study with the experts of the CCC. The CCC has an effective, efficient relationship with pediatric departments of university-affiliated medical centers and practicing pediatricians across the country, and can facilitate the development, implementation and completion of a multi-center study on Reye Syndrome and medication usage. By far, the preferred approach would be for HES to ask the Institute of Medicine of the National Academy of Sciences to plan, implement, and analyze such a study since such an approach would assure the highest quality and impartiality. In addition, and in recognition of the level of difficulty involved in this proposed study, the CCC recommends the formation of a working, consultative group with membership consisting Of representatives from academia, clinical medicine, epidemiology, the CCC, consumer advocate organizations, the Food & Drug Administration, industry, Department of Health and Human Services, National Institutes of Health, and the Centers for Disease Control. The function of this group wguld be to supervise and review aspects of the study and insure careful and complete compliance with the protocol. This degree of careful attention, to detail should facilitate agreement between all concerned parties, to the end that a carefully constructed, well-designed study will be performed, in COORDLNATThIC COMMTI'TEE Joseph F. Fiszgrald. M.D. Dacid). Lang M.D. Heinz F Eich,nsoald. M D . Cha:rman IsdO??OpOlC lnd:ano Bolt:::or,. Maryland Della,. T,zas Bsar,or H. Harris. M.D. James P. Orloscsk:. M.D. John Bases. M.D. Bose',. Massachawtts Clcelond. 0/co Roch,sstr. New York Robert A. Hoeke/man. M.D. CONSUI,TANT Haroey L. Chernoif. M.D. Rochester. New York Sorry Delis. M.D Bosinn. Maaaarhsa,r:s Sos:o:. Massachasaits PAGENO="0564" 558 May 6, 1983 Page 2 a manner sufficient to satisfy the questior.s of careful scientists. It must be recognized that a number of individuals and organizations in and out of government have taken a strong stand pro and con with regard to the aspirin issue; a committee consisting primarily of representatives of groups that have expressed such views would not be judged impartial nor could it be expected to- be. However, the input from this working group may be useful to a full, careful analysis of the problem. The CCC maintains that the development of careful protocols, well-trained investigatory teams, and the selection of physicians experienced in the recognition and accurate diagnosis of Reye Syndrome are essential components to a careful study. The CCC respectfully requests the opportunity to work closely with the Public Health Service in the design and implementation of a multi-center, case-control, retrospective epidemiologic study on Reye Syndrome and medication usage. Dr. Joseph F. Fitzgerald at Indiana University Medical Center, James Whitcomb Riley Hospital is a member of. the Coordi- mating Committee of the CCC, and serves as; Mid-West (Central) Regional Director of a multi-center study entitled the "Reye Syndrome Study Group.' This study group -consists of at least 16 medical centers wl~o have agreed to osmotherapy vs. pentobarbital- augmented osmotherapy in a randomized fashion on identical clinical protocols. Application has been made to the National Institute of Health for funding, with a site visit conducted on February 28, 1983. The principal investigator of the study is Dr. Wallace Berman at the Medical College of Virginia. This group has received word of a favorable site visit and that approval for funding is under consideration. As you know, the coordination of 16 or more medical centers in a collaborative study is an awesome undertaking, yet such undertaking has the considerable advantages, of large numbers of potential entrants into the study. These collaborating medical centers could serve as the framework to evaluate the role. that salicylates and other medications play in the -development of Reye Syndrome. The CCC would be willing to work with the Reyc Syndrome Task Force in the development of a protocol that effectively identifies and minimizes the problems inherent in case-control epidemiologic studies. Unless these studies are performed by investigators with experience in both the disease entity and the appropriate techniques employed in studying the disease, the results may again be seriously flawed and inconsistent with the dictates of scientific excellence. PAGENO="0565" 559 May 6, 1983 Page3 The CCC further recommends that a protocol development group be formed as quickly as possible, with representation from the aforementioned groups. The protocol produced by this group should be reviewed by appropriate experts, and should allow sufficient tine for careful deliberation; at~ the same time, however, we stress the urgency of this matter, and offer our full cooperation in having the study in place by the next flu season. Specific attention should be given to criteria for the diagnosis of Reye Syndrome, the selection of appropriate con- trols, mechanisms *for the control of various forms of bias, establishment of site visits, training investigators among the various collaborating medical centers and the development of a highly detailed standard to quantitate the severity of illness. The principles enunciated in Dr. Alvan R. Feinstein's comment to the Advanced Notice of Proposed Rulemaking (Federal Register 47:57886, December 28, 1982) sets forth the specific factors that constitute a `gold standard" that must be followed rigorously and adhered to for the study to~ hold scientific validity. Furthermore, Dr. Feinstein's December 23, 1982 article in the New England Journal of Medicine reinforces the requirements of a well-controlled study. These principles must become an integral part of any case-control study. Furthermore, the CCC recommends the adoption by the Reye Syndrome Task Force of the following criteria for the diagnosis of Reye Syndrome cases to be included in the proposed study: 1. A clinical history compatible with Reye Syndrome. A. Usually a variable course of respiratory illness, chicken pox, or acute gastrointeritis. B. Sudden onset of unexplained vomiting, protracted or relentless vomiting may be present. C. An alteration of consciousness and/or progressive neurological deterioration. D. The cerebral spinal fluid examined within 24 hours of admission must contain less than 10 white blood cells per cc and be sterile. E. Association of seizures, hypoglycemia, abnormal breath- ing pattern in infants. 2. Alteration of liver function without evidence of hepatitis. PAGENO="0566" 560 May 6, 1983 Page4 A. SGOT (AST) greater than two times the upper limit of normal and an SGPT (ALT) greater than two times the upper limit of normal. B. A free flowing venous or an arterial ammonia level greater than two times the upper limitof normal. C. Prothrombin time greater than two standard deviations above the mean. D. A serum bilirubin less than three milligrams per deciliter. 3. A closed liver biopsy consistent on light microscopy with Reye Syndrome obtained within 24 hours of admission. One of the most difficult parts of this study is to cor- rectly diagnose the disease. The CCC believes that the use of liver biopsy,* interpreted by experienced pathologists familiar with the staining technique and characteristic features of the disease, is an essential ingredient for this `study, and is a prerequisite for selecting medical centers to participate in the collaborative study. Another essential factor in this study should be the extra- ordinarily difficult task of matching cases with controls. Care must be taken to insure accurate knowledge of variables, such as aspirin or other medication. If controls are allowed some degree of leeway in the predisposing viral illness, then a biased study result will occur. The only independent variable must be aspi- rin. Furthermore, it is another essential prerequisite that the cases and controls be comparably ill with the identical specific' illness. For example, cases with influenza B cannot be matched to "controls' with other respiratory illness that do not predis- pose to Reye Syndrome. Specific etiologic identification of the illness of controls as well as cases is necessary. The Reye Syndrome studies in the past includ~d cases that were clearly more ill, with higher fevers, more dehydrated and required more fluid than the controls. Varying degrees of illness of chicken pox, influenza A and B were present. These factors suggest that children with Reye Syndrome may have some predisposition, genetic or otherwise, to have a more severe prodromal illness that may result in the subsequent development of Reye Syndrome. The protocol development group may want to consider quanti- tating the severity of illness via a non-specific toxicity score" (i.e. develop a standard measure of severity as assessed PAGENO="0567" 561 May 6, 1983 Page 5 by a physician with years. of experience in the diagnosis of Reye Syndrome). In addition, we believe that to achieve a good result from this study, it is essential to involve skillful, experienced clinicians all along the way. The use of inexperienced investi- gators, armed only with questionnaires, will bias the study such that it will be rendered meaningless. Also, careful case-control matching for race, sex, similar geographical location , socio-economic and other factors must be employed. There are some experts that believe that requirements for a case-control study, as set. forth in Dr. Feinstein's article, cannot be met. We vigorously maintain that if these criteria are not met, the study is not worth doing because like earlier ones, it will generate results that are misleading and incorrect. Had the studies of the past been carried out using the principles we have listed, no dispute would exist at the present time about the role of aspirin. It is thus our recommendation and request that the Reye Syndrome Task Force, in cooperation with the CCC and Dr. Joseph F. Fitzgerald, a member of Coordinating Committee cooperate to develop a protoco~, train investigators, and implement a well- designed and carefully controlled multi-center tri~tl that attempts to answer questions relating to the possible relation of aspirin and other medications to Reye Syndrome. Furthermore, this is to confirm that the representatives of the CCC have been in contact with you relative to a meeting with the Task Force dealing with protocol design and implementation. Furthermore, we understand that this meeting will take place as soon as can be scheduled and we look forward to discussing these matters in depth with you at that time. Very truly yours, C Heinz F. Eichenwald, M.D. Chairman, Committee on the Care of Children /kmp End. cc: Arnold J. Friedhoff, M.D. John Baum, M.D. Harvey L. Chernoff, M.D. Joseph F. Fitzgerald, M.D. Burton H. Harris, M.D. Robert A. Hoekelmann, M.D. David J. Lang, M.D. James P. Orlowski, M.D. Sidney Gellis,. M.D. Neil L. Chayet, Esq. PAGENO="0568" 562 August 3, 1983 FEDERAL EXPRESS Queta Bond, Ph.D., Director Divisions of Health Promotion and Disease Prevention and Health Sciences Policy Institute of Medicine National Academy of Sciences 2101 Constitution Avenue Washington, D.C. 20418 Dear Dr. Bond: We have received the United States Public Health Service Proposal for a Study on Salicylates and Reye's Syndrome. Pursuant to your request, we have analyzed the proposed study methods and design. Our comments are set forth below. Also, as we discussed, several committee members will make an oral presentation to the Institute of Medicine's Committee on Reye's Syndrome and Medication on August 8, 1983. I will contact your office on August 5, 1983 to make final arrangements. I. Background The Committee on the. Care of Children is a group of parents and approximately 1200 physicians which was formed as a result of the belief of a number of academic and clinical pediatricians that the debate over the safety of aspirin as it related to Reye's Syndrome was not being carried on in an unbiased, scientific manner. Aspirin is the most widely used over-the-counter drug in the United States, and any claims that it may n~t be safe in certain situations cannot be lightly disregarded. On the other hand, aspirin has been viewed as a safe drug for over 80 years and any claims that it may not be safe must be examined with great care. Unfortunately, the recent debate over the safety of aspirin seems to have focused more on the motivations of the participants than on a dispassionate analysis of the studies which questioned the safety of aspirin. PAGENO="0569" 563 It. Introduction Dr. Walter Dowdle and the members of the Reye's Syndrome Task Force are to be commended for the protocol they have developed. It is carefully construct~d and represents a major effort by the members of the Task Force. We are convinced that this protocol represents a first step towards answering the questions raised in the Ohio, Michigan and Arizona Departments of Public Health studies. These studies were poorly designed, replete with methodologic flaws that invalidate their results. As summarized by Dr. Alvan R. Feinstein in his comment to the ANPR of December 28, 1982 (47 Fed.Reg. 57886), "...1 would*be reluctant to consider the evidence from these three studies as being scientifically satisfactory. The only conclusion I would draw from the studies is that more and better research, of higher scientific quality, is needed to answer the question." (Comment, p.3) The "better research, of higher scientific quality" is the objective of the IOM's Committee, the CDC, and the Committee on the Care of Children. We believe that the Task Force Protocol may be adequate, with certain adjustments mentioned below, to meet this objective. However, there are potential problems in the protocol that must be addressed before the protocol will withstand careful scientific scrutiny. These potential problems, with our recommendations, are discussed below. I II. Recommendations - ~iver biopsies must be utilized to confirm the diagnosis of Reye's Syndrome (see t~ichtensten PK, et al; Grade I Reye's Syndrome, NEJM 1983; 309:133- 9). Should the study include cases that are not Reye's Syndrome, an unacceptable degree of inaccuracy will occur. Also, the histologic material be collected in a standardized manner, and that this material be reviewed by a panal of "expert" patholo- gists prior to statistical analysis. - Serologic diagnosis must confirm that identical antecedent illnesses are present in cases and their matched controls. PAGENO="0570" 564 Experienced clinicians and scientists at tertiary care medical centers should perform this study, to insure the diagnosis of Reye's Syndrome and the careful nanagement of the study. Using medical centers would enhance the quality of the study and the validity of the results. CDC control could be readily maintained through on-site visits, spot- checking of interviewing techniques, etc. Also, a multicenter study in progress has been funded by the NIH, which will examine two treatment protocols on outcome of children suffering from Reye's Syndrome. These same participating medical centers could perform this salicylates and RS study in a less expensive, more thorough fashion than other centers that do not have a study on Reyes Syndrome study. in place. Local departments of public health should not oversee this study. We respectfully submit that local public health participants are very likely infected with observer bias in ligh of their participation in the prior CDC studies in Ohio, Michigan and Arizona. The criticisms these officials were subjected to during critical analysis of these studies makes them unacceptable directors of this study. The interviewers must be blind to the research hypothesis. Otherwise, unacceptable bias will result. The attending physician, rather than a public official, should contact the "case' requesting enrollment in the study. The protocol does not call for the physician to be notified that his patient is to be enrolled. Such an oversight could create a situation where parents are asked to enroll their child in a study when they are not emotionally. equipped to answer the questions asked by the interviewer. Prior physician approval must be sought. The primary care physician for the "control" should also be notified before any serum samples are taken. The physician should draw blood samples from very young patients. PAGENO="0571" 565 - The "controls" and physicians caring for the cases devote an appreciable amount of time to this study. It should be considered whether to pay these individuals for their efforts. IV. Conclusion We recommend that the strictest possible criteria be generated for the selection of cases and controls for entry into this study. Cases must be evaluated by skillful clinicians, experienced in the recognizing of Reye's Syndrome. In addition to a compatible clinical course and the meeting of necessary laboratory criteria, histologic analysis of tissue obtained by percutaneous liver biopsy must be performed. All cases and matched controls must have the same predisposing, antecedent illnesses as determined by serology. In addition, we recommend that this study be conducted in a medical center setting, where experienced physicians will actively participate to see the study through to completion. Please call me or other members of the Committee on the Care of Children if we may answer any questions. Very truly yours, Heinz F. Eichenwald, M.D. HEE/ral Enclosures PAGENO="0572" 566 NIH, Japanese Studies Fail To Back Aspirin~Reye's Tie Mr,!, :1 Tr,hun, Rrp~~r~ Sr. Louis - Scientific presentations at the recent National Reye's Syndrome Foundation (NRSF) annual meeting here gave little attention to and no support for the connection proposed by case control studies last year between salic~ ate use in children and development of Reyc's syn- drome (RS). An "education campaign" had bei!n launched in 1982 by the Surgeon General warning the public not to use aspirin for children with varicella or influenza-like illnesses. A warning label on salicylate- containing products had been proposed but was not put into effect when questions about the validity of the data in the studies arose and the Committee on the Care of Children, a group of leading pediatricians. sought a federal court injunction against issuance of the label (MT. Jan. 26). The Centers for Disease Control (CDC) has not yet issued a morbidity and mortal- ity report on RS cases for 1982-1983. Ilowever. a chart of cases and mortality reported to the NRSF front December 1. 1982 to June 15. 1983, available at the meeting, listed ~4 eases and 27 deaths. Ohio topped the listwith 26 cases. two fa- tal. while Michigan and Texas followed with nine and seven, respectively. One tzL- tality occured among the former and four among the alter. I Itiwever, ni" inedtcatton use data were supplied, and difficulties in positive diag- nosis make interpretation of the statistics difficult. Dr. George Ni. Johnson. of Far- go. NI).. discoverer of the syndrome in the United States, commented that ``a ma- jor vuricella outbreak in North Da~ota has produced no KS cases" in the state. Ile noted th.ii this agreed with other investiga- tors' earlier suceestitins that RS was con- nected in sonic w a> with tnlltieni;i- U. whi~h did not prisitrec a major outbreak in the United .States this winter. Two preliminary reports at the meet- ini.!--sille on a n;ttittitwidc su~ cy of f 3 )j~f pediatric clinics in Japan (where KS l)ic- ~ioiisl~ has been reported) and the otherin a National Institutes of I Icalth study coot- pat tug l<.S sur~ us ors and heir un.tf fcet.d I iintl~ tttcmber~ in their ability to ``handle suhtcvlates'' - tutfered no cvid..'nec It) stp- port a salicylateiRS connection. Dr. Fumio Yamashita, a rnembef of the Japanese Ministry of Health's RS study committee, explained that the survey gath- ered information on both RS and "acute encephalopathy of obscure origin" to compare aspirin intake between the groups. Using CDC criteria for RS and de- fining the other group as having similar symptoms without SGOT and SGPT ele- vations, the investigators found the peak incidence of both to coincide with the height of a six-month influenza-B epidem- ic over 1981-1982. According to the Kurume University pediatrician, 54 RS and 75 acute encepha- lopathy cases have been reported, with confirnied aspirin intake in just 9.3% and 89~ of cases, respectively. Investigators are now following up on the 1 1% of both types of patients w hose drug intake is `un- known" and the 26% and 32c~, respec- tively. of patients on whom drug usage in- formation is "uncertain." Nearly half the reported KS cases had received nonste- roidal aitti-inflanintatory agents and anti- consulsants, as well as antibiotics. No drugs were given in 20.4% (if the RS cases, and in 29.3% of the acute encepha- lopathy cases. Dr. Yamashita concluded, "If this rep- resents the accurate incidence of salicylate usage. these drugs may not be a major nsk factor itt the paihi genesis of KS in Japan." L)r. Anita 1). (itu, NIH, reported on the first five KS surs i'~ors she tested for their response to.ispirin. compared to their non- RS fantily nietitbers. 11cr conclusion: "RS patient survivors did not have any difficul- ty handling safie> lates after their illness." Administration of' aspirin at 10, 20, and 30 nsg'kc a day, built up over a six-day hopitaf sta> . pri~lu~~d no clinical. hio- henncal . or hctii;itofog i~il ahuii'uiialittes, anti neither seruiti nor urine salicylate fey- cia differed significziiitly between the for- liter KS patients and fantily members. Neuropsychotogical tests revealed no sig- nificatut difference between R~ patients and their siblings. l'attents diii have higher intihod\ tiicr~ iii sariLelfi. incastCs, intlu- en.~,i- \. .iitd l~' k in Ran virus, and ``there 5' as no dicasi.' .issi ciatton with Ill .:\ i> )C. * [lie stud~. u eiiotiuiuing. PAGENO="0573" 567 ~p,c~czbIJ 4~JERAL Iaign, stare fran an underlying deficiency in the IDA's standards and procedures. Id., at 1-2. ~i the basis of this, and other opposition to the PDA's proposed warnings, the FDA's campaign to warn the public of the purported association betwaen aspi.rin and Reyes Syndrcxre is being reviewad and undoubtedly will be revised, pending the outcane of further scientific studies initiated by the Goverrrnent. It is always easier to state, in hindsight, that a particular publicity campaign was improper or excessive. Witness the 1959 contaminated cranberry publicity cairpa.ign and the 1979 nitrite publicity campaign. Howaver, had these proposed regulations, including the standard on reliability, been in effect prior to the aspirin/Hayes controversy, unwarranted publicity concerning a highly tenuous danger to public health might have been mitigated or avoided. Prior `to the publicity campaign, the FDA would have been required to determine whether the studies net generally accepted scientific standards for rrethodological and statistical significance. Upon that determination, a contrary decision with respect to the need for publicity may have been reached, and much needless public anxiety prevented. Standards for the Content of Publicity These proposed regulations establish standards for h~ the Agency crafts its publicity which must be net before the agency' issues publicity. Operating under the asstrrption that preventing PAGENO="0601" 595 misinterpretations and exaggerations of public announcetents is better than trying to ccrçensate parties after the fact, this standard helps the FDA tailor its publicity so that it achieves its intended cennunication. Agency rules regarding the content of press announcet~nts should vary depending on the ccxrplexity of the agency action, the sophistication of the likely aedience of beth the lreediate reporters as well as the ultinate readers and viewers - and the possibility of harm... .Agency rules should also indicate the proper tencr and format of publicity anno~mce~nts. Gellhorn, at 1430. There are nmny instances where, even though the content of a cont~rplated announcenent is literally accurate, the phraseology, timing of the release, or ncde of dissenination is likely to exaggerate or minimize in the mind of the public the significance of the iressage intended. These standards wettld require the FDA to take steps to minimize this possibility, and in sate instances, to refrain altogether fran issuing such a provocative announcErent. The recent aspirin/Reyes controversy illustrates the need for these standards. At best, the stndies relied upon by the FDA indicated a possible "association" between aspirin use and Reyes ~Syndrare. As part of the publicity carrpaign waged by the governirent, the Surgeon General in 1982 nade public service radio announcerent recordings explaining that there may be an association between Reyes Syndrane and aspirin, and sent approximately 8,000 copies of these radio anriouncenents to radio stations. (47 F.R. 57886 at 57897). However, the public's reaction to these am nanrents deronstrated its general inattentiveness to the scientific distinction between "association" and "causal relationship." The fact that the public (infers) .. .the causal nature of an association, has been det~n.strated by the effects of the FDA's "educational" progran regarding ~SA and RS. A PAGENO="0602" 596 pilot personal intercept interview study, c~thucted by Becker Research Corporation and carrnissioned by ~C, ocnfimt~ these fears.. .In the Becker study, one hundred three respondents ~re asked to listen to a taped massage fran the Surgeon General. Dr. Koop addressed the possible association bet~e.n PS and the use of ASA in children under 16. ~ respondents consisted of parents with children under 16.. .The objective of the research project s~~s to dete~nine parents' under-tanding of the Surgeon General's massage. After hearing the msage, 40% of the respondents stated that they believed that ASA causes PS. In addition, 43% of parents believed that if they did not give ASA to their children, they oculd prevent the developr~nt of PS. fl~se effects are oonsiste.nt with the experience of the ~ Coordinating Carinittee n~i±,ers, ~ have faced ntsrerous parents frightened by the publicity of the Goverrn~nt. The parents have responded to the Goverrsrents publicity canpaign in an irrational fashion rather than understanding the subtleties of the statistical "association". A survey of press coverage of the ~ "educational" caspaign confinns this unintended result.. .For exairple, in an article a~earing in the New York Timas on Nov~iiber 17, 1982, Jane Brudy, an e~~rienced health reporter, makes the stat9zEnt that "the only kna~'n possible preventive (of PS] is to avoid giving aspirin (salicylate) and rredications containing aspirin to children with viral illnesses... "Thousands of newspaper articles have been written which misinterpret the maaning of "association", encouraging parents to prevent PS by avoiding ASA, which, according to the newspaper accounts, has been sha~n by studies to "cause" PS. CtC Carmant, at 22-23. The public reaction to the Surgeon General's massage was predictable. It ~u1d not have been difficult for the governrrent to pretest its publicity massage prior to the news releases. The FDA, UJ~e any goverrre.nt agency, has an obligation to carrrn.micate in a manner that conveys accuracy in the public' s cat~rehension of FDA massages. These proposed regulations require the FDA to consider alternatives to publicity in achieving its goals. The Adeinistrative Conference reccznrethed in 1973 that "where public hann can be avoided by irrirediate discontinuance of an offending practice, a respondent should be all~ed PAGENO="0603" 597 an opportunity, where feasible, to cease the practice (pending a legal test) in lieu of adverse agency publicity." (38 P.R. 16839). ?dverse publicity often constitutes a deprivation not subject to effective judicial review, and therefore, should ho exercised only as a last resort if necessary to achieve a ccspelling public interest. I*~/PDA policy is "to avoid publicity that might adversely affect persons or organizations where a reasonable and equally effective alternative is available, (such as] . . .the discontinuance of a violative practice, ccxrbined with an effective recall of violative products fran the marketplace." (42 P.R. 12436 at 12439). `ft~se proposed regulations require the FDA to choose the least obtrusive rrethod of dissemination of its public massage, geared toward the narr~st audience possible for the carounication to be effective. ¶ihose regulations require the FDA to determine, first, the narr~sest audience it oust reach (e.g., physicians, pharmacists, hospitals, specific groups of the public, general public, etc.), and second, which nethod of dissemination will effectively reach that particular audience, but no further. Since a physician ~vuld be less likely than the general public to exaggerate the neaning of a specific warning, such as the "association" between aspirin and Peyes Syndrare, targeting specific massages toward specific audiences will be ouch trore effective in actually protecting the public. In the aspirin/Reyes controversy, for exasple, it quickly becare apparent that: The FDA.. .has no standards to determine whether a warning should be directed to the consuner of the nedication when he may be unable to determine whether he is at risk fran the hazard which pratpted the warning and unable to assess the significance and magnitude of that risk. Z'breover, where, as here, the subject of the proposed warning is a drug which has been widely utilized and studied for many years, the FDA oust consider the PAGENO="0604" 598 possibility that any warning will cause consi.sre~rs to shift to less ss~ll-kr~jn or less wall-studied drugs,. ~. [and result] in fear and confusion in the mind of the public. CCC CclTlrent, ~ at 2-3. N~ that the whole issue of whether there even is a statistically significant association betwaen aspi.rin and Reyes Syndrare is being restudied by the Governrrent, it is evident that;the publicity issued in connection with aspirin/Reyes was excessive. If nothing else, the ITanufacturers of salicylate-containing products have been ecor~nically damaged, patients question their physicians' advice to use such products, and the FDA's stature has diminished in the eyes of the public for "j~n~ing the guns. These proposed regulations are intended to avoid similar situations. Pi~vance Notice In accordance with the rec~rrr~ndations of the ~ninistrative Conference these proposed regulations provide for advance notice of proposed publicity to interested persons. ~ purpose of advance notice is t~fold: 1) to provide interested persons an opportunity in advance to prepare a response to such publicity; and 2) to provide interested persons an opportunity to catrrent on such publicity prior to its issuance in order to insure its accuracy and fairness. The class of persons entitled to advance notice under these regulations is broader than the car~a.rable class entitled to notice in }~S regulations (45 C.F.R. 17.1 et. ~.) governing adverse publicity, in that it includes any person who is likely to be, or in fact, adversely affected by the issuance of publicity by the FDA. This could include for exanple, rt8nufacturers of identified products, as wall as physicians who prescribe such products. These regulations are also broader than those governing publicity fcor~rly considered by the FDA PAGENO="0605" 599 (42 F.R. 12436) in that they require that advance notice be provided in circunstances where publicity, as defined herein, is contarplated in ounjunction with proposed rulanaking. Notice of contariplated publicity shall be by publication in the Federal Register, and/or such trade publications, joum~als and newsletters, as deened necessary for effective notice. The requirer~nt of providing advance notice of publicity serves as a procedural elerr~nt of due process protection for these liicely to be adversely affected by the ountariplated publicity. These regulations irrp~se on the FD?~ the further requirar~nt that the notice itself be carefully s~vrded so as not to precipitate a pranature public reaction. Therefore, the actual text of proposed publicity should not be included in notices. As previously indicated, one of the major reasons cited by the Mninistrative Conference for requiring advance notice of contemplated publicity is to afford those likely to be adversely affected "a reasonable opportunity to prepare in advance a response to such publicity." (38 P.R. 16839). The value of a response to publicity should not be underestinated. When a fire believes that ~ will be issuing publicity about its products or activities, immediate contact with the agency's Press Office by a professional public relations person on behalf of the fire is vital. Defensive releases, the s~rding of the PDA release, the nedia likely to be used, facts which undereine the agency's case, etc., are aLl. elements to be considered in defensive publicity. Since pi~licity bearing the official PDA stamp of approval often makes headlines, the finn should be prepared to irrirediately respond with its side of the disputed story, lest a next-day correction be buried on an inside page or anitted entirely fran the news. O'Reilly, James T., Food & Drug ~deinistration: Regulatory Manual, S22, at 47-48. (Sheppards 1979). PAGENO="0606" 600 These proposed regulations insure as ~ll that the FDA, as a result of the participation by interested parties, will be able to provide the public with full and ~ll balanced information. Retractions and Corrections m'ese proposed regulations establish procedures for the retraction and correction of FDA publicity that is shown to be erronecus or misleading. Similar statutory provisions require the Cons~.rtEr Product Safety Camdssion to take reasonable steps to publish a retraction of any inaccurate or misleading thfo~tion it had publically disclosed. 15 U.S.C. 2055(b) (7). The Aáninistrative Conference re~rrrended specifically that agencies issue retractions or corrections "in the sane manner (or as~close thereto as feasible) as that by which the original publicity ~as disseninated." (38 F.R. 16839). The proposed regulations require that a retraction or correction "be issued in a manner likely to reach those persons who received the original inforn~tion to the extent. this is reasonably feasible." The goal of reaching the sane audience with the new information, rather than siirply issuing a new statetent in the sane manner as the damaging staterents, is n~re likely to have the desired effect, and is consistent with the original FDA proposal for regulations governing agency publicity. (42 F.R. 12436 at 12441). Upon petition of a party adversely affected by FDA publicity, the FDA shall expedite the request for retraction or correction of erroneous or misleading publicity, so as not to vitiate its effectiveness through delay. In addition to correcting ioproper FDA publicity, these regulations provide for the Carrnissioner to seek corrective publicity in cases t~there PAGENO="0607" 601 the fault of misinterpretation or exaggeration lies with third parties. This discretionary approach was specifically proposed by the FDA: In cases where infontation by FDA has been misinterpreted by other persons or presented by the rredia In such a way as to be misleading to the public, the agency will ~sider the issuance of clarifying infonration. Although the agency is net responsible for publicity generated by an outside source that is adverse to a finn or product, the Ccxanissioner nay seek corrective publicity at his ~~in discretion, or at the request of the adversely affected party, if the agency has infonration available that ~.ould indicate that such publicity was grossly misleading to the public and that it ~uld be in the public interest. (42 F.R. 12440) In light of the Inçortant role that FDA publicity plays in generating public interest and Jc~.ilodge in matters of public health, it follovs that issuance of responsive publicity - to correct unwarranted public reactions injurious to particular persons, firms, professional groups or products - ~uld be equally inçortant in furthering FDA objectives. Conclusion In the absence of legislative or julicially iirposef guidelines governing the FDA's issuance of publicity, these regulations respond to the persistent cry for such control: "Unless the public `need' for an irrrrediate anno(mcmrEnt is substantial, the ideal procedure ~u1d be to postpone agency publicity which is likely to have a significant and adverse ispact until the naned respondent has had an opportunity for a hearing." Gelihorn, at 1429. Likewise, a manufacturer of a product maligned by improper publicity nay 1~e "cond~rned by publicity without a hearing or any other s~rblance of due process." Z~brey, at 177. These proposed regulations parallel the statutory provisions governing the release of information controlled by the Consuner Product Safety Act. 15 U.S.C. 2051 et. ~. Under the Act, the Consuaer Product Safety Connission may publicly disclose info~tion adverse to a manufacturer PAGENO="0608" 602 only after providing notice of the proposed disclosure and an opçortunity to subeit canr~nts, and after assuring itself of the accuracy of its infontation and the fairness to the rranufacturer of the publicity. 15 U.S.C. 2055(b) (1). Upon satisfying the proposed requirarEnts, the FDA ~u1d issue the proposed publicity. The detennination of the issuance of publicity sha.U co~rstitute final agency action for the purpose of appeal. An aggrieved party may challenge the FDA detennination in a court of ca~etent jurisdiction. Effective reviecq will be rrade possible by the existence of these regulatory standards and of a record of the FDA's fir~ings that ~re required prior to the issuance of the publicity in question. C. ~VII~r~]AL IMP~C~ Petitioner relies on the FDA's Proposed Policies and Procedures for canpliance with the National flivirorsrantal Policy Pct (NEPA), published Tuesday, Dec~nber 11, 1979, 44 Federal Register 71,742, providing for an exaiption to the requirarent for an envirorritEntal ispact analysis report. specifica-1.ly, petitioner relies on proposed 21 C.F.R. §25.23, Actions That Are ~c1uded Fran the Requiretent For the Preparation of An ~ivirorutental Asses~e~: (c) An applicant or petitioner requesting action of a type subject to categorical exclusion under §25.24 is not required to suheit an envirorsrental asses~rent if the applicant or petitioner specifies the provision of this part that exeopts the action fran the requirarent for an envirorrrentaJ. asses~rent and provides infonration that establishes to the agency's satisfaction that the action requested is incleded within an excluded category and rree~ts the criteria for the applicable categorical exclusion. §25.24 Catecorical ~cclusions provides: PAGENO="0609" 603 (a) General actions belonging to any of the classes designated in paragraph (b) of this section as categorical exclusions nornally do not require the preparation of an envirorrr~ntal asses~nt, because, as a class, they will not result in the production or distribution of any substance and, therefore, will not result in the introduction of any substance into the erlvirorlnEnt. (b) ~ctions of any of the follc~ing classes are categorically excluded: (1) ... (C]onduct of public affairs activities... (4) Liasai functions with.. .the public, and iedustrial finns or organizations. (9) Publication of notices in the Federal Pegister. (12) Issuance of procedural or adeinistrative regulations. This patition for the adoption of procedural or adoinistrative regulations governing the issuance of publicity fran the FDA falls squarely within the categorical exclusions entzrerated in §25.24(b). Petitioner relies as ~U upon the FDA' s prior deternination that an envirorsrental ixr~act stat~rent is not required in conjunction with a proposal for regulations governing FDA publicity. In the FDA's stat~nt of Publicity Policy in connection with proposed publicity regulations published Friday, March 4, 1977, 42 Federal Pecister 12,436, 12,440, the FDA stated: ~ Carrnissioner has carefully considered the environxrental effects of the proposed regulation and, because the proposed action will not significantly affect the quality of the h~zren envirorn~nt, has concluded that an environrrental iopact stat~rEnt is not required. As the regulations proposed herein are identical in nature to those originally proposed by the FDA, this exclusion likewise a~lies here. D. ~c~a~iic i~cr `Not applicable as of filing date of this petition. 52-266 O-85--20 PAGENO="0610" 604 E. ~~ICP~TI~ fl~ ur~ersign~ certifies, that to the best ]c~*tl~ge and belief of the uthersigned, this petition includes all irtfont~tion and views on which the petition relies, az~ that it includes reprsentative data and info~tion Ja~n to tha petitioner which are unfavorable to the petition. (Naire of Petitioner) C~4ffIT~ (~ ~ CARE CF Q~DREN 50 Milk Str~t (Mailing Address) Boston, Massachusetts 02109 (Telephone Ntrnber) (617) 451-0803 By Its Attorneys: Michael X. fr~rrell Neil L. O~ayet Henry T. Golc±r~an Peter A. Weasel ~ & STA~CP(LE 2121 K Street, N.W. Suite 750 Washington, D.C. 20037 (202) 861-6200 PAGENO="0611" 605 UNITED STATES DISTRICT COURT - FOR THE DISTRICT OF COLUMBIA CIRCUIT PUBLIC CITIZEN HEALTH RESEARCH GROUP, Plaintiffs, V. ) Penn., 3. DR. FRANX YOUNG, Commissioner, ) Civil Action No. Food and Drug Administration, ) 82-1346 Defendants. Defendants' Answers To Plaintiffs'lnterroga-tories And - Document Production Req~uest Interrogatory 1(a): Set forth in detail all reasons why the Food and Drug Adiainistration.(~FDA") has not issued a final decision concerning whether or not salicylate-containing drugs should be labeled to warn about the association between salicylates and Reye's Syndrome. Answer: The major reason FDA did not issue a final decision concerning whether or not salicylate-containing drugs should be labeled to warn about the possible association between salicylates and Reye Syndrome is that there is currently uncertainty about whether the reported statistical associa- *tion between Reye Syndrome and aspirin has any reasonable clinical significance. A statistical association does not necessarily imply causation. It can be a result of an PAGENO="0612" 606 artifact of the study methods used or the reported association could be a result of other unidentified factors which are independent of a causal relationship. These possibilities raise uncertainties about the propez interpre- tation of the scientific studies and there is a reasonable likelihood that the study now underway and described in more detail below will resolve that uncertainty. The current uncertainty about the possible association between Reye Syndr~one and aspirin is reflected in the November 8, 1982 statement of the Executive Board of the American Academy of Pediatrics ("AAP"). The AAP stated that while "there should be cautious use of any antipyretic medi- cation in the treatment of influenza or chickenpox[,]... [the Board didj not feel that labeling aspirin-containing preparations as being contraindicated in these illnesses is in the best interest of children or the practice of pedi- atrics.~~ This statement, represents the first expression of doubt by an independent scientific body concerning the need for a label warning on salicylaté-containing drug products. While the agency is not bound by the P~AP statement, the statement could not simply be ignored. The, AAP is the domi- nant voice representing the nation's pediatricians. The AAP statement caused the agency to rethink its position regarding the label warning and is primarily responsible for the PAGENO="0613" 607 agency's decision to seek additional studies before making a final decision on label warnings. It should be emphasized that the FDA is now and was in November of 1982 well aware of the disagreement bçtween the Committee on Infectious Diseases of the American Academyof Pediatrics and the Executive Board concerning the November 8, 1982 statement. However, the Executive Board speaks for the AAP and the agency considers the November 8 statement to represent the views of the AAP. In view of the lack of con- clusive data on the possible causal relationship between Reye Syndrome and aspirin, the agency is not surprised that there is some difference of opinion between scientists within the AAP as to the approach adoptad by the Executive Board. Indeed, the agency was in November of 1982 arid is now aware of considerable disagreement in the scientific com- munity as a whole concerning whether the evidence suffici- ently establishes a clinically significant association between Reye Syndrome and aspirin. The agency believes that these disagreements between reputable experts emphasize the uncertainty of the current data. It is therefore prudent to await the results of the additional study that is now .underway before issuing a final decision on whether to require label warnings. The uncertainty about the adequacy of the four epidemi- ological studies on Reye Syndrome is reflected not only in PAGENO="0614" 608 the disagreement among prominent and qualified experts, but also in the scientific studies themselves. While the agency emphasizes that it does not consider all of the studies to be scientifically invalid, there are deficiencies inthe design and implementation of the studies that lessen the confidence that can be placed in the results of the studies. These prominent deficiencies include the following: (1) lack of formal protocols defining the study rules; (2) lack of comparability between cases and controls as to time between illness onset and interview; (3) lack of consistent and comparable verification of medication brand names and recording information from labels; (4) lack of data collection and analysis in such a way as to be confident that the medications were being used for the treatment of the antecedent illness rather than Reye Syndrome; (5) lack of sufficient characterization of the ante- cedent illnesses to demonstrate that the controls had illnesses of severity comparable to that of the antecedent illnesses in the cases; (6) reliance on school absentee lists to generate matched controls with the consequent uriderrepresent- ation of pre-school children and chic)cenpox associ- PAGENO="0615" 609 ated cases (which has peak incidence in late spring and summer); and (7) lack of adequate precision in disease diagnosis to be confident that all cases truly had Reyes Syndrome. -` The agency is also aware that the reported association between Reye Syndrome and salicylates might be explained by the use of salicylates for treatment of the symptoms of Reye Syndrome. Although this hypothesis has not been proven, neither has iTt beer~ ruled out. The deficiencies enumerated above were known to the agency at the time it initially decided to propose a label warning for salicylate-containing drug products. The agency was nevertheless willing to rely on these studies because of the then perceived broad support of the scientific coimnunity. When the AAP issued its November 8 statement, however, the scientists and policyi~iakers within FDA gave credence to the statement and re-examined the issues. The agency's concerns about the deficiencies in the studies were thus amplified. Considering the deficiencies in the studies, the disagreement inong experts, and the position of the AAP, the agency concluded that the conduct of an additional study was necessary before a final decision on the need for label warnings could be made. PAGENO="0616" 610 The agency emphasizes that it has not totally rejected t~e scientific studies completed to date. Indeed, these studies form the basis for the agency's decision to go for- ward with a public education campaign. The agency believes that at the present time the public education campaign is adequate to inform parents that they should consult a physi- cian before administering aspirin or any other medication to their children to treat flu or chickenpox. The decision that the current scientific data are ade- quate to support an educational campaign, but not suffici- - ently certain for a final decision as to whether a label warning is necessary is obviously one that involves a large degree of judgment. The agency is aware that in certain cir- cuxustances suggestive but not conclusive data may be suffi- cientto support a regulatory action such as the one sought here. In exercising its judgment in this instance, the agency has considered carefully the sufficiency of the current data and the likelihood of possible harm from a delay in making a final decision. The agency has concluded that the likelihood of harm from a delay -- in light of the ade- quacy of the public education campaign as an interim measure -- is minimal and that the need for additional reliable data to resolve the current controver~y is significant. Because the agency believes that such data can be generated in a reasonable period of time, the agency has concluded that it is in the public interest not to make a premature final decision as to the need for a label warning and to instead wait until an additional study is completed before making such a decision. (The precise timetable for the ongoing study on Reye Syndrome is set forth below in Answer to Interrogatory 1(b).) PAGENO="0617" 611 The above is a portion of a document filed under the penalties of perjury by: Joseph P. Mile associate Commissioner for Regulatory Affairs Food and Drug Administration Margaret A. Cotter Assistant Director Office of Consumer Litigation Gerald C. Kell Attorney: Office of Consumer Litigation - Civil Divi~iom - U.S. Department of Justice It reflects the question of interrogatory 1 (a) and the answer thereto. PAGENO="0618" 612 1. SCIENTIFIC STANDARDS AND REQUIR~ENTS IN AN EXPERL~NTAL TRIAL OF A THF.RAPEUIIC (OR OTHER) MANEUVER Baseline Criteria: *Zero-time: date at which an appropriately eligible person is randomized for start of treatment. *Eligibi]it~: persons treated at zero time must have suitable clinical condition, warranting treatment. .Temporal precedence: treated persons must have no baseline evidence of an "adverse event" whose later diagnosis might be ascribed to the treatment. 2. SCIENTIFiC STANDARDS AND REQUIRENENTS (cont'd) Baseline Similarity: Treatment assigned by randomization, so that compared groups will be similar in clinical severity and prognostic susceptibility to outcome event. Identification of Treatments: Determined by ongoing inquiry, as treatment is received, before occurrence of outcome events. Identification of Outcome Events: Objective (or "double blind") methods to avoid bias caused by knowledge of preceding treatment. 3. SCIENTIFIC STANDARDS AND REQUIRL'ENTS (cont'd) Avoidance of "Transfer Bias": Follow-up obtained for all eligible people who are treated, so that outcome events represent full spectrimi of occurrences. Results are reported and analyzed for everyone, with no arbitrary exclusions. Quality of Data: Check for observer variability and errors in getting data, and in converting raw observations to coded classifications. Institute improvements when problems are noted. PAGENO="0619" 613 4. SU~O~ARY OF SCIENTIFIC STANDARDS AND PROBLEMS STANDARD CURRENT PBS PROTOCOL Zero-tine `Not specifically identified in both "cases" and `controls'. Eligibility `Status cannot be determined in absence of zero time. Temporal `Case group may include "monophasic" Precedence cases whose treatment was given for early manifestations of Reye's Syndrome. 5. SUMMARY OF SCIENTIFIC STANDARDS AND PROBLEMS (cont'd) STANDAB CURRENT PBS PROTOCOL Baseline `In absence of a zero-time to denote Similarity baseline, baseline states cannot be clearly identified or compared. sIn choosing treatment, parents or pediatricians may use different criteria that are not considered or accounted for. `Baseline "severity" cannot be well demarcated from check lists of unstandardized daily ratings for diverse clinical attributes, or from "matchings" based on fever and etiol~gic diagnosis of baseline state. 6. SUMMARY OF SCIENTIFIC STANDARDS AND PROBLEMS (cont'd) STANDARD CURRENT PBS PROTOCOL Identification `No specific strategy (e.g. separate of Treatments control group) used to avoid (or detect) "recall bias". `In absence of a demarcated zero-time, when did "treatment" begin? `What dosages, cc~binations of agents, or sequential changes in pattern will constitute "treatment" with a particular agent? PAGENO="0620" SUMMARY OF SCIENTIFIC STANDARDS AND PROBLDtS (cont'd) - STANDARD CURRENT PHS PROTOCOL Identification of Outcome Events `Although false positive diagnoses will be checked, what will be done about false negative diagnoses in borderline cases deemed negative because they did not receive a suspected drug? `Cases reported to State Health Departments may not represent true clinical spectrt~ of the disease. `Bias is created by excluding "controls", but not "cases", with chronic illnesses requiring salicylate treatment or frequent visits to physician. Quality of `Despite careful attention to many Data issues in quality, problems in observer variability or errors are difficult to monitor, detect, and correct in pre-coded data forms. 614 7. Avoidance of Transfer Bias PAGENO="0621" 615 ?rHEUNWERSfrV~,TEXAS H~EDKLLAS s+Nv1.E'3TERJe M4D~NOO. A TM N .A/~... f ~4i~ Si t'~'~ti DALLAS. TEXAS 75235 August 10, 1984 TELEP7IONE(214)61$.3112 Dr. M. Harry Jennison Executive Director American Academy of Pediatrics 1801 Hinman Avenue Evanston, IL 60204 Dear Harry: Thank you for taking time from your busy schedule to meet with the group from the Committee for the Care of Children. In accordance with your request, I am listing some of the major objections raised by panel members of the Institute of Medicine Committee , CCC consultants and myself, to the protocol developed by the PHS for its planned study of Reye Syndrome and its relationship to aspirin administration. None of these suggestions appear to have been accepted. It should be pointed out that the voluminous document containing the protocol was received only seven days prior to the meeting of August 7 and thus detailed analysis was not possible, especially not of the various ques.tionnaires that had been prepared. The ~ objections are the following: 1. Definition of cases. The so-called CDC criteria have been demonstrated to overdiagnose a substantial number of cases (20 to 25%); the proportion of under- diagnoses remains unknown. The PHS proposes to continue to use the present criteria. I presented some of our own data that clearly show their lack of speci ficity. 2. Whether a case i Reye Syndrome will be judged by a committee (membership unspecified) reviewing unspecified documents (hospital records?). It is my under- standing that they will be asked to classify cases as "yes" or no"; obviously there will be a sizeable group of "maybe's" but apparently no provision is made for this. Similarily, cases verified by liver biopsy will not be separately analyzed. 3. The concept of "zero time' is absolutely crucial to the performance of a study of this type (as explained in written material prepared by Dr. Alvin Feinstein). No provision is made for this in the PHS protocol. PAGENO="0622" 616 * Page. No. 2 Dr. N. Harry Jennison August 10, 1984 4. It is impossible to estimate when Reye Syndrome begins in monophasic cases and thus the relationship of the illness to medication cannot be determined. The PHS will include monophasic cases and will not analyze this group separately. In addi- tion this group of patients seems to include a substantial proportion of cases that are not Reye Syndrome. It is our belief that patients showing a biphasic clinical course represent the only group suitable for analysis. 5. In order to match cases and controls, it is necessary to match them for severity of the prodromal Illness. The PHS plans to develop `a severity index after the study has been completed, using the data generated, which is, of course, entirely improper from a statistical standpoint. 6. One of the three state health departments chosen for this study is Ohio. As you know, this organization has been severely critized for its activities during the so-called `Ohio Studies," because arbitrary exclusion of cases occurred as well as other serious data errors which have never been satisfactorily explained. The IOM Committee had specifically recommended that Ohio should be excluded from any parti- cipation. 7. Recommendations for changes in the protocol made by the American Academy of Pediatrics and by the IOM have, in general, been disregarded. 8. The results of the preliminary study which was designed to identify various problems will not be fully analyzed or be available in detail until October 1 or later, yet the PHS will submit the `final" protocol to the 0MB on September 1, a date which, for all practical purposes, means that no action can be taken at this time to incorporate any suggestions for significant changes. The ION Committee indeed was told that no extensive changes can be made, so the whole meeting of August 6 was an exercise in futility. 9. The preliminary study performed by the PHS generated some strange numbers: the mean age of the patients with Reye Syndrome was over 10 years, the mortality rate was 25% (compared to the less than 5% found in the second Ohio study). No attempts were made to explain these findings or to determine why the proportion of severe cases in the preliminary study was considerably greater than that recorded in other investigations. It is our belief that the proposed PHS study will not be the definitive one that has been promised but once again data will be collected that can be manipulated to pro- vide any desired answer. It is particularly worrisome that few, if any, suggestions from the IOM, the AAP, or the CCC have been incOrporated into the protocol and that the door is now closed to any further discussion or changes. All of this has created the impression that the PHS is not interested in discovering the truth but only wants to justify previous recommendations and activities. PAGENO="0623" 617 Page No. 3 Dr. M. Harry Jennison August 10, 1984 I would, of course, be pleased to furnish any additional information that you might require. With warm regards. Sincerely, L.. ~ Heinz F(Ei~chenwald, M.D. William ~t~chanan Professor of Pediatrics HFE/ag cc: Mr. Neil Chayet PAGENO="0624" 618 GASTON SNOW &ELY BARTLETT COUNSELLORS AT LAW ONE FEDER~~L STREET BOSTON, MASSACH CS ITT S 0~ 10 617/420-4t,00 FEDERAL EXPRESS December 6, 1984 Eugene S. Fturwitz, M.D. Medical Epicemiologist Center for Disease Control 1600 Clifton Road Atlanta, Georgia 30333 Dear Dr. Hurwitz: I am very pleased that we had the opportunity to talk last Friday and discuss in some detail matters related to the Reye Syndrome Controversy. I would like to note that our telephone conversation was precipitated by a call from you last Friday morning which I returned a few hours later. You began our discussion by inquiring as to the starting date of our study and requesting a copy of the study protocol, which is enclosed with this letter. I will be meeting with Drs. Feinstein and Horwitz in New Haven next Tuesday, December 11, to discuss additional details and updating of the protocol; we further anticipate that the Coordinating Committee of the Committee on the Care of Children (`CCC") will be approving the final documents in the very near future. You also inquired as to the starting period. At the present time it is our intention to mail to all pediatricians inthe country as soon after the first of the year as practical. we are at the present time working on the final stages of securing funding for the study, as well as establishing an independent scientific advisory committee and a special International Science Exchange oversight committee. The basic policy for the study will be governed by the CCC Coordinating Committee, the scientific advisory committee and the Yale University Group, all of which will remain fully autonomous on all policy matters. We will notify you as to the PAGENO="0625" 619 GASTON SNOW & ELY BARTLET actual starting date as soon as it is set. I would note parenthet- ically that even with the full resources of the federal government and the assistance of the Institute of Medicine, it took longer than expected to get the government study underway. Suffice it to say that the CCC Coordinating Committee, the International Science Exchange and all interested parties are desirous of commencing this study as soon as possible. We also discussed the manner in which the study would be performed and specifically we discussed ways in which the govern- ment study and the clinician-based study could work cooperatively, particularly in areas where the same cases are encountered. We also discussed the possibility of a meeting to discuss this and other issues and I would like to confirm by this letter that we are very much looking forward to such a meeting as soon as possible; I will be telephoning your office from Yale on Tuesday to further discuss this. You also inquired as to whether or not the study would contem- plate the prospective use of aspirin by clinicians as a part of the study. Although we both agree that this would be ideal from the point of view of the study, we also both concurred that there could be serious resulting implications. If one believes that the early studies are inconclusive, it would be completely appro- priate for a prospective study to be done; but I believe there would be serious legal and ethical problems given the unfortunate and premature publicity surrounding this matter. I'm also concerned that in view of the low incidence of Reye Syndrome, that any kind of prospective study involving any medication would not be feasible and that we are thus forced by legal, ethical and scientific con- straints to utilize only a retrospective case control study model. I should add however that at the recent ccc meeting held at the Annual Meeting of the American Academy of Pediatrics in Chicago and attended by approximately 200 pediatricians, one doctor sugges- ted that he would be willing to follow, on a prospective basis, his patients with influenza and chicken pox; when the entire group was asked if they thought that busy pediatricians would be willing to engage in such prospective activity, nearly all those present responded affirmatively. We also discussed the pilot study. As I informed you, the CCC Coordinating Committee has not sought the release of those data because of very serious concerns that it is inappropriate to release the pilot data. As we discussed, the goal of all involved in this àontroversy should be the seeking of scientific trust; as you are aware, our complaint has been that the regulatory activity and publicity has been premature and exaggerated and we believe that releasing the pilot study results would simply com- pound and confuse that situation. PAGENO="0626" 620 GASTON SNow & ELY BARTLE You also inquired as to the status of the CCC/Public Service Announcement (PSA). Although you made it clear that this matter is within the jurisdiction of the Secretary and the FDA, you expressed interest in its present status. As I informed you, we are dismayed at the events of November 5, 1984 and subsequent action by the FDA, the result of which has been great confusion amongst the public. Because of that confusion, we will during the next week be making an attempt to meet with the FDA and work cooperatively to prepare and release a single clear message to the public. As we discussed, the CCC/PSA was released to counter the government PSA of last season, the impact of which was to convince 40% of the people who viewed it that aspirin was the sole cause of Reye Syndrome and 45% that not giving aspirin could prevent Reye Syndrome. It is indeed unfortunate that the FDA, acting on information from the Health Research Group (HRG), believed that our PSA had just been released when in fact it was released nearly one year ago. I would hope that you would agree with the recommendation that a single message be released at this time to ameliorate the confusion and if so, that you would make your views known to the appropriate parties. I am extremely pleased that we were able to coinmeuce a dialogue with regard to these matters and look forward to talking with you next week and hopefully establishing a meeting date in the very near future. Sincerely, / ~-~- c ~- ~ ~` / Neil L. Chayet NLC:nfp Enclosure cc: Heinz F. Eichenwald, M,D. Arnold Friedhoff, M.D. Ralph Horwitz, M.D. Alvan Feinstein, M.D. Thomas Reardon, J.D. (dictated, but not read) PAGENO="0627" 621 GASTON SNOW &ELY BARTLETT COUNSCLLORS AT LAW ONE FEDERAL STREET BOSTON, MASSACHTJSETTS 02110 617/426-4600 "5/ese-a~co FEDERAL EXPRESS January 16, 1985 O~~D*33~3~ Mark Novitch, M.D. Deputy Commissioner Food and Drug Administration 5600 Fishers Lane Rockville, Maryland 20857 Dear Dr. Novitch: I am writing to confirm our telephone conversation of this afternoon. On behalf of the Committee on the Care of Children, we are extremely pleased that you have granted our request that physicians and scientists working with the Committee have the opportunity to review the raw data upon which the Reye Syndrome pilot study is based. Our conversation of this morning follows that of last Friday in which I requested this opportunity and we appreciate very much your prompt response to that request. You requested the names of the individuals who would be reviewing these data and they are as follows: Heinz Eichenwald, M.D., David Lang, M.D., Alvan Feinstein, M.D. and Ralph Horwitz, M.D. All of these individuals are doctors and, of course, will fully respect any part of the data which is confidential in the event that any identifiable hospital or medical information is part of the review process. This is also to confirm the nature of the raw data that we have requested. It includes the computer or other tapes which have been prepared in the course of analysis of the data, the original questionnaires and case report forms as filled out by the interviewers, the hospital records of the patients, and the physician reco:ds if available. You indicated that you saw no problem with the scope of this request and would be asking Dr. Henry Meyer to contact me today or tomorrow to arrange the logistics of the review of this material. As we discussed, Dr. Lang is planning to come to the East Coast in conjunction with the review of this material and it is, therefore, imperative that we work out the logistics of the review as quickly as possible. PAGENO="0628" 622 GAsToN SNOW & ELY BAHTLET1 Mark Novitch, M.D. January 16, 1985 Page 2 We also discussed the nature of the review. You asked if we were intending to `nit-pick" these data; this is to confirm that we have no intention of engaging in such a practice, we are only interested in ascertaining whether there are or are not serious flaws in this study or its methodology or conclusions, and if there are not, we have no intention of attacking the study. We are still, at this time, very hopeful that we will be able to proceed with a proposed clinician-based study of this matter and we have already requested a meeting with Dr. Hurwitz in this regard. I am enclosing a letter which Isent to Dr. Hurwitz following a telephone conversation. I also spoke with him again last Friday and appreciate his statement that he would recommend that we would be permitted to see the data, although he did state that he is not in possession of it as it had already been turned over to the FDA. I also reiterated my request for a meeting as soon as possible to discuss ways of cooperating with regard to the clinician-based study and the government study, and he restated his beliefs that such a meeting would be appropriate and indicated. I am also enclosing a copy of a mailgram we have sent to television stations indicating that we are about to review the raw data of the pilot study and requesting that the Public Service Announcement which we sent to stations nearly one year ago not be aired pending review of the pilot study data. We also discussed present efforts relating to labeling and our concern that labeling being worked out between industry and the government also include careful attention to the impact of such labeling on the physician and patients. I appreciate your recognizing that doctors and patients have a real interest in these discussions and also appreciate your willingness to include us at an appropriate time prior to final agreement between the Agency and industry in this regard. Such involvement is extremely important to all of us who have been concerned with this matter. Thank you for your attention to these matters. With kindest regards. S. 1, i . ~ayet NLC:md Enclosures PAGENO="0629" 623 GASTON SNOW &ELY BARTLETT COUNS~LL0RS AT LAW ONE FEDERAL STREET BOSTON, M&SSACHIYSETTS 02110 617/426-4600 January 31, 1985 Mark Novitch, M.D. Deputy Commissioner 0055, SEW 0055 0005 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 Dear Dr. Novitch: This is to confirm my telephone conversation with your office of January 29th. I am most pleased that we will be meeting at your office next Tuesday, February 5, 1985 at 11:00 A.M. I thought that I would drop you a note to confirm this meeting and to indicate to you that I will be accompanied by Dr. David Lang who is coming from Los Angeles especially for this meeting and Dr. Ralph Horwitz who will be coming from Yale. The purpose of this meeting will be to informally discuss ways in which we can work with your office in reviewing the raw data of the pilot study. I should note that I have just received from the FOl Branch the materials provided by Mr. Elengold and we expect to be reviewing this material prior to our meeting. It is my further understanding that Dr. Meyer will be joining us and we very much look forward to seeing you both at that time. With kindest regards. Sinc Neil L. ayet NLC:md cc: Henry Meyers,.M.D. David J. Lang, M.D. Ralph Horwitz, M.D. PAGENO="0630" 624 GASTON SNOW&ELY BARTLETT COUNSCLLORS AT LAW ONE FEDERAL STREET BOSTON, MASSACHTJSETTS 02110 617/426-4600 January 28, 1985 Mark Novitch, M.D. N~~55 0005 Deputy Commissioner Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 Dear Dr. Novitch: I am writing by way of follow up to my letter and to our telephone conversation of January 16, 1985. As you may recall, you indicated Dr. Meyer would be calling me on January 17, 1985. When I did not hear from him, I telephoned him and he informed me that nothing could be done with regard to our request for data until after Inauguration Day, January 21, 1985. However, on Friday, January 18, 1985, he telephoned to inform me that a meeting would be held in his office on Tuesday, January 22, 1985, and we were invited to attend. We arrived at the appointed time and were informed that Dr. Meyer could not be present; however, representatives of the FDA and CDC were present and a full discussion of the various requests for data regarding the Pilot Study ensued. Dr. Faich, who chaired the meeting, informed us that a public meeting was going to be convened by the Institute of Medicine on February 13, 1985. He further informed us that efforts were underway to provide all interested parties with a data tape and copies of the case report forms and questionnaires. However, he stated that it was unclear as to exactly when these materials could be made available, because all potentially identifiable data had to be purged from both the tape and the case report forms. In fact, he stated that there could be no guarantee that the material would be ready in time to conduct an independent analysis prior to the intended public meeting. At this point, Dr. Ralph Horwitz and I reiterated the request I made to you during our telephone conver5atiOr~s and in my letter that it is essential that the doctors be permitted to examine the medical records of the cases. As PAGENO="0631" 625 GASTON SNOW & ELY BARTLETT Mark Novitch, M.D. January 28,. 1985 Page 2 we have discussed, it is essential that we be able to ascertain the date of onset of the disease, and the clinical course of both the prodromal illness and the Reye Syndrome. Further, it is essential to ascertain whether or not the cases were monophasic or bi-phasic, and also to observe the nature of the pathological findings. Dr. Faich and Mr. Elengold responded that it would not be possible for US to obtain this information. The reasons given were that the records contain identifiable patient data and even if names, hospitals, and states were stricken, it would still be possible to trace back the records to the individual because of the various dates. We have no desire to trace back any of this information and would in no way be contacting the family or making any use of the data other than to examine the records. The doctors would be ethically bound not to breach the confidentiality of the records, and furthermore would be willing to agree to any special arrangement to safeguard any conceivably confidential data. In addition, however, Mr. Elengold stated that all parties including the physicians interested in this matter would have to be treated as if they were the "Washington Post." We would hope that the doctors who have been involved with this matter, and who have been invited to assist the Institute of Medicine and other parties for two consecutive years, would be able to be treated in a manner which differed from the Washington Post, and we respectfully request that further consideration be given to this matter and that the doctors be able to secure the needed data, which includes the patients medical records, screening logs, if any, as well as the data tape and questionnaires. We were also dismayed to learn that despite the recommendation of the Institute of Medicine to release the Pilot Study results, no one from the IOM has yet seen any of the underlying data. We were informed that a committee of physicians did see the patient records, but there was much uncertainty on this point. We would appreciate it if you could ascertain whether any group or individuals other than the contractor, Public Health Service Representatives, and representatives of the CDC have seen these data. I believe that you informed me that no one at the FDA had seen the raw data either, and we would appreciate it if it could be ascertained exactly who has reviewed the underlying data. Lastly, we were informed that even if the FDA, PHS Task Force, or the CDC wanted to allow us to see the medical records, this would not be possible because they are not in the possession of the government. Further, those present at the meeting were uncertain as to whether or not the records PAGENO="0632" 626 GASTON SNOW & ELY BARTLETT Mark NovitCh, M.D. January 28, 1985 Page3 were in the possession of Westat, the study contractor. We hope that we will not be in the position of being told that the records are not available because they are not in the possession of the government, and also not available because Westat is bound, as an agent of the government, not to nake the records available because of federal agency confidentiality restrictions. We urgently request that you assist us in securing these data as quickly as possible. It is extremely difficult to accept the fact that the study results were publicly released three weeks ago, although the data was gathered many months previouslY~ and yet, more than three weeks after the release, with further public meetings planned, we are still unable to obtain any of the underlying data. I will be telephoning you shortly to discuss whether there is any way the physicians who have been involved in this matter can obtain the material they need to evaluate the pilot study and its conclusions. With kindest regards. Sincerely, Neil L. Chayet NLC : md PAGENO="0633" 627 GASTON SNOW &ELY BARTLETT COUNSELLORS AT LAW ~OstPG *AR?~(TT ONE FEDERAL STREET BOSTON, MASSACHUSETTS 02110 ~ALO*LTO,C*U~Op~*gA3O5 617/426-4600 TCLEX:94 OSSO GASTON SSN CGUFORN!ASTq~iG~, February 21, 1985 Richard J. Riseberg, Esquire Assistant General Counsel Public Health Services 5600 Fishers Lane ~z/e~S-7SOO Rockville, MD 20857 Thomas Scarlett, Esquire Chief Counsel Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 Gentleman: I am writing to confirm our meeting of Tuesday, February 19th. I very much appreciate the opportunity to discuss with both of you, in depth, the situation concerning further efforts to secure the raw data of the Reyes Syndrome Pilot Study. As we discussed, it would indeed be paradoxical if the material which is presently being released in accordance with the Freedom of Information (FOl) A~t procedures was to result in identification of patients being made possible, while Doctors vitally interested in this matter were unable to review the clinical and hospital records which they are seeking. On behalf of the Committee on the Care of Children, we are requesting that the Food and Drug Administration and/or the Public Health Service request of its contractor, Westat, the production of the hospital records of the 29 cases referenced in the Pilot Study. By production, I would like to emphasize that we would leave full discretion to you as to the precise manner in which these records would be made available. It may well be possible that they could be kept in a central deposi- tory for viewing without copies being made and taken and, in any case, we feel quite certain that the appropriate direct identifiers can be struck from the records in a manner which will make individual patients unable to be identified. Fur- thermore, we would be willing to adhere to any reasonable pro- cedure which would bind the Doctors who will review these PAGENO="0634" 628 GASTON SNow& ELY BARTLETT Richard J. Riseberg, Esquire Thomas Scarlett, Esquire February 2!, 1985 Page 2 records not to attempt to to identify or contact any of the patients involved. We believe that the Freedom of Information Act permits, and in fact mandates, that this material be made available. Case law clearly indicates that the Act favors disclosure over very narrowly construed exemptions. Furthermore, the balancing test applied to the medical records exemption clearly tips in favor of disclosure where there is a public interest, particularly when personal identifiers are eliminated. You indicated that the medical or hospital records were not a "deliverable" under the contract and are therefore not in the possession of the Agency. We believe that a government request that this mater- ial be made available as a modified deliverable under the con- tract, would remedy this situation and free the contractor from any contractual problems relative to the Freedom of Informa- tion or Privacy Acts. Finally, as we discussed, we believe that it would be most unfortunate if the posture of the government were to be that it is not in possession of the records, while, when we turn to Westat, we are informed that we are unable to obtain the records from Westat because of Freedom of Information and Pri- vacy Act requirements provided for by contract. I would hope very much that we would not be faced with this kind of "Catch 22" situation. On the other hand, we do recognize that there are serious questions involved as to the privacy of indi- viduals, which privacy we fully respect and would not want to see breached. The above is a suggested means of securing the raw data which is essential for review of the study and if you have any suggestions as to other ways in which the material can be obtained, we would most appreciate hearing them. In any case, time continues to be of the essence with re- gard to this matter, and we urgently request that the materials requested be made available as soon as possible. With kindest regards, Sincerely, Neil L. Chayet NLC : md cc: Thomas Reardon, Esq. Heinz Eichenwald, M.D. PAGENO="0635" Potentiation of the Toxic Effects of Acetaminophen in Mice by Concurrent Infection with Influenza B Virus: a Possible Mechanism for Human Reye's Syndrome? hi. G. MACDONALD.3?) P. P. MC(~RATH. D. N. MCMARTIy4, 0. C. WASHINGTON, AND 0. Ht'DAK Dc'parirnent "I Child IIi'uhh and Den'/iipinvni. (ieo'irt' itiI)hji7~)i)fl L'niii'eniti'. tiathinv'hn. 1) C and Dhi'iiiun ui Buikh('?fl)Or) wud (ii Iuiuiiutv O//ti('uu/ 1tiuuluuu,'ui.i. I'ixuiand i)uuuit iulu,uu,uuuiraiju,,. 8liiu.uda. t!a,uiand t.S Summary Using weanling mice of two different genetic strains we dam- onstr,zled a potentiation of the lossc affects of acctaminophen by prior infection with influenoa B uiruwlheC57Bf,/6N(B6)str,ijn of mice is genetically predisposed to increased tn5icit) from acetaminophen when the hepatic c~tochrome P450 mixed func- tion otidase s~stem is preinduerd. When 36 animals are pre- treated with iniluenea B nirus and an mixed function oxidase s~stem inducing agent before admiflistering aectaminophen, ne obscrsed a significant incidence if at~ pical"fattp" user p'jihotogy on light microscopy similar to llte microsesicular steatosis seen in human Re~e's syndrome. F3ectron microscopic changes in the user of these animals resemble Ihose published to dale in human Reye's sndrume. Abbresiations El1)~., egg infectious dose 50% EM. electron microscopy ER, endoptasmic reticulum l.M. light microscopy 3-MC, 3-meth~lehulanthrene \ll'O, mixed function oxidase P hS. periodic acid Shifrs reagent RS. Re~e's syndrome SER. smooth endnplasmic reticulum TCID., tissue culture infectious dose, 50% ~hllD., mouse infectious dose This study was designed to test the hypothesis, now supported by several investigators, that RS in humans may be caused by the interaction of viruses. environmental factors, and host genetic factors. There is a body of animal data demonstrating the poten. ttatton of effects of viral infection on the host by chemical agents, especially insecticides (6. 8, 16). Acetaminophen toxicity has been shown to be potentiated by alcohol, and in too patients with mononucleosis (9, 13. 23). Theophyltine tosicity is in- creased by concomitant infection with either inlluen~a A or tnlluenza B virus ((2. 211). Viral potentiation xtfcersain chemical tosuns. e.g.. .t-pentenotc acid and allatosin. results in an esperi. mental syndrome very simitar to human RS (4, 24. 321. Possible explanations for these ellects include the adverse elli,'cts of xc' nobtotics on the integrity and function of the immune s~stem, and effects related to the huotranstbrmation 01 foreign agents, which may he metabolized to pharmacologically active inter- mediates by components ot'ihe cstochrome P45(1 bIK) s~stem. RS. or very similar clinical disorders, are found in many different geographic regions of the world. A review of the item. tore would suggest that RS can be precipitated by many chemi. cally unrelated compounds, each 01 which has the capacity to cause subclinical, biochemical, and functional abnormalities of the liver and immune system. We elected to study the e(Tects of influenza B virus infection (which us commonly implicated in the prodromal illness before tinsel ol RS( on two inbred strains 0)' mice which are known vi diller signulicanily in the way that their hepatie MFO system responds to chemical agents. We chose to study .tcenaminviplien l'or two reasons. First, because it isa commonly used antipvrenic in children which is Icing promoted in the LISA. and can he obtained without prescription. Second, because the metabolic pathwa~s (or the drug have been well worked out and linked with the aromatic hydrocarbon responsiveness of the MFO sys- tem in mice. In general, all high(y tipophihic senobiotics are rendered more water soluble and hence. more readily excreted, by the micro- suuinal %IF() eniy me s~stem located in the SER 01 he liver and tither tusues. Molecular oxygen and reduced NADPH are re~ quired (or the reaction. tnductiiun of this enzyme system is associated with an increase in microscopicatly visible SF.R. and it is interesting that prvuhfrranuon it SER has been presiousiv reported in cases il RS (2. ~(ul. vlust NIFO reactions are nnedi.ted thruuugh the hemeprotein cytochromz P.450. Mitchell, slid. (141 showed that acetaminophen.induced he. paste necrosis is caused by a toxic metabvuhite 01 the drug, which hinds cuvatently to tissue macromolecules, including nucleic acidu and proteins. The toxic metaholite represents a small part ol'the original dose of acetuminophen (approximately 4i'i) whets the drug is taken in therapeutic doses. The maJvtnt~ of the drug is conjugated directly with sulfate of glucuronide and then ex- creted. The toxic metahohite shown in Figure I is thought to be produced by metabolism via the cytochrome P.450 enzyme system. This metabolute us detositied by preferential conjugation wuth a nucleothitue sutphsdrst trupeptide. glutathione. In anuuttal studies, when glutathione in the liver is either depleted (e.g.. due to malnutrition) or overwhelmed by a very arge dose of acet. aminophen, the activated metabuu(ite remains unconjugaued and free to combine citsalently xiuth vital nucleophilic macromole- cules in the hepatocyte, leading to eventual hepatic cell death in a typtcat centrolohular distribution Fig. 21. Tttvurgeirseen, en al. 31(1 linked metabolism of acetam(nophen by the cyiochrom P.4511 system to the inducihility of a~l hydro- carbon hydrimxsIa~e in inbred mice. I'he degree of aryl hydrocar- lion hsdrovyla~ responsiveness has. in turn, been linked lvi tIme presence or absence of the gene locus known as the Ah locus, which is inherited as an autowuntat dominant in mice(3t), There 629 ACETAMINOpIIgyI, VIRUS, AND REYE'S SYNDROME OflSt.jAsijOA/mguiiaiu$)suum,n PFt)ty URiC Ri SF situti Copinghi Oil lnlu.niaiutn*t Peduui'ic Resmicii Foui,dation. inc. Vol IX. No. 2. `154 I":.Iud,ni.% I. PAGENO="0636" 630 ANIMALS WTTRI AR LOCUS RECEIViNG 3MC. ACETAMINOPPIEN ANIMALS WITH Al. LOCUS RECEIVING ANIMALS WITH AC LOCUS RECEIVING ACETAMINOPREN AND INFLUENZA BVIRUS `I). ~ i-I A B C I D OOMIOEARSO~.RSr~ ANIMALS WITH AN LOCUS RECEIVING INFLUENZA B VIRUS' 3MC ACETAMINOPHEN E Fig. 3A Fig. 38 Fig. 3C FIg. 3D F~g. 3E Fig. 3F ANIMALS WITHOUT Ah LOCUS RECEIVING INFLUENZA B VIRUS' 3MC' ACETAMINOPHEN F ACETAMINOPHEN. VIRUS. AND REYE'S SYNDROME Liver samples were taken immediately into glutaraldehyde for macroscopic lesIonS WerE recognizable in the liver, representative EM. Other ttver samples from the same animals were prepared sectIonS were taken from these areas and, when possible, also appropriately for trozen Section. and subsequently stained with from apparently normal areas of the same livers. Oil.red.O for lipid. Further samples were ftsed in Bouins for Microsomal preparations were made from the livers from (5 Giemsa and PAS staining, or homogenized for microsomal pre~ animals tn each study group (including controls) (33). The ani- aratlon. Sections for LM were prepared by Baker Histology roals "crc kIlled hy cervical dislocation. TIte livers were imme~ Great Falls, VA( and were examined by two of us. M.G.M. and diate(y removed and. aller raptd collection of specimens for LM. D.N.. a vetennary pathologist. D.N. was unaware of which weighed and siashed with ice cold 0.02 M Tris-HC1/0.l 5 M treatment schedule the animals had receised. Necrotic and non- KCL huller. pIt 7.4. They were then homogenized in 1.5 vol. necrotiC lesions were quantified and graded by the method of umes olthe same huller, using a glass homogenizer with a Te(lon Chalkley 13). pestle. The homogenate was centrifuged at 2.0(03 g for 15 mis. Seventy number coded electron microscopic samples. `epre. and the supernatant was decanted through a double layer of line sentative of study groups and controls. were examined by P.M. meshed gauce. The supernatant was then centrifuged at (115.0(0) and G.W.. also without knowledge of treatment schedule. When g for 45 mis at 4C. The resulting pellet was washed by resus.. PAGENO="0637" 631 MACDONALD AT 4L pension in 0.1 M sodium pyrophosphate buffer. pH 7.4, to remove remaining hemoglobin and recentnfugcd at 05.000 g For 45 mm. The pellet w~s resuspended in 2 ml of 0.02 M Tris- HCI/0. 5 M KCL buffer. !sn:txnt' ussar. The protein concentration of the microsomal suspension was determined by the method of Schacterle and Pollack (25) and the cyrochrome P.45(1 concentration by the method of Omura and Sam (17) from the CO dil%rence spectra of reduced microsomes. using as extinction coell'icienl of 91 mM-I em-I br .~ 490-451) nm. RESULTS LI! findip,ç's (34). 1) When acetaminophen was given alone. significant cen. trolubular necrotic lesions(35) typical of acetaminophen toxicity were first recognized on l.M at a dose of 300 mg/kg in both B6 and D2 mice (Fig. .3a. 2) When acelaminophen was gtscn to 116 and D2 animals pretnfected wiih tnlluenza B virus. significant ccntrohib. ular necrosis 11mm appeared am a dose of 2)0) mg/kg suggesting some potentiation of acetaminophen tosietly by the sirus (Fig. 3b1. 3) When the chtochrome P.450 enzyme system was in- duced with 3.MC. as would be expected, the toxic el%'cts of acetaminophen were markedl~ potenmiamed in the 86 mice, and stgnilicant centrolohular lesions were first recognized in these animals at a dose of ISO mg/kg (Fig. 3d. A minor potentiation of acemaminophen cth,ct was seen in D2 animals (Fig. 3d). 4) Significant potentiation of the toxic effects of acetamino~ phen was recognized in both 86 and D2 animals when pretreated with tnlluenza virus belbre receistng acel~ aminophen and 3'MC(Fig. 3e and I). In a small number of animals, treated with all three agents. we recognized the appearance of a distinct histologic patliolisgy in the liver a ditTuse microxexicular steatosis. Srsiv percent of those with microvesicular smeatosis did not base coexist- ing centrolohular necrosis. The incidence ol this linding was significantly greater in the 86 animals, and appeared to be dose related over the range 150-251) mg/kilo. 5) Mortalily(wimhin 40 h of acetainintipheis adminisiration) was markedlb increased in 116 animals. by prior induc. lion of the MFO s~stcm with 3.MC when aceiaminophi.'n was given at a dose of 25(1 ntg/kilo. in otin.tntluced animals, there was no excess mortality oser control animals (approximately 0.5%). With prior induction of the MFO system the rate rose to6%. When Ihese animals were also pretreated with influenza B virus the mortality rate increased to 19%. (A smaller increase in mortalily (-12%) was seen in infected D2 micej. Inflammatory lesions were seen in less than 2% of the liver samples. Glycogen depletion, recognized tin PAS'siained liver sections, was most often associated with severe centrolohular necrosis, but was not specific to any treatment regimen. 1.1! Iindinr5-s. A total of 70 mouse livers were examined by EM. including livers from 86 and D2 mice, receiving 1511 or 200 mg of acetaminophen plus influenza B virus and 3.MC. Also examined were livers from untreated animals, and aitimal re- ceiving: I) sterile saline alone or in combination with virus, acetaminophen. and/tsr 3-MC: 2) sterile altantoic ttuid alone, or in combination with one of the two tither active agents and/or 3-MC. No remarkable changes were seen in the controls, except in the case of some 02 aitimals receiving undiluted inituenea B virus examined 0 d alter infrction. Ihese aiiinials showed an increase in number a) miertihiiijies in some cells antI some disruptions of lie mimochondrial ulirastruciure (Fig. 4). the 1)2 animals receiving 1511 mg acetaminiip(icn plus 3.MC and virus showed some loss of gl~cisgen and slight distention of the endoplasntic reticulum. 1hz 02 anintals recetsing 2(01 nig - . -~`-~`- . v~. ``~"~~-~r.' ~ ~ a -- ."~v,~*1I .,~5_. - , ~ `-.` ~ *-,: -"~ ~` *` t, ~ i_, :,~`. - --- ~~~`f*rzt, ~ 4 -~ - ,,~ 1' -- S ,,,d.4,~w -i~~ :,, 4 ~ Fig. 4. D2 mouse. lIcensing inituenna B virus only. showing increase in micmolsudiesiairio, 1 and some miiochondnal changes (it). ofacetaminophen plus 3-MC and virus showed almost complex.- ltisv,iiglyctsgcn. gitiiig the liver parench~ nsal cells a momh.catcn appearance. Except (or a slight spor.tdie distention 01 the I R. the tither cstoplasmic organdIes were spared (Fig. 51. The Oh mice receiving acetaminophen. 3.NIC. and sirus showed profound cltanges. The 86 animals receiving 15(1 mg ti) acemaminophen plus 3-~stC and virus showed what appeared lii be numerous vacuoles in the cell cytoplasm. Closer examination of these sacuoles revealed the fact that these structures were dismentions of ihe endoplasmic reticulum. Other organdIes ap- peared relatively normal (Fig. 61. The B6 mice receiving 2(0) mg of acemaminophen plus 3-MC and virus showed progressive distention of the ER. with almost complete disruption of the normal cymop(asmic architecture in many of the liver parenchyma) cells (Fig. 71. In some animals the organdIes appeared so prtsfoundlv disrupted that mans txf tIme cells were dead, and the nuclear ultrastruclure showed loss of normal organization. Fatty accumulation, corresponding to the microvesicular steatosis seen on Lbt. appeared to be within the distended ER lFig. 6(. Tlti.'~e changes seen in the B6 mice were mostly confined to the liver parench~ ma) cells, hut in occasional Kupferce(I showed similar changes. The other cells of the liver, such as the cuhoidal epitliclial cells tif the bile ductules and endothelial cells, appeared un;il)icted. Lit:ciiti' a.s.vais. Arithmetic means of she espet-imental data were compared using Student's (test, with P < 0.05 Ibm the two. laded test as the limit of significance. The expected increase in cbittchrome P.450 on induction with 3.MC was conllrmed. But PAGENO="0638" ~qi~ ~ U U -n z~ ~ `U > -4 2 0 X m 2 C 0 2 0 0 PAGENO="0639" MACDONALD AT4L addition to acetaminophen and 3-MC. Similar changes in the ER have been reported on EM examination of the liver of an adult male .vullbring rim aeetaminiiphen overdiise, and Isv ihaler ci a!. (29) Svobisi* ci a!. (28) tn human R.S (18). Fat deposits, corresponding Its thosi.~ seen on l.M, vvere within dis- tended areas of he ER. Svoboda eta!. (2)1) studied the livers of sin patients with RS by LM and EM. and attempted to correlate he changes seen with the clinical course of the disease. They found that on l.M. intlammation and necrosis were especially prominent in fatal cases and that "Aside from loss of mains dense granules, alter- Swiss in mitocheindrial structure were minimal or absent. No ultrastructural batures served to distinguish-patients who died from those who survived." They concluded that Althiiugh de- rangement of mitochondrial unction may be inttxirtanl in the pathogenesisof RS. such derangement iv nut necessarily reflected in the ultrtvtructure olthe mitoehondria." Thaler ci a!. (29) noted the presence of numerous microbodies in liver cells on EM. They were not impressed by any significant mitoi:hondrtal change. Several incontptete reports have been published, such as the one by Morales ciii!. (15) which merely relbrsto "rniti~hondnal changes and dilatiiin of the endiiptasmie Structural changes in the hepatic cell milochondria in RS have been emphasized by Pants ci a!. (26). These authors believe that there is a parallel between recovery of mitochondriat ultrastruc- ture and clinical improvement of the patient, and vurgest that mttoehondnal damage is important in the evolution of RS. Although mitochondrial changes did become apparent with progression of the toxic process in our study mice, they were invanably preceded by swelling of the ER. Our findings resemble those descnbed by Ssoboda elI!. (28) and to a lesser extent by Thaler cI a!. (291. Direct companson of our mouse samples with liver samples frism humans was handicapped by the lack iii availability ot human biopsy specimens, because liver hiipsv is nil lunger regarded as a routine procedure in diagnosing Rh (221. Our review ol publushed [Ms led us to cviitclude that dilatation ol the ER proceeds significant hepatic mitisihuindrial damage in the progression of huntan RS, hut that the ER changes are ol(en overloiiked by the authors when describing EM findings. Studies to date on tlte ellects of drug-virus interaciiiin tin lie immune system have indicated that stimulation of interibron production by the virus will depress the MFO system 17, 2. 201. Our histologic data suggest that activation of certain components at the cylochrome p.450 MFO system might he a mechanism br potential acetaminophen lonicity in our study mice. In light of this, the results of cytochrome P45(1 enzyme assays ire contrary to expectations: however. interpretalion is handicapped by methuidologic problems. It was our intention to attempt iii correlate cytischreime P.450 values, not only with individual treatment regimens. hut also with histologic findings in hut individual muiuse livers. This was the reason for attempting enzyme estimatiuins on the sante livers from which samples vvere obtained fitr LM and. in slime cases. EM. In fact. enutynie- histology correlation vs-as not possible, because animal livers hid to be pooled tn order lit separate sufficient microsomal material for subsequent enzyme assay. \lthouglt our results do not indi- cate that microsomal P.45(1 induction us a mechanism by which the tunic ellects ul acetaminophen are puitentiated by inhluenea B virus in these animals, it is certainly possible hal studies ui) larger numbers of animals and use of more sensitive meihuds for eney nne assay: along with methodology to separate out mdiv toil types of P.450. might produce dillering results. The pitfalls of direct estrapolation from animal data to he human are well recognized. But, the finding that the typical liver toxicity iifacetaininophen is signilicantly enhanced in mice Isv eonciimitant viral iiilectiuin is of nta~or potential signilicance ii the human. Animal studies by McLain ei a!. (13) and Gilmhiin'eer cliii. ti), on lie ciinshined ellects of alcoltiil and aectaminophen have been confirmed in humans. Aletihilie subjects may sutfor serious tosie ellects Irons usually inituscuuius quantities of dcci- aminuphen. paitcularlr if they are abusing 16cr chemical sub- stances. Acetaittinuihen tiivi~iy alvii aiilicars iui be pmicii:r.icd by cunconpitant miiitonuclciisis 123). .hcetaittintiphen isa coiiiniuils used antipvretic in children aid is being promoted in tie United States. This promotion is hose lacilitated by the apparent indictnicitt if s.ulieyLutes us a causal agent in RSI2I(. The evidence (tat tither commonly used drugs are nut ettuitogicalt~ associated vs ith RS us estremels weak. Taking into consideration the numerous agents which have been causally related to an RS.like syttdru.ume in man, we In. pothesize that virul-seniihiuptie interaction may be an underlying ntechanism by which many foreign chemtcals might produce Rh in a susceptible individual (27). Those all'ected may have reit- dercd susceptible by prtor conlact with some noxious environ- mental substance. and/tsr by genetic factors, perhaps manifested through the immune system. REFERENCES AND NOTES i. .Siias.S VnxsdlE5andNpep'p.DWGeneijceonpsoofint..uiiujuivai Psi idiuoisimis ui aivi tpsdvcarpsn h~druu*pLuu in uuliuc.i huni,cnissph,s-viey(.uccpR.yims-avi.uiiuu7,~ 2. Rivu. R. L md SLmuipe. St 5- 11 vaiheiugs ui R cue's mdi,,, I, in: 1) 1 Pii.mek. Rise's sumPdron~n. p. 77 Gun,, and tiravu. \u~\,urk.i'i'ai 1. Chaikirs ii. W.; Stcihuul fun' iSo quaniiiative morpPinio~ic aiscimsis if i. Nai (aocu,'rRes.4 dlii'idSi. a ci,.. v R .1 edema. F.. Purdm. V., and S~ndPn'g. D H.: Viral Vuiu,Pu,ti.u, ui uheinuc.mi iuuuns us iSo exunnienidi nndpuunpe nihipogivcu..i,ia. unmet's. 633 Fig. 7. )lepatueyte from Rh mouse receiving 3-Mt. virus, and 211) mgulacctaminuiphen. with distended rnvltipicsmie retieuluniil)t.Rtuiid ulirastructural alteration of mitisihondriamNil. PAGENO="0640" aloputby and fatty sheets) dernenasion. Am. 3. De~ Die.. /9:1091(1974). 5. Cracker. 3. F. S.. Rozee. K. R., Onene. R. L. Osgoso. E. S.. and Hulaings?. 0.: Insecticide and ctnal election as a cause of fauy oiscm'sJ chaegm and rncrphatttpsthytn the mouse. Lzm'tn2 22)1974). 6. Crocken. 3. F. S.. Bent. H. R. H.. MacDonald. 8. C.. 0mm. 8. L and Fxtdsschon. 0. 3.: Reyn's syndrnmen A diwate of chrnsuott anti strut inter- In: Di. Poilat,k., Ree'ssysdrnme.pp.33t...54t(Crs.oseandStnatton N~m York. 974). 7. 0mIiioa. L B. and Manncnng. C. 3.: Srttueniiai admsnozsation ttfpihoi- nosinic acid and polftnhncyttdylic acid indace interferon and depress he hepouc cytocht'ome P-t50dependens mononygenaae system. Biixhem. S,o- phis. Ret. Commun. IlK 9471(982). 8. Fnend, M. and Teainer. D. 0.: Polnch)oeinated Biplsnny). intenaction 04th du~k hcpatttisntnus. Silence, 1O. 13(4(1970). 9. Coldtingcr. R.. Ahmed. K. S.. Pitchumoni,C. S.. and Wtyc)ey. S. A.: Concom- tan) alcohtd and drug atrstse enhancing acetamineplsets tonicity. Am. 3. Gauteuentenn).. .0: 3051(978). (0. Cunesoto. M.. Tomhattgh. C. C.. and Sohoanno. K. B: Reyn'snnndnrnte mode) tns)nnttnphospboer,u(P.l,f,..Jiutr. Ret. (atnstrat.'t(. Itt. 194)19421. It. Ke(knnnan. C.. Sham. C. 8.. and Lynen.Keflernnun. M.: Any) hytlritcarhon hydrosotase isducibilisy and bennchogesic cunninonta. N. Erg). 3. Med.. 2,96 934(1973). 2. Kramer. M. 3.. Funtkanta. C. 1.. Karp. 3. R.. Shapiro. C. C.. rtenr,tn. W. E.. and Brenman. C. W. Altered iheoplsylline cteaamnce dunngan influenza ,tutlts'eak. Pediatnirs. 69 4761(9)21. Ii. McLatn.C.J..Krenshons.J.p..pnnennees.F.j..andHeitnsun.j.t..:poteociac.tn olacetatninophen hepatosoutcity by alcnttn(. 3. Am. Med. Mane.. 244. 251 ((0)0), 14. btisohefl. 3. R.. itdtom. 0. 3.. Fount. W. Z.. Ci(tcne. 3. R.. and Bit/tn B. B.: Acenaminophen-induced hepauc necroste. WV. 3 Pttarnnacol. foR Then.. (.87 185(1173). IS. Morales. A. 8.. Bourtettis. C. H.. Jr.. Ts,tpu(.dt. S.. and ChuLachantu-. E.: Encephatopashy and laity dogonenatutn otthe uisceea. An electron Micro- st.ttpscnudy. Am. 3. ((in. PattsoL5. 755(l'ihft). (6. Mullen. P. W.: Immunopharmacologtcal considerations tn Rein's syndromes a possible senobinsic initiated disorder? Bittcttem. Phaennac,tL 27: laS 1(r)). 17. Omura. T. and Sato. 8.: The emboss mononide lending pigments of (june mionosontmn. 3. Blot. (hens. 230: 237)1) t tOut. 10. Petenstin. P. and Vdstnup. H.: Relation hesonen liner function and hepatitcote ultmustructume in a case ot paeacesansot intonicatton. Digessioss. 19. 4)5 11979). 19. Po(lack. 3. 0.: Models of chemical and uteus ntenacsiois and best relation to a multipleetiokspr otReyessondnome. In:J. F. S. (nicker Reye'ssyntieunsz. II. pp. 34t-Jh094jrure and Stnuo.an, Nest York, 197')). 20. Renton. K. W.: E(TectsotInfecstne and ImmuneStimulaston oas Thenpby)tine Miitabtoltsm. Semtn. Pinnnn.ttel..5. 17)110)11. 21. Report on the scsenttltc morkslsop on Reyn's syndrome and its ptmutb(e aunit- ct.attos roth salteylate use. Department of Health and Human Serutcns. 187 Public ))ralth Sernice. Food and DrugAdminisseas,oe Held May 24th (982. at National Inssttutesofltealth. 22. Reyes Syndromec National Institute of Health Consensus Denn(opnsens Con. lcscni.e. Man.h 11)8). 23. Rosenberg. I). M.. Meyer. A. A.. Manning. I. I).. and Nuiclito. F. A.: Aunt- aminoplton and hoyaiic dyuluncsiun in niActious monitnucleosis. South. Mcd. J.. ii 161) ((977). 24. Ruben. F. I .: Rct:rnt :kiili.pnuonis and ,:i:ntn:hui,,.ns lire enponnnrntal mln(rlsi')Roucssni%(si.mc.(n:.trs(ro9koroeyessnndrome(tpp 395-397 (intro and Stnoit,,n re.. ~ Yoik. 9799 25. &hautrn(o. (1 9. and PolLick. 8. I..: .7 nimphlied nncuh,uI Ion hr quanu:iat.e asian 01 ..mal( aniouot.sof protein in hiiAo~ic nuatunal. Anal. Oau:hem.. 51 6 `4 I 117 Ii 26. Schubert. W. K.. Ptntn. I C.. and Panin I S.: fnorph::li:pathc and 14117 liter (Royi s nun,(riitnn). In: It. P::ppon and F. S.haltiicc )`nogics.s in Liuor t)ttoasu-s. Viii. 4 pp 490-493. (Grune and Siuoiuitn Noun York. 972). 27. Sult:tan.t).tlnat. 3. Z and Corey. L: Epidomialiigy of keyes syndrome. Eps- (em. Ruin I (21(1941). 26. Studsisia. I) I md Ruiuidn. /. K.: Pathology of the liter in Reins S1ndrome. Lab. trtucst. .f 57) ((975). 29. Thulee. M Rruhn. F. W.. .Npprlluaum. 94. 74.. and Goodman. I.: Reyes nnndn'.tmeinto,ns.J.Prijiatr.. 7' 639(11)70). 30. Thiurgitirnoon. S. S. Fclton. 3. S.. and Nolrens. D. W.; Gerniicdiflrnrrcen in ihe aromatic hndriorurbon.induu:(n(r n.hydniisulation if 2.uurtylain,no (linurene and ai.cuaminophe,s produi.ed hepatotuso.ity in mice. Mid. Pharmaco(.. II: St. Th:ynoursscn. S. S. and Notniuns. D. W.: The .hh Incas and the uncuainolisos of chennuca)tarctnogens and other ioicugo compounds. Ado. Cancer Ret.. 25: 32. Wotsb. S. K.. Gel). P.C.. Brysuin. M. S.. Llounrllyn. C. C.. and Madgn. C. E.: Rrtr's snndriumr.like disean in mice led z(latouin and mitt-ted uilh Conua.kio tines. Presented at the Reyes syndrome III Symposium: Detroit. Nontimber. (`190. 33. In order to ,uhsain a miononuimal pullet ofnu(Ttrirns size (icr enzyme assay, it (itund nru.rouann 10 `ut-il the liters friima minimum uf ihten animals. 34. Using Stopuinr Prugerusite logistic Ruigeession. all compansoss quoted lob- nine uigni/uant to (`<0:911. .55. Censiui)otrular nrcru'tis uau considered nipniflcant uhen is oat u(eaety mrog. cited in (i)°i in mitre tithe hopalic (obulesenamiord. Sb. The authors thank Dms. 0. W. Nrlens and C. MeLuren for their inualuable .idu ice and support kin the pninprul. 37. Ru'quonts for roimnno uhould liii addressed to: Dr. Vlhain C. `McDonald. (hi(drro's ltintpitat National Medical Center. Ill Michigan A nenue. NW. A.tnhirgiiin. I)C. 21)1(11. JO. Ihiu soccarch oat sizrtoned by he Dtuinion of Denn(opmenual Phannaoology. ant) the Si,reau of 9uligu's. FDA. 31). Rc'coisod Sir nulsiu:amii,o lelsnuary 0, liftS. 40. Accepted (lie putslicaiion Augusa 17. 1983. 634 ACETAMINOPHEN, VIRUS. AND REYES SYNDROME ANNOUNCEMENT The annual meeting of the American Society of Pediatric Nephrology will be held at the Hilton Hotel in San Francisco on Tuesday. May 1. 1984, from 9:00 a.m. to 5:30 p.m. The morning session of the symposium will focus on reflux nephropathy-anatomical, bacteriological, genetic and radiological implications- and the afternoon session will cover prostaglandins in newborn physiology and renal function. For further information, please contact Dr. Russell Chcsney, Secretary-Treasurer. American Society of Pediatric Nephrology. University of Wisconsin Clinical Science Center (Rm H4/452), 600 Highland Avenue, Madison, Wisconsin 53792. PAGENO="0641" 635 Mailgram sent to all television stations on January 17, 1985 MAILGRAM TEXT I am writingto you on behalf of the Coordinating Committee of the Committee on the Care of Children. We have received inquiries as to the status of the Public Service Announcement on Reye Syndrome which was sent to your station by this Committee nearly one year ago, (February, 1984.) Last week, the Department of Health and Human Services released the results of a pilot study which showed a strong association between aspirin and Reye Syndrome. We are making every effort to secure the data on which that study is based and to review that data as quickly as possible. In the meantime, we request that the Committee's Public Service Announcement not be aired. We will notify you as to the results of our review as soon as they become available. Thank you for your attention to this matter. Thomas M. Reardon, Esquire Gaston Snow & Ely Bartlett One Federal Street Boston, Massachusetts 02110 (617) 426-4600 52-266 0-85-21 PAGENO="0642" 636 PREPARED IN CONNECTION WITH THE TESTIMONY ON BEHALF OF THE COMMITTEE ON THE CARE OF CHILDREN BY: DAVID J. LANG, M.D. CHAIRMAN, DIVISION OF PEDIATRICS CITY OF HOPE NATIONAL MEDICAL CENTER, DUARTE, CALIFORNIA COORDINATING COMMITTEE BEFORE THE COMMITTEE ON HEALTH AND THE ENVIRONMENT OF THE COMMITTEE ON ENERGY AND COMMERCE OF THE HOUSE OF REPRESENTATIVES HONORABLE HENRY A. WAXNAN, CHAIRMAN ON H. R. 1381 "THE EMERGENCY REYE' S SYNDROME PREVENTION ACT OF 1985" The following is to provide you with some comment on the CCC's preliminary review of the data from the pilot case-control study conducted by the CDC of the possible association between aspirin use and the risk of Reye's Syndrome. CCC has initiated an impartial review of the data tape and other material made available by the FDA. Unfortunately, the tape contains only a portion of the data that were available to the investigators, and we have not yet seen any of the original questionnaires or medical records for patients included in the study. Consequently, our comments pertain only to the data contained on the tapes and cannot be considered as a criticism of the overall study or the preliminary results reported by the investigators. We shall first present our specific comments on the data reviewed on case subjects with Reye's Syndrome, and conclude with a brief summary statement. PAGENO="0643" 637 Specific Comments 1. The preliminary report made public by the CDC investigators was based on 29 cases of Reye's Syndrome. (There were three additional cases with a prodrome of chicken pox who were not included in the preliminary report or in the data made available to us. No explanation is provided for this exclusion.) However, the data we were provided contained 27 cases, including three subjects who were excluded because they failed to meet the diagnostic criteria for Reye's Syndrome (subject numbers 90015, 90017, 90030). 2. For eight cases (including the three who were excluded by the investigators) we are unable to confirm the presence of central nervous system symptoms necessary for the diagnosis of Stage II Reye's Syndrome. Although some of these cases were reported to have had lethargy and/or excitability, none were reported as confused, combative, delirious, or disoriented (subject numbers 90015, 90017, 90022, 90024, 90029, 90030, 90031, and 90032). From the data included on the tapes, we are unable to discern the reasons for excluding three of these cases and including the other five cases. 3. Each of the three excluded cases were classified as not using aspirin during the patient's illness. 4. For some subjects the documentation of symptoms appears to be incomplete. For example, subject 90001 was coded as having severe confusion on day 1 of illness and day 5 of illness, but no evidence for confusion on days 2-4. Without the medical record, we are unable to determine whether this unusual clinical course accurately reflects the patient's illness or may be an artefact of the strategy used for collecting data. In the pilot study the investigators asked patients to focus on a particular symptom (e.g., cough or vomiting) and to recall whether the symptom was present on each illness day (e.g., day 1, day 2, day 3, and so on). This strategy is quite different from the customary method for taking a clinical history in which the patient is asked to describe all of the features of their illness on each day. Using this method, the patient would report fever and cough on day 1, the addition of nausea and vomiting on day 2, and so on. We cannot be sure that the two methods would yield similar data, but the distinctions are obviously crucial (e.g. for case 90001, we are unclear whether Reye's Syndrome began on day 1 or day 5 of illness). PAGENO="0644" 638 5. In at least two cases we have serious concerns about the possible occurrence of errors resulting from temporal precedence -- i.e., did the case subject receive aspirin before or after the earliest symptoms of the onset of Reyets Syndrome. For case 90001 and 90027 the first dose of aspirin was taken on the same day that the subject had evidence for Reye's Syndrome onset. Without examining the medical records and reviewing the questionnaires we are unable to exclude errors due to temporal precedence. 6. Only six of the 24 cases had a clear cut biphasic illness, and the mean duration of the prodromal symptoms before the onset of Reye's Syndrome was just 4.6 days. 7. Our review of the data tapes emphasized the importance of specified criteria for defining a patient exposed to aspirin. Some patients in this study who were classified as aspirin users took a single tablet early in the prodrome and became ill with Reye's Syndrome many days later. Other patients took no aspirin until the day the symptoms of Reye's Syndrome began. Both of these types of patients were combined with subjects who used aspirin regularly from the beginning of the prodronal illness to the onset of the Reye's Syndrome. We have previously proposed that patients be classified according to their pattern of aspirin use and separately analyzed. No atten- tion to this issue is evident in the preliminary analysis of this data. Summary We wish to emphasize that our comments are based on a small portion of the data already coded by the investigators and made available to us as part of a special data tape. We did not have access to any of the questionnaires or medical records of the subjects included in the pilot case-control study. Perhaps the most important conclusion of our review is the need for more data. Without the medical records, we cannot perform a careful and thorough assessment of the work completed by the investigators, Consequently, we are not able currently to conclude that the pilot study provides convincing evidence for a valid association between aspirin use and the risk of Reye's Syndrome. PAGENO="0645" 639 Mr. WAXMAN. The Centers for Disease Control, American Acade- my of Pediatrics, Secretary of Health and Human Services, the Food and Drug Administration, all believe there is credible evidence of the connection of aspirin to Reye's Syndrome. The Aspirin Foundation, which I assume is made up of aspirin manufacturers, has been willing to undertake a voluntary labeling. Is that right, Dr. White? Dr. WHITE. Yes, but not accepting that there is any connection. Mr. WAXMAN. I see. Now, the central issue to parents is whether or not they should give their children aspirin to treat the discom- fort of chicken pox or flu. And, if you believe that there is a suffi- cient scientific evidence to justify a precautionary warning, what possible purpose is served if that message is not clear and unambig- uous? Dr. White, don't you think that message ought to be clear enough to warn parents not to use aspirin for those symptoms? Dr. WHITE. I think if you look at our total package it is clear. We have great concern about labeling properly because of all the things that should be on the label and perhaps they all have equal weight, and on the other hand, when we deal with Reye's Syn- drome, which we do in the case of public service announcements, and also the posters, we not only describe there is the potential for this relationship, we also describe the symptoms of the onset of Reye's Syndrome and what the action of the parents should be at the time. Mr. WAXMAN. Are you willing to say that your position is that there is a potential connection between aspirin and Reye's Syn- drome and therefore a parent should be aware of that if they are going to give their children aspirin to treat chicken pox or influen- za? Dr. WHITE. I am saying that there is-- Mr. WAXMAN. Would you subscribe to what I just said? I will repeat it. Is the statement you would subscribe to, there is a poten- tial enough connection between aspirin and Reye's Syndrome that parents may not want to give their children aspirin to treat dis- comfort of chicken pox or flu? Dr. WHITE. As I said before, just a few minutes ago, we do not subscribe to the link that has been proposed. We do believe that there are some people who are willing to accept it and being con- fronted with the request, voluntarily-keep in mind that that means-to label, we decided that it was reasonable to cooperate and that is what we are doing. Mr. WAXMAN. OK. I appreciate the testimony each of you has given. I think the clear statement you have made is that whatever is being done is being done voluntarily, and to the extent that any- body voluntarily is willing to make some kind of statement that shows the connection depends on each individual company. There is only one company that has made a clear, unequivocal statement close to that label, that is Schering-Plough. Isn't that a fair characterization? I might just point out Schering-Plough's product is St. Joseph's aspirin for children~ It is aspirin for chil- dren. Therefore, one might wonder if their warning label is more explicit because of their fear of liability because their aspirin is geared for children. PAGENO="0646" 640 Dr. WHITE. I can't speak to that, but I do know they are market- ing a nonaspirin for children. Almost every other physician who has been up here today has asked what about his children and his grandchildren, and I have said on public television I have made no effort whatsoever to communicate any concern on my part to my son about his son and my grandson in regards to Reye's Syndrome. Mr. WAXMAN. Do you figure that he is one of the 80 percent that has heard about it already from the public service announcements? Dr. WHITE. That may be the case, but I haven't tried to reinforce it or tried to lead his knowledge of that by calling him up ahead of time. Mr. WAXMAN. Have you asked whether he has knowledge of it? Dr. WHITE. No, I haven't even done that. Mr. WAXMAN. Thank you very much. Mr. Wyden. - Mr. WYDEN. Thank you, and this has been an important panel, and helpful panel to me. Dr. White, I came to this hearing not having any misgivings about the safety and effectiveness of aspirin. I think it is a tremen- dous medical program in and of itself, but I really hope the indus- try will now take steps to answer some of the serious questions that have been raised. I want to get into just a couple of the areas very briefly. You heard the testimony of the American Academy of Pediatrics, their advice to parents and physicians is extremely clear-in the case of chicken pox and flu, be safe, don't go with as- pirin. It seems to me that by not mentioning a Reye's Syndrome in the precautionary label and instead asking parents to consult their physicians, we are essentially diluting the effectiveness of any warning. Do you agree with that appraisal? Dr. WHITE. We have some concern about what impact this pro- posed warning would have on the other warnings that are on the label. One of the most important ones is concern this product ought to be out of the reach of children. There is much more of a problem in the United States with that than there is with Reye's Syndrome. Mr. WYDEN. Proceeding, if I might, to get your reaction to this very impressive testimony of the American Academy of Pediatrics, the approval and scientific body for pediatricians, I would like to know whether you suspect individual pediatricians might exercise different risk assessments than those used by the academy in eval- uating the danger of aspirin in young children? Dr. WHITE. I believe that Mr. Chayet has very good evidence there are a lot of pediatricians who don't hold to that position. These groups that are groups of physicians very seldom represent the rank-and-file position. Mr. WYDEN. I think that is certainly making light of approval of an association with enormous prestige in this field. The APA is rec- ognized as the premier representative of pediatric medicine, and you seem to think that they are just not very important. What do you advise a worried parent, then? Go with the advice of the Amer- ican Academy of Pediatrics, or go with the critics? You are telling me- PAGENO="0647" 641 Dr. WHITE. I am telling the individual, first of all, they ought to seek some kind of professional help; that it is an individual deci- sion and their doctor ought to make the decision. Mr. WYDEN. But the professional association made up of those doctors, clearly singled out by those doctors as prestigious and phil- osophical, a professional association with great stature, has given us counsel and yet you seem to think that worried parents should look at something other than what the pediatricians are saying. I am just wondering what parents should look at in that case. Dr. WHITE. What we are doing right now, I believe, is cautioning people not to use aspirin for children and teenagers who have chicken pox or flu without first consulting their doctor. We are not convinced of the cause-and-effect relationship here. We have agreed that there is enough concern and there is enough confusion that there ought to be a single message and here it is, and we are very serious, spending day and night trying to get that message out. Mr. WAXMAN. Would you yield? Mr. WYDEN. Yes. Mr. WAXMAN. The Secretary of Health and Human Services is allowing you to decide voluntarily whether to warn people about something you don't believe, that is there a clear connection be- tween taking aspirin and Reye's Syndrome. The Department claims they believe it but they are saying the best way to get the message across is to let you, who do not believe it, communicate that mes- sage. I think what we have is a clear communication of the fact you don't believe it and therefore nobody is going to get that opin- ion from you. It seems to me that is quite an amazing position for the Food and Drug Administration and the Department to take to let somebody who doesn't believe in a position be the one to communicate that position. Mr. DICKSON. May I address that, because it does address the dis- cussions we have had with the Food and Drug Administration. Mr. WAXMAN. I said it more rhetorically. It is Mr. Wyden's time. Mr. WYDEN. Thank you, fine. Mr. DICKSON. The fact is the Food and Drug Administration is not saying that there is a definite link between aspirin use and Reye's Syndrome. In fact, the Food and Drug Administration has told you today that they did not have enough evidence to regulate. Under that circumstance, a voluntary program makes a lot of sense. Mr. WYDEN. The Food and Drug Administration said there was a probable connection, No. 1, and we brought out an incredible array of prestigious scientists-the chairman just read them off-all of them agreed there is a link. What kind of evidence would convince you? How much more evi- dence do we have to have? Only an industry-done study-is that basically it? Mr. DICKSON. No; that is not basically it. But a good study, sir, and the data that have been discussed today, the pilot study that has been talked about, was a preliminary study, just to look at methodology. PAGENO="0648" 642 FDA has said the study they are running must be completed. We have not yet seen the protocol for FDA's study, so we don't know what it is going to look like. Mr. WYDEN. Let me read you from the Department's pilot study: Recently completed for the Department of Health and Human Services substan- tially strengthens earlier evidence of association between the use of aspirin contain- ing drugs and the development of Reye's Syndrome. So all the evidence is cascading upon us. I wrap this up by put- ting it in a personal context: I am a parent of a 1-year-old who we hope we will see as a backcourt star for the Portland Trail Blazers in a few years and I come away from this hearing having signifi- cant doubts about whether or not what we are doing in this critical area is going to promote public health and safety. You have taken somebody who had no doubts 3 or 4 hours ago when we started and I have been convinced that there are many unanswered questions. I am very fearful that we are going to let this problem slide through the next flu season and more and more parents and more and more children will suffer and it is all unnecessary. Thank you, Mr. Chairman. Mr. WAXMAN. Just for the record, Mr. Chayet, you say in your testimony "It is essential the committee indicated," refers to the committee you represent, That it works in areas which relate to industry and would be funded primarily by industry because of the belief that industry has an obligation to fund arms length efforts to seek the truth with regards to matters of controversy. I want to point that out. Mr. CHAYET. We believe that strongly, Mr. Waxman. There has got to be a search for truth. Industry has to-I asked Dr. Wolfe's organization for money, I don't know whether the check is in the mail or not-but really, I am serious. Where will the funding come from? Mr. WAXMAN. Are you a scientist? Mr. CHAYET. I am an attorney, sir. Mr. WAXMAN. OK. Mr. CHAYET. I have spent my life with scientists and I look for the ones that I can trust and believe in, and all the people you have heard from today, they are fine people, they are under tre- mendous pressures because of the early errors that were made by the-- Mr. WAXMAN. You are an attorney and represent an organiza- tion that has funds from the aspirin industry; is that a correct statement? Mr. CHAYET. You can say that real quickly, but that is the way it really is, because this is a matter of life and death and I believe that my profession has an obligation not to just say things, because we are attorneys, that we don't believe in. It is about time we change that. I have to tell you I have gone everywhere and I will bring you with me to the scientists to seek the truth. I can tell you if we ever found out, and not after 10 years of study, and without nitpicking, if we ever found out that there was a relationship be- tween Reye's Syndrome and aspirin, we would be the first to be before you to say so, sir. Mr. WAXMAN. That is what they say in law school. PAGENO="0649" 643 Mr. CHAYET. I resent that comment; I am sorry. Mr. WAxM~i~. You have to make the best case you can. That concludes our hearing for today. We thank all the witnesses for participating. Our meeting stands adjourned. [Whereupon, at 1:05 p.m., the hearing was adjourned.] [The following letters and statements were submitted for the record:] PAGENO="0650" 644 GASTON SNOW & ELY BARTLETT COUNSELLORS AT LAW JO6~0W80~TLETT (1901-1960) ONE FEDERAL STREET BOSTON, MASSACHUSETTS 02110 PALO ALTO CALIFORNIA 94306 617/426-4600 TELECOPY4I5/65 6-9299 March 28, 1985 CO~A~GABL~5,FLORI The Honorable CABLP:REEKOM Henry A. Waxman Subcommittee on Health & Environment 006006 6600 U.S. House of Representatives Room 512, House Annex I PCOENIO,ARIZONA8SOI6 Washington, DC 20515 Dear Congressman Waxman: Once again, on behalf of the Committee on the Care of Children(CCC), I would like to express our appreciation at having been invited to present testimony to you and other mem- bers of the Subcommittee. As I indicated to you at the opening of my testimony, Dr. David Lang, who was to appear as a member of the Coordinating Committee of the CCC and present its testi- mony, was unable to be present because of a medical emergency in his own family; I expect that you received his telegram expressing his regret, the reason for his absence, and his endorsement of the testimony presented to the Subcommittee on Friday, March 15, 1985. I am enclosing for the record a final copy of the statement and attachments presented and would appreciate it if you would see that the final copy of the statement and this letter are entered into the record. I would also appreciate it if you would provide me with a transcript of my oral remarks for review at your earliest convenience, in the event any corrections are necessary prior to insertion into the record. There are several points that I would like to clarify fol- lowing the hearing, and also several requests that I would like to make on behalf of the Doctors. First of all, I would like to reiterate that legislation calling for mandatory labeling is well-motivated, based on the information that you and your staff have apparently received. Your repeated statements that the "science is not in question" indicates that you have not been made aware of the fact that not only is the science in question, but a great deal of the previous science on which the PAGENO="0651" 645 GASTON SNOW & ELY BARTLETT The Honorable Henry A. Waxman Subcommittee on Health & Environment March 28, 1985 Page 2 bill is based has been discredited. The action of former Secretary Schweiker in reversing the call for the labeling of aspirin was not merely a fluke, nor was it because of industry pressure; it was, we believe, because of the stark realization that the scientific basis simply was not present to support such action. Similarly, the statement of the Executive Board of the Academy of Pediatrics, supporting that reversal and calling for new studies, was also not based on industry pres- sure, but again, on the realization that the scientific basis for the action was fatally flawed. I would be very pleased to provide you with additional materials which indicate just how poor the early studies were and also to arrange for you to meet with those who have reviewed this material in depth. I would like to. reiterate that it is the CCC's opinion that the massive publicity campaign in the face of the discrediting of the early data is inappropriate and dangerous. We believe that children may have died because they were the victims of delayed diagnosis of Reye's Syndrome, with their parents believing they could not possibly have Reye's Syndrome, because they did not take any aspirin. In addition, we believe that, as was made very clear at the hearing, there is no question but that the publicity is leading parents and children to take other drugs which could possibly be implicated in Reye's Syndrome. I call your attention to a copy of an article, enclosed with our statement, which appeared in the respected journal, Pediatric Research, indicating that acetaminophen could be implicated in Reye's Syndrome. Thus, your no doubt well-intentioned remarks concerning Tylenol could turn out to be tragically wrong. Most physicians and scientists with whom we have spoken doubt that either aspirin or acetaminophen are implicated in Reye's Syndrome, but the fact is that the question has not been well-studied, and the article raises the spectre that millions of people may be sent down the wrong road with no justification whatsoever. Prior to the hearing held on March 15, we believed that the present course of events was merely misleading and dangerous; following the testimony presented by the parents who appeared befQre you, we now believe that it is not only misleading and dangerous, but that it is extraordinarily cruel to parents who have lost their children to Reye's Syndrome. If there was ever any question that the actions of the government and other groups have convinced people that their children would not have PAGENO="0652" 646 GASTON SNOW & ELY BARTLETT The Honorable Henry A. Waxman Subcommittee on Health & Environment March 28, 1985 Page 3 died but for their having given them aspirin, the hearing has erased any such doubt. To fasten this burden upon these parents--that they contributed to their childrens' death--on the basis of the scientific evidence available to date, is unconscionable. The fact that publicity and inappropriate labeling could cause death or disability by delaying diagnosis, together with the burden placed on parents who had given their children aspirin in an attempt to help them, vastly overshadows all other aspects of this matter. It must be noted, however, that this entire matter has had a devastating impact on the physician-patient relationship, as well. It is true that the results of the pilot study have been recently released and that this study has been endorsed by the Institute of Medicine. The pilot study indicates an association between aspirin and Reye' s Syndrome. We would very much like to be supportive of this study, and as I indicated to the Subcommittee at the hearing, we will not hesitate to endorse it if such endorsement is indicated following a review of the raw data on which the study is based. Since the announcement of this pilot study, however, we have made an attempt to secure the raw data on which it is based'and thus far have been unsuccessful in secur- ing what is needed to analyze the reported results. What we have found has led a noted researcher and clinician to conclude that a valid association cannot be confirmed at this time. In addition, Dr. Floyd Denny, who has been involved in observing this study, has recently been quoted as stating that the study is flawed. Representatives of the government have been consid- ering our requests for additional data and thus far have indi- cated that they cannot be made available because of Freedom of Information and Privacy Act considerations. We earnestly request your help and that of the Subcommittee in helping to secure the release of this data, without which we will not be able to fully review the study. The Doctors have no desire to identify any of the patients or families involved and, in fact, are ethically and legally bound not to violate any confidentiality, and would be willing to enter into any further agreements to reassure all parties that such violation would not occur. The question now remains ~is to the future. Because of the past difficulties that have surrounded and continue to surround PAGENO="0653" 647 GASTON SNOW & ELY BARTLETT The Honorable Henry A. Waxman Subcommittee on Health & Environment March 28, 1985 Page 4 the government studies in this area, we believe that it is essential for another study to be launched as quickly as pos- sible. P preliminary protocol has been prepared by a group of excellent researchers and clinicians at a leading University. This protocol, if implemented, would involve thousands of clinicians throughout the country in a study of Reye's Syndrome. This study would not be carried out in a manner that would be adversarial or hostile to any further government stud- ies, and, in fact, extensive efforts are underway to assure that such a study will be carried out cooperatively. The pre- liminary protocol which has been prepared is excellent and innovative. In addition, steps have been taken to insure that the protocol, its implementationS and the study results are credible. The American Academy of Pediatrics has appointed a liaison to the study; this distinguished physician has, in turn, been asked to chair an Advisory Panel which will consist of some of the best clinicians and epidemiologists from throughout the country. In addition, there is being consid- ered ways to involve all those who have had an interest in this matter, including patient and consumer groups, as well as rep- resentatives of the press and the government. We would also hope that a member of your staff could participate in this pro- cess. The goal is to insure that the study is carried out with complete integrity. There is another matter to which I would like to call your attention. I expect that the reason I was called to the table with the Aspirin Foundation and the Proprietary Association was because of the need for economy of time. As I indicated to you and to the other members of the Subcommittee, the CCC does not represent and is not a part of industry; it never has been and it never will be. We believe, however, that industry has an obligation to find out whether its products are causing harm to the public, and if industry claims that a government study is faulty, it has an absolute duty not only to criticize that study, but to see to it that such studies are impartially reviewed, and that additional studies are carried out at arms- length. Lastly, I would like to clarify one further point. You asked me if, in fact, I was an attorney representing this group of physicians and I replied in the affirmative; I also added that in matters such as this which involve life and death, I believe that an attorney has an obligation to represent both PAGENO="0654" 648 GASTON SNOW & ELY I~ARTLETT The Honorable Henry A. Waxman Subcommittee on Health & Environment March 28, 1985 Page 5 the interests and positions of his clients, and also to be cer- tain that the position of his clients is fully supportable. ~From the very beginning, it was the clear wish of our clients that we secure the best and most impartial clinicians and scientists to advise all of us with regard to this matter, and we have done so. I would respectfully request the following of the Subcommittee: 1. That action on H.R.l38l be delayed pending further analysis of the conclusions of the pilot study; 2. That, in order to hasten this process, which will take a relatively short time once the data is made available, that the Subcommittee assist in securing the data as quickly as pos- sible; 3. That the Subcommittee assist in the monitoring of the review of the data of the pilot study, the proposed government study, and the clinician-based study referred to above; 4. That a member of the Subcommittee staff be commissioned to review the raw data of all studies to date, a process which we would be pleased to assist in any manner deemed appropriate; and 5. That the Subcommittee assist in expediting the Citizens' Petition enclosed with the attached statement, which would establish ground rules and criteria for public warnings. Again, we appreciate the opportunity to be of assitance to the Subcommittee in this most difficult situation. Sincer y, Ne~'~C~ Enclosures PAGENO="0655" 649 Natonal Assodatkn of Tn~ck Stop Operators 1199 N. Fairfax Street Suite 801 P.O. Box 1285 Alexandria. Wginia 22313 (703) 549-2100 March 28, 1985 The Honorable Henry A. Waxman Chairman Subcommittee on Health & Environment House Committee on Energy & Commerce 2415 Rayburn House Office Building Washington, D.C. 20515 RE: H.R. 1381, Emergency Reye's Syndrom Prevention Act of 1985. Dear Chairman Waxman: The National Association of Truck Stop Operators wishes to go on record as opposing certain provisions contained in Section 2 of H.R. 1381, requir- ing retail establishments which sell aspirin and salicylate-containg pro- ducts to display the notice prescribed elsewhere in the Section. Although the association understands the objectives sought to be achieved in the bill, subjecting truck stop operators who sell these products to criminal misbranding penalties under the Food, Drug and Cosmetic Act is unwar- ranted, unjustified and beyond the proper scope of that statute. The National Association of Truck Stop Operators ("NATSO") is a non-profit trade association located in Alexandria, Virginia. Among its membership are approximately 800 individual truck stop operators who collectively provide a full range of services to the trucking industry and the travel- ling public. These businesses represent a significant portion of the fuel marketing, motel, restaurant, convenience store operations, and repair services available along with the nations Interstate and federal highway system. In addition, NATSO members are predominantly small businesses. As independent marketers of petroleum products, truck stop operators have fought to minimize government intrusion into various areas of energy regulation. Similarly, the truck stop industry has contended with efforts to force these businesses to shoulder unfair burdens under the environ- mental laws, as well as heavy tax burdens. The effect of H.R. 1381 is to impose yet another unreasonable burden on truck stops in the form of the proposed posting provision. It is to this almost-hidden aspect of the bill that NATSO takes strong exception. PAGENO="0656" 650 The Honorable Henry A. Waxman March 28, 1985 Page Two Truck stop operators are not well suited to comment on the parent major elements of H.R. 1381. NATSO truck stop members do not manufacture or principally distribute the over-the-counter (OTC) medicines to which the bill is directed. Neither do NATSO members undertake, ir~ any organ- ized effort, to advertise such products, the sales of which represent inf in- itesimal percentage of the business conducted by this industry. Appro- priate responses on the labeling and media advertising requirements which would be imposed by the bill are best left to those groups who are direct- ly affected. However, NATSO members stock and sell OTC medicines, including aspirin, because they are commonly requested by customers. Consequently, truck stop operators would be subject to the warning display provision and the related criminal penalty for "misbranding" proposed by the bill. NATSO submits that this proposed posting provision and penalty for retail establishments exceeds the jurisdiction Congress has fundamentally placed in the Food & Drug Administration. The Food, Drug and Cosmetic Act as it presently reads does not empower the FDA to promulgate regulations applying to retail establishemnts and H.R. 1381 should not mandate that such authority now be created. Any amendment which would have the significant and pervasive effect of rewriting FDA's basic jurisdiction should not be adopted as "throw" to a bill addressing a specific health question. Such a change should only be adopted after Congress has conducted a detailed study and evaluation of the effects it would have. NATSO is aware that the FDA has previously issued a posting requirement effecting retail establishments in its saccharin regulations. This lone action, however, does not establish that the agency in fact possesses the authority to regulate retail businesses in the sale of otherwise regu- lated products. Moreover, Congress should be aware that this singular example of a retail posting requirement has been ineffective at best. The FDA has no capacity to enforce such a regulation and it therefore has not attempted to do so. Indeed, the posting provision proposed in H.R. 1381 would require an army of investigators trooping throughout the countryside invading grocery stores, drug stores, convenience stores, bars, airports, truck stops and nearly every conceivable type of retail establishment whose customers may expect to purchase a bottle of aspirin. Since the improbability and impracticality of this situation is apparent on its face, this subcommittee should refuse to consider imposing any posting requirements. The lack of legal basis to regulate retail businesses and the impossibility of enforcing such a provision should convince this subcommittee to reject the proposal. If not, NATSO contends that many retail establishments would be forced to elect not to sell aspirin and other salicylate-containing products rather than risk exposure to criminal penalties. The vagaries of happenstance enforcement, along with the inconvenience and expense of trying to comply with the provision, would make unacceptable the need to retail these products which do not constitute a meaningful amount of business for truck stops and other similar establishments. Although we doubt this subcommittee is seeking to remove these products from the shelves of these stores, that result would be the prudent course for many businesses, Instead, the subcommittee should focus its attention on ways to inform and educate the public, such as those described in the testimony of the Propietary Association and others who have suggested ways to achieve this goal. In conclusion, the National Association of Truck Stop Operators opposes the posting provisions of H.R. 1381 and recommends to the subcommittee that it seek other alternatives that would not impose an unnecessary and erroneous burden on retailers such as truck stops. We ask that this letter be included in the official record of the subcommittee's hearing on this bill. Sincerely RONALD L. Z GL FV President PAGENO="0657" 651 AMERICAN REYE'S SYNDROME ASSOCIATION STATEMENT ON H.R. 1381, THE "EMERGENCY REYE'S SYNDROME PREVENTION ACT OF 1985" The American Reye's Syndrome Association submits the following statement on H.R. 1381, the "Emergency Reye's Syndrome Prevention Act of 1985." H.R. 1381 would require a warning in the labeling and advertising of salicylate containing products and a notice in retail establishments where such products are sold to the effect that such products should not be administered to persons under 21 years of age who have chicken pox, influenza, or flu symptoms because the products are "strongly associated" with the development of Reye's Syndrome. Introduction The American Reye's Syndrome Association is a not-for- prof it, tax exempt organization composed of health professionals and laymen who seek to find the cause(s), cure(s), and treatment(s) of Reye's Syndrome. The Association is dedicated to informing the American public about all facets of Reye's Syndrome, with particular attention to the need for timely recognition of its symptoms. While there exists no cure for Reye's Syndrome, several treatment modalities are often effective in containing physiologic damage and minimizing residual effects such as neurologic injury. Early recognition of the symptoms is critical to the effective utilization of these treatment modali- ties. PAGENO="0658" 652 The Association has made its intellectual resources available to the federal government to render any assistance it can in efforts properly directed toward educating the public about Reye's Syndrome and toward the design and implementation of research programs directed at determining its causes and iden- tifying appropriate treatments and a cure. The Association will continue its efforts in this regard. The Association has been keenly interested in the debate concerning the alleged association between the use of salicylates and Reye's Syndrome. It has participated in numerous government and privately sponsored symposia regarding this alleged asso- ciation and, by virtue of its medical advisory panel and experience, is considered expert in the matter. In September, 1982 the Association's executive director testified as an expert witness before the Subcommittee on Natural Resources, Agricultural Research and Environment, Committee on Science and Technology, which investigated that alleged association. Reye's Syndrome Reye's Syndrome is a condition of unknown etiology which strikes between 600 and 1,200 children and adolescents in the U.S. per year. Some cases have also been reported in adults. It was first identified in 1963 by an Australian physician, Douglas PAGENO="0659" 653 Reye, and was later described in the U.S. by Dr. George .Johnson. Its symptoms classically appear following viral infections such as varicella and influenza. Those symptoms include unexpected vomiting, lethargy, personality change and, frequently, coma. Reye's Syndrome affects many body organs, particularly the brain and liver. Its mortality rate is believed to range from a low of 20 percent to a high of 40 percent. Surviving patients may incur neurologic damage. Others recover with no detectable residual effects. While there is no known cure for Reye's Syndrome, it can be treated by monitoring body fluids, relieving cranial pressure, aiding respiration, administering drugs, and implementing anti- convulsive measures. Such treatment significantly reduces the mobidity rate of the disease. Proper early diagnosis is criti- cal, however, to the administration of such treatment. Unfortunately, Reye's Syndrome is extremely difficult to detect and isolate because its symptoms are common to several well-known diseases. This difficulty is compounded by the fact that the lay community and even the medical community have only a limited familiarity with the disease. Thus, absent a confir- matory analysis of the liver tissue, misdiagnosis of Reye's Syndrome is believed to occur in 25% of cases. PAGENO="0660" 654 Position of the American Reye's Syndrome Association on H.R. 1381, The "Emergency Reye's Syndrome Prevention Act of 1985" The American Reye's Syndrome Association opposes H.R. 1381, the "Emergency Reye's Syndrome Prevention Act of 1985," because it would require manufacturers to misinform consumers that an association has been established between the use of salicylates and Reye's Syndrome. Such an association has in fact not been established. As the Subcommittee is aware, many cases involving Reye's Syndrome show no history of salicylate use or show the use of medications other than salicylates. Some studies suggest an association between certain environmental toxins and the disease. As the Subcommittee is also aware, the Department of Health and Human Services has concluded that present evidence is insuf- ficient to establish that such an association exists. The Association believes that since a relationship between salicylate use and Reye's Syndrome has not been established, warnings such as those required by H.R. 1381 could mislead con- sumers into thinking that by avoiding salicylates they would eli- minate the risk of Reye's Syndrome. In so doing the bill could actually hinder proper efforts such as those of the Association which are directed toward educating consumers about Reye's Syndrome in order to facilitate early recognition, diagnosis and treatment. PAGENO="0661" / 655 Discussion Studies conducted in Ohio, Michigan, and Arizona in 1981 prompted early interest in the question whether salicylate use was associated with Reye's Syndrome. The Association expressed its views on those studies in comments to the Food and Drug Administration dated February 25, 1983. Essentially, those views were that the studies were scientifically insufficient to warrant a Reye's Syndrome warning on salicylate-containing products, that additional studies should be undertaken, and that the resources of the federal government were better directed in the interim toward encouraging the early recognition, diagnosis, and treat- ment of Reye's Syndrome. Since then the results of the pilot phase of the U.S. Public Health Service study on the use of medications and Reye's Syndrome have been released. Those results showed a higher correlation between the use of aspirin and the incidence of Reye's Syndrome than between the absence of aspirin use and the incidence of the disease. As noted, the Department of Health and Human Services does not regard the results of that pilot study as sufficient to require a Reye's Syndrome warning on salicylate containing products. Rather the Department believes that the public should be informed of the results of the study, as it has been doing, and that the full study should continue. PAGENO="0662" 656 In addition, the Department and the aspirin industry have agreed that until the PHS study is completed, certain measures should be undertaken in the interests of protecting the public health. Those measures include removing label indications for flu from children's aspirin; labeling aspirin products with war- nings directing the consumer to his physician before admi- nistering aspirin containing products to children (including teenagers) with chicken pox or flu; and accompanying those efforts with an appropriate public education campaign. The Association supports these efforts as consistent with its goal of informing the public about all facets of Reye's Syndrome. The Association also urges that studies such as the PHS study be continued in order to determine with credible scien- tific evidence whether an association exists between the use of certain medications and Reye's Syndrome. The Association con- tinues to believe, however, that unless or until such an asso- ciation is demonstrated efforts such as those required by H.R. 1381 are misdirected because they would lull consumers into thinking that by avoiding the use of aspirin they will avoid the incidence of Reye's Syndrome. In so doing those efforts would hinder legitimate efforts such as those of the Association which are properly directed toward facilitating early recognition of the symptoms of the disease. PAGENO="0663" 657 The American Reye's Syndrome Association has concentrated its efforts on educating parents and physicians about Reye's Syndrome and its early warning signs. While empiric evidence is lacking as to the success of such programs, experience suggests that they are in fact extremely effective in increasing early awareness of the. symptoms of the disease and thereby help ensure adequate treatment. The Association will continue these public awareness campaigns via public service announcements, brochures, lectures and otherwise. Undoubtedly, the mission of the Association in this regard is an enormous one and merits the full cooperation and support of the federal government. The Association believes that undue preoccupation with the question whether an association exists between salicylate use and Reye's Syndrome has already done significant damage to early recognition programs. The Association is concerned that if war- nings of the type contemplated by H.R. 1381 are put into effect, efforts directed toward increasing early recognition of Reye's Syndrome will continue to be inappropriately undermined. Conclusion The American Reye's Syndrome Association supports the efforts of the Department of Health and Human Services and the aspirin industry as announced on January 23, 1985 by 11115 PAGENO="0664" 658 Secretary Margaret M. Heckler to remove label indications for flu from children's aspirin; to label aspirin products with warnings directing the consumer to his physician before administering an aspirin containing product to children, including teenagers, with chicken pox or flu; and to accompany these efforts with an appropriate public education campaign. Such efforts will have the effect of educating parents about Reye's Syndrome. The Association also believes that the proper and construc- tive role for the federal government is to fund further research on factors which may be associated with Reye's Syndrome, possibly including certain medications; to continue basic research on the disease; and to educate the public and the medical community about the disease g~ disease, especially early recognition of its symptoms and proper treatment thereof. The American Reye's Syndrome Association continues to pledge its full intellectual resources to aid in such efforts. The Association opposes, however, measures such as those contained in H.R. 1381, the "Emergency Reye's Syndrome Prevention Act of 1985," which would require warnings to the effect that an association has been established between use of such products and Reye's Syndrome. The present body of credible scientific knowledge on Reye's Syndrome does not establish such an asso- ciation. Warnings which state that it does would only serve to undermine efforts aimed at properly educating the public and the medical community about Reye's Syndrome. Respectfully, AMERICAN REYE'S SYNDROME ASSOCIATION PAGENO="0665" 659 Statement of the American Pharmaceutical Association The National Professional Society of Pharmacists THE AMERICAN PHARMACEUTICAL ASSOCIATION, THE NATIONAL PROFESSIONAL SOCIETY OF PHARMACISTS, IS PLEASED TO HAVE THIS OPPORTUNITY TO PRESENT ITS VIEWS ON FLR. 1381, THE "EMERGENCY REYE'S SYNDROME PREVENTION ACT OF 1985". WE WELCOME THE OPPORTUNITY TO PRESENT THIS STATEMENT FOR THE RECORD OF THE HEARING HELD BY THE HEALTH SUBCOMMITTEE ON H.R. 1381, THE "EMERGENCY REYE'S SYNDROME PREVENTION ACT OF 1985". As YOU KNOW, THE AMERICAN PHARMACEUTICAL ASSOCIATION (APHA), AND ITS THOUSANDS OF PHARMACIST MEMBERS HAVE HAD A CONTINUING DEEP INTEREST IN COMBATTING THE REYE'S SYNDROME PROBLEM, AND IN PROVIDING TO THE PUBLIC ACCURATE AND RESPONSIBLE INFORMATION TO ASSIST IN AVOIDING THE OFTEN TRAGIC CONSEQUENCES OF THIS DISEASE. APHA HAS COOPERATED FULLY IN EFFORTS TO IDENTIFY AND IMPLEMENT AN EFFECTIVE PUBLIC EDUCATION PROGRAM SINCE 1982 WHEN THE REYE'S SYNDROME ISSUE WAS FIRST BROUGHT TO ITS ATTENTION. BEFORE PROCEEDING TO SPECIFIC POINTS REGARDING THE BILL CURRENTLY UNDER CONSIDERATION BY YOUR SUBCOMMITTEE, WE WISH TO REVIEW THE ACTIONS TAKEN BY APHA TOWARD THIS END. PAGENO="0666" 660 IN THE FALL OF 1982. THE HEALTH RESEARCH GROUP (HRG) PROVIDED APHA WITH INFORMATION REGARDING FINDINGS OF AN ASSOCIATION BETWEEN THE USE OF SALICYCLATE CONTAINING DRUG PRODUCTS. PRIMARILY ASPIRIN. AND THE EXISTENCE OF THE DISEASE IN THAT POPULATION DEEMED AT RISK OF REYE'S SYNDROME. THE ASSOCIATION WAS REQUESTED TO SUPPORT A VOLUNTARY LABELING PROGRAM INITIATED BY HRG THAT WOULD HAVE PLACED A WARNING LABEL ON THE CONTAINER OF AFFECTED DRUG PRODUCTS SIMILAR TO THAT NOW SPECIFIED IN H.R. 1381. APHA, ALONG WITH THE AMERICANPUBLIC HEALTH ASSOCIATION, DID OFFER ITS SUPPORT FOR THE PROPOSED LABELING PROGRAM. HOWEVER. THE HRG PROGRAM PROVED TO BE SHORT-LIVED AT THAT TIME. THE HRG VOLUNTARY LABELING PROGRAM BECAME ENMESHED IN A STORM OF CONTROVERSY AS TO WHETHER SCIENTIFIC EVIDENCE ACTUALLY SUPPORTED THE ACTION PROPOSED. NONETHELESS. THE DEPARTMENT OF HHS PUBLISHED IN THE FEDERAL REGISTER ON DECEMBER 28. 1982 AN ADVANCE NOTICE OF PROPOSED RULEMAKING THAT WOULD HAVE REQUIRED BY REGULATION THE LABELING OF AFFECTED DRUG PRODUCTS WITH A REYE'S SYNDROME WARNING. IN RESPONSE TO THIS NOTICE. APHA FILED COMMENTS SUPPORTING THE HHS PROPOSAL AND SUPPORTING FURTHER STUDIES. APHA ARGUED THAT IN THE ABSENCE OF A CLEAR CONCLUSION BASED ON DATA THAT ANY ERRORS RESULTING THEREFROM SHOULD BE ON THE SIDE OF OPTIMUM SAFETY. PAGENO="0667" 661 SUBSEQUENTLY, THE HHS PROPOSAL WAS WITHDRAWN WITH AN INDICATION THAT ADDITIONAL SCIENTIFIC STUDIES SHOULD BE UNDERTAKEN TO RESOLVE THE SCIENTIFIC CONTROVERSY THAT HAD RAGED SINCE THE REYE'S SYNDROME ISSUE HAD BEEN PUBLICIZED. ALTHOUGH APHA THUS JOINED ALL INTERESTS IN AWAITING THE OUTCOME OF FURTHER SCIENTIFIC STUDIES, THE ASSOCIATION NEVER LESSENED ITS INTEREST IN, OR CONCERN ABOUT THE ISSUE, AND IT HAS CONTINUED TO KEEP ITS MEMBERS INFORMED ABOUT DEVELOPMENTS REGARDING THE PROBLEM. THE NEXT SIGNIFICANT EVENT, FROM APHA'S STANDPOINT, WAS THE RELEASE IN JANUARY 1985 OF THE REPORT OF THE NATIONAL ACADEMY OF SCIENCES INSTITUTE OF MEDICINE: "THE PHS STUDY OF THE REYE SYNDROME: RECOMMENDATIONS BASED ON A REVIEW OF THE PILOT STUDY DATA". IT IS NOT NECESSARY TO RECOUNT THE DETAILS OF THE IOM REPORT. FOR APHA, IT WAS SUFFICIENT THAT THE STUDY REPORT WAS DEEMED TO SHOW "A STRONG ASSOCIATION BETWEEN THE REYE SYNDROME AND THE USE OF ASPIRIN." THIS INFORMATION, COUPLED WITH THE IOM OBSERVATION AND RECOMMENDATION THAT "CONSIDERING THAT DATA FROM PREVIOUS STUDIES ALSO SHOW AN ASSOCIATION OF USE OF ASPIRIN AND REYE SYNDROME.. .STEPS SHOULD BE TAKEN TO PROTECT THE PUBLIC HEALTH BEFORE THE FULL STUDY IS COMPLETED", CAUSED APHA TO REACT AS PROMPTLY AS IT COULD. THE FEBRUARY 1, 1985 ISSUE OF AEJIARMACY WEEKLY, THE APHA NEWSLETTER. SENT TO APPROXIMATELY 50,000 APHA MEMBERS. PAGENO="0668" 662 CARRIED AN INSERT POSTER WARNING THE PUBLIC ABOUT REYE'S SYNDROME AND THE ASSOCIATION BETWEEN THE DISEASE AND THE USE OF ASPIRIN IN THE POPULATION AT RISK. APHA MEMBERS WERE URGED TO USE THE WARNING POSTER AND PERMISSION WAS GRANTED FOR ITS REPRODUCTION. A COPY OF THE POSTER IS ATTACHED FOR THE INFORMATION OF THE SUBCOMMITTEE AND FOR THE HEARING RECORD. THE APHA ACTION WAS CONSISTENT WITH, AND RESPONSIVE TO, THE URGING OF HHS SECRETARY HECKLER THAT THE PUBLIC BE GIVEN SUCH WARNING. IN ADDITION, APHA CONTINUED TO REPORT TO ITS MEMBERS ON THE ACTIONS OF THE U.S. ASPIRIN MANUFACTURERS IN VOLUNTARY LABELING CHANGES IN THEIR PRODUCTS AS PART OF A NATIONAL EDUCATION PROGRAM. APHA WILL CONTINUE TO KEEP ITS MEMBERS INFORMED OF REYE'S SYNDROME DEVELOPMENTS. THE MARCH 1985 ISSUE OF THE ASSOCIATION'S JOURNAL, AMERIcAJi PHARMACY, CARRIES A COMPREHENSIVE ARTICLE REGARDING THE CURRENT STATUS OF THE SITUATION. A COPY OF THIS ARTICLE ALSO IS ATTACHED FOR THE INFORMATION OF THE SUBCOMMITTEE AND FOR THE HEARING RECORD. WHATEVER THE OUTCOME OF FURTHER STUDIES CONDUCTED WITH REGARD TO AN ASSOCIATION BETWEEN THE USE OF SALICYLATE CONTAINING DRUG PRODUCTS AND REYE'S SYNDROME. APHA IS SATISFIED THAT TAKING STEPS TO ALERT AND EDUCATE THE PUBLIC REGARDING THIS SITUATION IS PRUDENT. WE ARE SATISFIED THAT THE ASSOCIATION HAS ACTED BOTH RESPONSIBLY AND JUDICIOUSLY IN RESPONDING TO THIS PROBLEM. PAGENO="0669" 663 TURNING TO H.R. 1381, APHA IS CONCERNED THAT THIS VEHICLE FOR ACTION MAY. HAVE AN INHIBITIVE EFFECT ON VOLUNTARY EFFORTS IN THIS AND FUTURE SIMILAR SITUATIONS. THIS STATEMENT HAS NOTED THE EFFORTS MADE BY APHA TO ALERT ITS MEMBERS AND THE PUBLIC TO THE REYE'S SYNDROME PROBLEM AND MANY IMPORTANT FACTS ABOUT IT. THESE STEPS WERE TAKEN BY THE ASSOCIATION IN ITS SENSE OF PROFESSIONAL RESPONSIBILITY. Now, THE ASSOCIATION FINDS THAT THE INFORMATION AND MATERIALS IT HAS PROVIDED ITS MEMBERS WOULD BE OUT OF COMPLIANCE WITH THE SPECIFIC REQUIREMENTS OF H.R. 1381. WE WOULD ALSO CALL TO YOUR ATTENTION THAT PROVISIONS OF THE BILL REQUIRING INCLUSION OF THE WARNING "IN ALL ADVERTISEMENTS" PLACED BY PHARMACIES WOULD BE IMPOSSIBLE TO SATISFY IN MANY INSTANCES. IN CASES WHERE THE TECHNICAL REQUIREMENTS CAN BE MET, THE PRACTICAL RESULTS STILL LIKELY WILL BE ELIMINATION OF PHARMACY ADVERTISEMENTS FOR AFFECTED DRUG PRODUCTS. THE PROBLEM EXISTS BECAUSE OF THE REQUIREMENT THAT THE WARNING IN SUCH ADVERTISEMENTS BE PRINTED, AT LEAST IN PART. IN YELLOW AND RED INK. MANY PUBLICATIONS CARRYING PHARMACY ADVERTISEMENTS DO NOT HAVE THE CAPACITY FOR MULTICOLOR PRINTING OR THE CAPACITY TO PRINT IN THE COLORS SPECIFIED. MOREOVER. THE PAGENO="0670" 664 COST OF REQUIRED MULTICOLOR ADVERTISEMENTS, EVEN IF TECHNICALLY POSSIBLE, IS SO MUCH GREATER THAN A "BLACK AND WHITE" AD, THAT PHARMACIES CAN ONLY BE EXPECTED TO FOREGO THE ADVERTISING OF AFFECTED DRUG PRODUCTS. APHA BELIEVES THAT H.R. 1381 ALSO IS TOO BROAD IN ITS APPLICATION TO SALICYLATE CONTAINING DRUG PRODUCTS. THE SUBCOMMITTEE SHOULD BE AWARE THAT MANY TOPICAL DRUG PRODUCTS (LIMITED TO EXTERNAL USE) CONTAIN SALICYLATES. To APHA's KNOWLEDGE, THERE IS NO EVIDENCE WHATSOEVER, NOR HAS THERE EVER BEEN ANY SUGGESTION. THAT SUCH DRUG PRODUCTS ARE IMPLICATED IN THE CAUSATION OF REYE'S SYNDROME. To THE ASSOCIATION'S KNOWLEDGE, ONLY DRUG PRODUCTS THAT ARE INGESTED HAVE BEEN ASSOCIATED WITH THE DISEASE IN THE POPULATION AT RISK. MR. CHAIRMAN, APHA PLEDGES ITS CONTINUED SUPPORT OF EFFORTS TO ERADICATE THE THREAT OF REYE'S SYNDROME AND TO EDUCATE THE PUBLIC REGARDING THIS DREAD DISEASE. THE ASSOCIATION STANDS READY TO ASSIST IN VIRTUALLY ANY WAY THAT IS PRACTICAL AND REASONABLE TO ACHIEVE THESE OBJECTIVES. WE WELL RECOGNIZE THAT YOUR MOTIVATION IN THE INTRODUCTION OF H.R. 1381 HAS THE SAME AIMS. PAGENO="0671" 665 WE MUST NOTE. HOWEVER. THAT ALTHOUGH APHA BELIEVES THAT CURRENT STEPS TO ALERT AND EDUCATE THE PUBLIC ABOUT THE ASSOCIATION BETWEEN SALICYLATE CONTAINING DRUG PRODUCTS AND REYE'S SYNDROME ARE FULLY JUSTIFIED. THE FINAL SCIENTIFIC JUDGMENT IS YET TO BE MADE WITH REGARD TO THIS ISSUE. FURTHER PLANNED STUDIES SHOULD PRODUCE SUFFICIENT DATA TO ASSIST IN THE RESOLUTION OF THIS SCIENTIFIC CONTROVERSY. APHA PLANS TO WORK WITH OTHER ORGANIZATIONS TO CONTRIBUTE TO AN ANALYSIS OF THE DATA. THE APHA AND THE AMERICAN ACADEMY OF PEDIATRICS (AAP) WILL JOINTLY REVIEW THE DATA SOON TO BE RELEASED ON THE ASSOCIATION BETWEEN SALICYLATE CONTAINING DRUG PRODUCTS AND REYE'S SYNDROME. THE SCIENTIFIC EXPERTISE OF APHA's ACADEMY OF PHARMACEUTICAL SCIENCES AND THE CLINICAL EXPERTISE OF AAP WILL FORM THE BASIS OF APHA POLICY ON THIS MATTER IN THE FUTURE. AND FOLLOWING OUR REVIEW WE WILL BE PLEASED TO DISCUSS THIS WITH YOU IN GREATER DEPTH. 0269P PAGENO="0672" 666 t~u~ A study by the Federal government's Centers for Disease Control has found a strong association between the use of aspirin in children with flu or chicken pox and the development of the potentially fatal illness Reye's Syndrome. Symptoms of Reye's Syndrome include vomiting, fever, lethargy, and convulsions. The symptoms generally appear as the child seems to be getting better. * Do not use aspirin for children or teenagers with the flu or chicken pox without first consulting a physician. * If symptoms of Reye's Syndrome appear, immediate medical attention is required. For additional information, consult your pharmacist. The American Pharmaceutical Association ` The national professional society of pharmacists PAGENO="0673" 667 HHS Gets Voluntary Label Warning On Aspirin-Reye's Syndrome Link Plough, Inc., which makes the St. paign to ensure that parents [are] be a consequence of the "decline in Joseph line of aspirin products, made aware of the possible link." use of salicylates among younger agreed on January 10, 1985, to co- One specific measure taken by children in recent years." Unaware operate with the request from Health Heckler was to ask that "makers of of the possibility of Reye's in their and Human Services Secretary Mar- aspirin products take two steps vol- older children, parents may be con- garet M. Heckler to add warnings to untarily. tinuing to give aspirin to them for aspirin labels about a possible link * First, to immediately remove any chickenpox or flu. between aspirin and the sometimes labels which recommend that aspi- In CDC's pilot study, nearly 50% fatal children's disease, Reye's syn- on products be used to treat flu or of ail cases investigated occurred in drome. chickenpox in children or teenagers; children over age 10, and 15% were By the next day, other major man- I Second, to label all aspirin prod- in those aged 15 and older. ufacturers, acting through the As- ucts to indicate that there is a pos- pirin Foundation, had also decided sible association between the use of Industry Response to go along with the HHS recom- aspirin and Reye's syndrome in chil- In responding to Heckler's re- mendations. dren and teenagers, and that aspirin quest about new labeling, Plough In early January, the National should not be used in those cases Inc., stated that the company would Academy of Sciences' Institute of unless a physician is first con- go along with the suggested changes, Medicine (IOM) released its critique sulted." although it still has its doubts about of the Centers for Disease Control's Heckler asked that the new label- the reality of any health risk to chil- pilot study of the alleged connection ing be retained until the full-scale dren from using aspirin. between the use of aspirin in chil- CDC study has been completed and In a statement on its action, a dren who contract chickenpox or flu its data thoroughly analyzed. Plough spokesperson said, "We in- and the later onset of Reye's. Be- The Aspirin Foundation agreed to tend to cooperate with the secre- cause of the strength of the findings, delete from children's aspirin label- tary's request for label changes lOM, which had previously been ing any suggestions for use in flu, pending further studies. Within adamantly opposed to releasing the and to add: "Consult a physician be- minutes of the secretary's state- preliminary results of the pilot phase fore giving this medicine to chil- ment, Plough started examining all of the investigation, reversed itself dren, including teenagers, with reasonable steps to develop a pro- and strongly recommended that: chicken pox or flu." Labels will ap- gram in response to the secretary's 1. The Public Health Service release pear on products by the next flu sea- request." the results of the pilot study to the son. On January 16, Ralph Nader's public and to scientists for review Heckler also stated that she was Public Citizen Health Research and analysis. planning to communicate with me- Group, long an advocate of warning 2. Because analysis of the pilot study dia leaders, including the presidents labels about the Reye's-aspirin con- data reveal a strong association be- of the major networks and the nection, petitioned the Federal Trade tween Reye's syndrome and the use American Newspaper Publishers Commission to require that all ad- of aspirin, in concert with previous Association. She asked that they run vertisements for aspirin include cau- investigations of the epidemiology public service announcements al- tionary statements on the potential of the illness, "steps should be taken ready supplied to them, and also give link. Public Citizen asserts that even to protect the public health before the new data special news coverage, if aspirin labels are changed, the in- the study is fully completed." dustry's print, television, and radio 3. The publicity generated by the New Trends commercials "currently mislead par- release of the results is not likely to One important point, she said, ents into believing that there is no prejudice the results of the full-scale deserved particular emphasis. Sur- danger in giving aspirin-containing study any more than "the current veillance data reported to CDC dur- medications to their children who climate of public opinion." ing 1984 revealed that only 190 new have chickenpox, flu, or flu-like cases of Reye's syndrome occurred symptoms." Labeling changes (compared with 379 in 1974 and 198 Although it has not y~t taken any Based on these recommenda- in 1983); however, the number of of the request, FTC spokesperson tions, Secretary Heckler issued a for- cases among children over 10 years Susan Ticknor commented that "we mal statement on January 9, which of age has actually increased. do have measures we can take to act reiterated her earlier request for a CDC suspects that the downward quickly" if the situation is judged to "vigorous public education cam- trend among children under 10 may be an emergency. 12 American Pharmacy Vol NS25, No.3, March 1985/140 52-266 0-85-22 PAGENO="0674" seemstobegettingbetter. * Donotuseaspirinforchildcenor teenagerswith thefluorchickenpoxwithout flontconsultinga physician. * UsymptomsofReye'sSyndromeappesc. Inunediatemedlcalattention isrequired. CDC Study Data Occasionally getting lost in the subsequent call to battle were the actual data from the CDC study. The investigation was conducted between February and May 1984, and included 29 Reye's syndrome cases and 143 controls. The control cases were children with similar anteced- ent diseases to those who developed Reye's syndrome, but hadn't con- tracted Reye's, who had been ad- mitted to the same hospital or emergency room, attended the same school, or were identified by ran- dom-digit dialing. Ninety-seven percent of the case children were reported to have re- ceived salicylates during the prodro- mal illness, compared with 28% (emergency room controls), 23% (same hospital), 29% (school), and 55% (random digit dialing). Conduded CDC: `The risk de- fined in the pilot study was com- parable or greater than that determined in previous studies." One interesting observation, which shows something about the way the media work in this country, is that the original report on the pilot study had stated that the statistically com- puted risk for development of Reye's after aspirin was 12-26 times more than without aspirin. However, in its first letter to be picked up by the media, Health Research Group re- ferred solely to a risk factor of 25; the fact that a range of possible risk (depending on which statistical model is used) was actually reported has somehow been lost in the strug- gle to simplify, for quicker and eas- ier reading. Study Limits In its comments on the pilot study, the IOM cautioned that "in spite of this association [between aspirin and Reye's], questions remain because of the small sample size and the lim- ited sources of cases." Elsewhere, tOM noted: "The pilot study data suffer from changes in methods during its conduct and the limitation of a small and geograph- ically limited sample." lOM therefore concluded; "Data from the full study are needed to determine if the pilot study findings are reliable," and added, "Because of uncertainties characteristic of ob- servational studies, ideally a num- ber of studies should be available to corroborate scientific findings." More information on Reye's syn- drome and use of medication is needed, commented IOM, "to guide both clinical practice and public health measures." Pharmacist Role Obviously, pharmacists can play a vital role in disseminating the new results about a stronger link be- tween aspirin and Reye's syndrome. William Grigg of FDA's Press Of- fice said that pharmacists no longer need to hedge in counseling pa- tients about giving aspirin to chil- dren with chickenpox or flu: "Our advice is not to use aspirin in chil- dren with these illnesses unless there's some overriding reason-an uncontrollable fever, for instance. And in that case, parents ought to consult a physician before giving as- pirin; we are currently sending out letters to all family physicians and pediatricians informing them about the new data." Also available is a poster designed by FDA about the dangers of giving aspirin to children with flu or chick- enpox. Copies are available from: Publications Office, Room 15B18, HFW-40, Food and Drug Adminis- tration, 5600 Fishers Lane, Rock- vile, MD 20857. 668 ~u~o AstudyhytheFederalgovernnsent'sCenters forOlseaseContoolhas founda strong asaocialionbetweentheuseofanpirinmn children with flu orchicken pon and the development of the potentially fatal illness Reye', Syndrome. Symptoms of Reye's Syndrome include vomiting, fever,lethargy.andconvulsioos. Thesymptomsgenerallyaooearasthechild For additional information, consult your pharmacist. ® TheM ,aoPhaemamsficalAssodatioo Th.oatlcoalpeofss.losulsactetyafphsemad.ts APhA distributed a poster warning of the link between aspirin use and Re~ge's syndrome as part of the February 1, 1985, issue of apharmacy weekly. Pharmacists were urged to display the poster as a public health service to their patients. Amedean Pha,macy Vol NS25, No.3, March 1985/141 PAGENO="0675" 669 Statement of the. National Association. of Chain Drug Stores, Inc. INTRODUCTION The National Association of Chain Drug Stores (NACDS) respectfully submits the following statement for inclusion in the record with respect to legis- lation (H. 11. 1381) the "Emergency Reye's Syndrome Prevention Act of 1985." NACDS is a trade organization founded in 1933 which represents the manage- Isent of 171 corporate drug chains. As an industry, our members are operat- ing in excess of 17,000 retail drug stores throughout the United States with annual sales of more than $22 billion In 1984. In the Over-The-Counter analgesic category, NACDS estimates that chain drug stores registered $320 million in sales during 1983. GENERAL COMMENTS Concerning the overall focus of the legislation currently before the House Energy and Commerce Health Subcommittee, NACDS commends Chairman Waxisan for his efforts in stimulating further dialogue and discussion with respect to this important health care issue. NACDS also applauds all voluntary efforts by the Federal Government, the Pharmaceutical Industry and the Medical Com- munity in developing programs and materials to advise consumers, parents and individuals under 21 years of age about the potential link between the use of aspirin and aspirin-containing products and Reye's Syndrome. We believe that these efforts have greatly helped to elevate an awareness among the general public of the possible dangers of aspirin use and Reye's Syndrome which will help to ensure that parents will consult with a physician before PAGENO="0676" 670 giving aspirin-type products to children who have flu of chicken pox. In our view, the voluntary approach is very effective and it must be an on-going pro- cess with commitments from all health related organizations, especially those associations which represent pediatricians and general practitioners that come in direct contact with parents and their children. SPECIFIC INDUSTRY CONCERNS NACDS noted with interest the testimony which was presented before the Health Subcommittee on March 15, 1985. Statements by the public witnesses were very compelling, and it is apparent that more information needs to be com- municated to the American public so that future incidences and the personal tradegy of this dreaded illness can be avoided. As to the specifics of H. R. 1381, the bill in its present form would pose several major problems to Chain Drug Stores in terms of compliance with the effective date of the Act. Based on an informal survey of a number of our corporate IFembers, it is our concern that Chain Drug Stores would not be able to logistically meet the 30-day deadline for compliance with labeling, advertising and the display of warning notices in retail stores. In that NACDS represents a number of large corporate drug chains that have in excess 1,000 retail outlets in a dozen or more states, compliance with the various requirements of the 30-day deadline would be impossible. From the date of enactment, the turn-around time to disseminate the necessary information to our members who must then advise all of their stores is insufficient under H. R. 1381. NACDS, therefore, recon~mends the following timetable with regard PAGENO="0677" 671 to compliance by retail drug stores: We believe that our corporate members could have in p1-ace at the retail level the warning notice in 60 days. Con- cerning retail advertising, the Chain Drug Industry would need at least 90 days in which to modify print and media advertising that has already been purchased. The labeling deadline poses the most significant challenge to our industry which stocks and offers for sale a wide range of private label and brand-name aspirin containing products. In order to convert aspirin labeling, our industry would need at least 270 days to comply. This time-frame would start from the point at which revised labeling is received from manufac- turing companies. It is our concern that a delay by manufacturing companies in supplying adequate labeling for goods shipped before the effective date and for those goods already in the distribution pipeline not be imputed to retailers. When complete revised warning labeling for all aspirin related products is in place, NACDS strongly recommends that the requirement for displaying retail warning notices be eliminated. In our view, once the new labeling is available, it is unnecessary to mandate warning notices at the retail level. VIOLATIONS - CRIMINAL PENALTIES Additionally, NACDS is extremely concerned about the criminal penalties that are contained in H. R. 1381 for misbranding violations. If the legislation is enacted into law, the Chain Drug Industry will make every effort to fully comply. However, much of our ability to respond to the requirements of the Act will depend solely on how quickly manufacturing companies provide corpor- ate drug chains with revised labeling. We, therefore, strongly recommend that the penalty provisions not be applied to retail drug stores until a minimum of 360 days following enactment of the legislation. To conclude, unless the legislation is amended to reflect the concerns that NACDS has expressed relative to the compliance aspects impacting upon retail drug stores, we are opposed to H. R. 1381. NACDS appreciates the opportunity to provide testimony on the "Emergency Reye's Syndrome Prevention Act" and it is our hope that this statement will be given full consideration. PAGENO="0678" 672 ~)~ESS (P ThE UNIT~ STATES HOWE (P REPRESENTATIVES before the StBCXt4NITTEE ON HEALTE P1~D TEE EE~II~J~1ENT C(}IMERflS CF TEE AMERICN~I ADVERTISING FEDERATION ON H.R. 1381, The E~tergency Reye `s Syndrai~ Prevention Act of 1985 This stat~nt is respectfully sthnitted by the Aserican Advertisir~ Federation, a national trade association which includes within its nembership all of the varicus elaients of the advartisim industry. The itentbership of the AAF includes canpanies which mam.ifacture and sell consuter products, advertising agencies, newspaper and magazine p.t)lishers, radio and television broadcasters and neb,orks. J~pproximately 22 other trade associations with nemberships canposed of cx~panies engaged in varicus advertising pursuits also hold riembership in the AAF. The Federation also represents the "grass roots" of the advertising industry because it is the parent body of sore than 200 local advertising clubs and federations located thrcughout the United States and having a canbined nembership of approximately 36,000 advertising practitioners. These local organizations, like the parent body, include advertisers, advertising agencies and advertising nedia Within their nembership. PAGENO="0679" 673 We share with the sponsors of this bill a great concern with respect to the illness knovn as Reye `s Syndrans. Because of its potentially deafly nature this disease is a prc~er subject of attention by the health authorities of the United States governnent. A crash program is already underway to determine the cause of thin malady and great strides have already been taken in alerting the ptlic to the possible connection beteeen the disease and drug products which contain salicylate thra.igh a major voluntary public service ad~rtising campaign. As ~e will point cut in sore detail later, PAF pled~s to do all it can to assist in furthering and accelerating these important efforts to alert the public. We are not persuaded, h~ver, that this matter is a prcper subject for legislation at this time and thus submit these canrrents in cpposition to the enactment of the a1~rtising provisions of H.R. 1381. While sate of air views may have broad application to the entire bill, our expertise concerns ad~rtising and therefore ~ direct cur cassents to the prcposed requirenent to include in "all ad~rtisenents" a 48 s~rd disclosure with respect to the suspected connection beteeen Reye `s Syndrane and the use of products which contain a salicylate. We ladc the expertise to independently camient substantively on the connection betMeen the disease and the product tot instead rely upon the ~inions of experts, and in partirular, the Food and Drug Administration. As ~u kncw, Catunissioner Fraak E. Young has unequivocally stated that this legislation is "unnecessary" because "definitive scientific data are still not available" and because the public is being inforned by an "extensive public education program". PAGENO="0680" 674 In partioilar, ~e direct ~ur attention to the position of the FI~ on four epix3eniological sttz3ies (state surveys) and a pilot stody which began in November, 1983 and determined the protocol for the national stody which is nn~ underway. This record evidence sakes it crystal clear that the country's sost qualified experts and expert bodies are ~rking at tc~ speed to readi a determination as to whether salicylates are involved in the occiirance of Reye `s Syndrare. In sbort, a law reguiring irendatory edvertising disclosures is premature for it vRuld have as its premise only preliminary stodies whose findings are in dispute. Surely, national legislation sheuld have a better basis. In view of the voluntary progran it cannot be said that information as to the suspected lir~ is not reaching the Airerican poblic. In fact, the voluntary approach nay be sore effective than the system which ~uld be imposed by the bill. Pt~lic service television and redio anna.incarents (PSAs) are a sore effective naans of disseminating the necessary information than product edvertiserents which contain the reguired disclosure together with the usual selling nessage. Viewing and listening take place in an atsosphere characterized by conflicting demands for attention created by the prograinning and the large iuther of eds seen or heard during arry viewing period. An advertisacant which tries to convey canplex, technical information with mulitple nasseges will not achieve its camminications objectives. (~ the other hand, a pLt)lic service anricEncarent, which has a single terse nessage, can penetrate the viewer/listener's consciousness and be understood. This has been daannstrated by an experinent conducted by the Stanford Heart Disease Prevention progran in the mid-nineteen seventies. A report on that stody, PAGENO="0681" * 675 which involved the airing of 50 television and 100 radio spets together with other nedia efforts, sh~ied that information as to heart disease can be caninunicated via electronic madia if that is the central itessage. Lancet, June 4, 1977. In the typical broadcast viawing or listening situation, the audience is stbjected to a multiplicity of massages each clamoring for attention. Advertisers are well aware of this and tailor their ads to get across as simple and clear a massage as pessible. Additional canpiex information quickly falls victim to the perception phenunenon knce~'n as "information overload'. Simply stated, the information processing ability of hunans is finite with the result that as information input is increased, its assimilation decreases, understanding falls off and confusion increases. Thus, a warning massage in electronic advertising accanpanied by the usual selling massage will catniu~nicate neither stateitent effectively. The warning may be ccmpletely misunderstood or, sore likely, mantally "tuned ait". One does not have to be a madia expert to recognize that a massage of 48 words, i.e., the massage which would be mandated by the bill will almost caupletely preenpt the typical 30 second television or radio spDt. Because the advertising massage cannot run fran the very beginning to the very end of a 30 second ad, two to three seconds are lost. This prc~osed massage would take up to 18 seconds of the 27-28 seconds which are available. Can anyone question that it would be econanically unrealistic to pay the rates for 30 second broadcast spets and receive only 9-10 seconds of selling time? PAGENO="0682" 676 And it is not the answer to state that the advertiser could buy longer, 60 second ccissarcials. A 60 second spot will cost s~.t)stantially sore without necessarily providing the corresponding increase in effectiveness. In fact, it is our vie~i that the impDsition of a warning reguiresent upon advertising would severely limit broadcast advertising in this area. The added cost of longer cansarcials would be stagering. In the FTC's antaãid rulenaking proceeding, its Bureau of Econanica estimated that the cost of inserting only a 6 second sodiun warning in a 30 second television spot would cost the three largest antacid manufacturers $5.3 million. This bill's effect would be to increase enornously the cost of readilag the audience via television and radio advertising. Cbviaisly this advertising requirenent would sake advertising for salicylate-containing products practically ilnpDssible in c*.itdoor advertising and severely burden and clutter all other forms of advertising. Thus, the likely result of this bill would be to reduce the anount of surh consusar product advertising in these categories and have the exact cpp)site effect of the one desired, at least in terms of providing incentives for increased constrer information. Imposing a burden of this type on product advertising is bad p~blic policy due to the broad, unwarranted precedent it establishes. Clearly, surh a precedent is likely to be extended to to other products, especially where contra-indications are involved. It is difficult to see where Congress would drag the line once it assunes the FTC's and FW~'s authority in this field. PAGENO="0683" 677 Finally, this bill directs the Secretary of Health and Human Services to pranulgate the regulations reguired to enforce its labeling and advertising provisions. Thus it would place the Departhent in the field of regulating consuter advertising, a field where it has no expertise. Without question the hardest fought and irost debated issue faced by the 73rd, 74th and 75th Congresses while enacting the Federal Food, Drug and Cosmetic Act ~es jurisdiction over false advertising. Early bills gave the Department of Agriculture or the smbryo Food and Drug Administration jurisdiction over both. The FTC and a large number of members of Congress objected. Judge Davis, then the Chairman of the Federal Trade Ccinmission, testified: The Canmission has generally been against the pDlicj of legislators to create overlapping jurisdictions and different procedures; and it is suggested that that is exactly what is done here; and s~ think that it would be sore expensive, and think that it would create sore confusion, not only frcm the standpoint of the Covernment, but fran the standpoint of the p~blic. Hearings on S. 2800, Senate Cceimittee, 73rd Congress, Mardi 1934. p. 231. In air view, Chairman Davis' canrrents make as much sense today as they did fifty years ago. H.R. 1381 would recpen this ancient schism and blur the bright line of division between the jurisdiction of these two agencies. The Congress sheuld leave advertising regulation of consuter products including over-the-counter drugs to the FTC, the agency qualified to deal with it. Conclusion As noted, the Canmissioner of the Food and Drug Administration has testified that this legislation is "unnecessary". He has stated that PAGENO="0684" 678 "the evidence needed to suprort mandatory labeling is not, in our view, available at this time." Clearly, if there is not enough evidence for mandatory labeling, there certainly is not encugh evidence to mandate unprecedented advertising warnings for over-the-counter drug products. In a true and accurate sense, this bill constitutes a sentence on a case in which the evidence is still being gathered and, in which a verdict of associaton has not been rendered. It is reminiscent of the farous demand of the Qieen of Hearts in Lewis Carroll's Adventures In Wonderland: "Sentence first - verdict afterward.' Such a procedure was deemed odd in the nineteenth century and it is not less so today. We ask the Subccumittee to place this matter in abeyance pending a definitive decision by the Ccxnmissioner of the Food and Drug Administration. In the meantime, the public education progran will be wrking and will be attempting to reach that n~ ever snaller percentage of the population which may be unaware of this possible medical problem. For our part, we pledge to alert cur general membership including air local advertising clubs throughout the United States and strongly urge then to assist in every way pessible to educate the public about the Reye `s Syndrcrre issue through public service advertising. As members of the board of directors and the executive canmittee of the Advertising Council, we will contirue to. suppurt their efforts to disseminate information on this subject. We also will ~rk with all elements of the advertising canmunity including the media in cooperating with these ilnprtant efforts. Again, we share the concern over this serious public health issue bit we cannot agree that lawful product advertising is an apprcpriate or effective vehicle for the dissemination of warnings of this kind. If this legislation were to be accepted it s~uld create extremely broad precedents for the whole over-the-counter drug area and place a dark shada~i over marty other product categories as well. Respectfully submitted, Ha~ard H. Bell, President American Advertising Federation 1400 K Street, N.W.' Suite 1000 Washington, D.C. 20036 PAGENO="0685" 679 U.S. HOUSE OF REPRESENTATIVES Before the Subcommittee on Health and the Environment of the Committee on Energy and Commerce COMMENTS OF THE AMERICAN ASSOCiATION OF ADVERTISING AGENCIES, INC. on H.R. 1381 - These comments are respectfully submitted by the American Association of Advertising Agencies, Inc. (the `A.A.A.A.") in opposition to H.R. 1381. That bill would, among other requirements, mandate that all advertisements of products containing aspirin or other salicylates -- including broadcast advertising, print advertising, oui000r anc even transit aOverUsIng -- contain a specific, 1,6-word warning surounded by a black border and bracketed by color-coded signs and symbols.* * That warning must expressly state: `WARNING: This product should not be given to individuals under the age of 21 years who have chicken pox, influenza or flu symptoms. This product contains aspirin or another salicylate which has been strongly associated with the development of Reye's Syndrome, a serious and often fatal childhood disease." The warning must be blocked within a box and surrounded by yellow and red warning signs. PAGENO="0686" 680 The A.A.A.A., the national association of the advertising agency business,* respectfully submits that the requirement in H.R. 1381 that all advertising of aspirin products include a warning regarding aspirin usage by those younger thafl 21 years is not in the best interest of either current and potential aspirin product users or aspirin manufacturers and marketers. Specifically, the requirement of a warning: (1) fails to pay heed to the legitimate but limited functions of product advertising, and (2) fails to recognize that numerous alternative means already exist for transmittal of full and fair health information to purchasers of aspirin products. Advertisements are, in essence, attempts to communicate the most helpful and relevant selling information to the largest available audience at the.least cost, with the goal of persuading potential consumers to select a particular product from a given class. Concise communication of truthful information perceived useful by the consumer is the only effective means of attaining that goal. The task of creating an effective advertising communication is difficult under any circumstances, requiring an advertising agency that isexpert in communicating with the public at large.** In the broadcast media in particular, given the limits of a 15- or 30- or 60- second radio or television advertisement, an advertiser and its agency must `zero in" on the crucial message in as little time as possible, and must avoid cluttering the advertisement with data not directly relevant to the commercial's principal purpose. Limited available time and space must be used to best advantage, and inclusion of information not easily understood by the viewing audience must be avoided. * The A.A.A.A. includesin its membership approximately 700 advertising agencies with offices throughout the United States and the world. In addition to creating and placing most national advertising, A.A.A.A. member agencies handle a substantial amount of local and retail advertising for goods and services. ** What is the most helpful and relevant consumer information regarding any particular product depends, among other things on the product's characteristics and the desires of the purchasing public. An advertising agency's job is to understand such considerations and to devise a message that memorably and effectively presents salient information about the offered goods or services. PAGENO="0687" 681 By its very nature, then, advertising can convey only a limited quantity of information. Most product advertising is intended to alert consumers to the availability of either a product or a brand; not to overwhelm the consumer with an avalanche of product data or information not generally applicable. When too much information is forced into a confined space or time, the result is simply a less effective communication as a whole. When too much `message' is placed in an inappropriate medium, the risk of consumer confusion and erroneous perceptions increases dramatically, as does the chance that some consumers seeing or hearing the advertisement will simply ignore it entirely. It would be particularly unfortunate in this.context if consumers who are not at risk of any adverse consequences from aspirin use -- a group which we understand constitutes nearly all aspirin consumers -- were to develop an erroneous impression that they should avoid aspirin usage altogether as a result of brief contact with the bill's required warning. The A.A.A.A. does not represent itself to be an expert in the complex fields of pharmacology and medication, so it is not in a position to comment on the general advisability of the language of the warning proposed in H.R. 1381. * However, if the policy objective ~ th~ hi1~ tc ~`~`-e~e ~o~'su"~e'- awa'eness of pote'~tial conse.~uences of aspirin intake by particular sub-groups of our society, surely there are more approopriate means than advertising to disseminate such detailed information. For example, package labels and inserts, physician pamphlets and verbal instructions, pharmacist suggestions, and other industry and medical education efforts -- all of these would appear to provide more appropriate mechanisms for dissemination of the substantive information with which H.R. 1381 is concerned. While some of the alternative methods of communication surely offer more promise than others, all of them appear to be potential ways to disseminate the intended message without requiring a misguided effort to make advertising perform a duty for which it is ill- equipped, and for which it has never been intended. * We note that Dr. Frank Young, Commissioner of the Food and Drug Administration, explained to this subcommittee on March 15, 1985 that "the definitive scientific data are still not available," so that "the evidence needed to support mandatory labeling is not, in our view, available at this time." Statement by Frank E. Young, March 15, 1985, page 3. PAGENO="0688" 682 In sum, the A.A.A.A. believes that whatever policy goals are to be served by H.R. 1381, they should be sought by the numerous available means of information dissemination other than advertising. Advertising, as a unique and specialized form of communication, should be left unhindered to perform its immediate, concise, and practical function. Respectfully submitted, THE AMERICAN ASSOCIATION OF ADVERTISING AGENCIES, INC. Executive Vice~Rt~dent Washington, D.C. 20036 (202) 331-7345 Of Counsel: David Versfelt Donovan Leisure Newton & Irvine 30 Rockfeller Plaza New York, N.Y. 10112 (212)307-4100 PAGENO="0689" 683 / of the AMERICAN NEWSPAPER PUBLISHERS ASSOCIATION and the MaGAZINE PUBLISHERS ASSOCIATION The American Newspaper Publishers Association (ANPA) is a national trade association, representing about 1,400 newspapers responsible for publishing more than 90 percent of U.S. daily circulation. The Association includes a number of non-daily newspapers as well. The Magazine Publishers Association (MPA) is a national trade association, representing approximately 750 consumer magazines within the United States. We appreciate this opportunity to comeent on H. R. 1381, The Emergency Reye's Syndrome Prevention Act of 1985, legisla- tion which we believe raises certain First Amendment issues which Congress should carefully consider. Our concern centers on Section 2 of the bill. Section 2(v) mandates that all advertising of drugs containing aspirin or another salicylate contain a specifically-worded statement regarding the hazards associated with the use of aspirin by children. Because the bill would amend already existing legisla- tion, failure to carry the warnings in advertising would invoke criminal pen- alties. The section directs the Secretary of Health and Human Services to prouvlgate regulations to implement the required warning statement. The sec- tion also requires that the warning statement be centered in a rectangular box between two yellow arrows each containing the word "warning" and two red circles. Although ANPA and MPA understand the public health concerns which have motivated this legislation, we believe the Congress should proceed with cx- t~eme sensitivity and great caution when it considers regulating speech as a method of regulating the sale and use of an entirely legal product. By seeking to extend the warning label requirement to advertising, to specify the precise words to be used in such advertising, and to direct the promulgation of regulations by which the government would judge the contents PAGENO="0690" 684 of advertising and impose criminal sanctions for the failure to carry the ad- vertising, H.R. 1381 proposes a substantial expansion of governmental control over the commercial speech of advertisers and, indirectly, over the newspapers printing that speech. ANPA and MPA strongly suggest that the expansive reg- ulatory scheme embodied in H.R. 1381 goes well beyond anything the record might support. FIRST AMENDMENT CONCERNS In a series of decisions including Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, Inc., 425 U.S. 748 (1976), Central Hudson Gas & Electric Corporation v. Public Service Commission of New York, 447 U.S. 557 (1980), and In Re R.M.J., 455 U.S. 191 (1982), the U.S. Supreme Court has recognized that advertising enjoys significant First Amendment protections. While the Court has indicated that some of the full protection of political speech may not be accorded purely commercial speech, the burden is on the government to show a compelling need for regulation and also to show that the regulation is no more extensive than necessary. See, In Re R.M.J., !!.~* Enactment of H.R. 1381 would be a significant escalation of regulation of speech in this area. It is one thing to mandate a warning label on aspirin containers and quite another to specify statutorily the precise language which must be contained in advertisements as well as in packaging, and to provide for a system under which the government would judge the content of advertising to determine if criminal penalties should be imposed. PAGENO="0691" 685 ANPA and NPA reiterate that the First Amendment protections offered com- mercial speech are not absolute, and that some forms of regulation are permis- sible.For example, place and manner restrictions are applicable, as is regula- tion of commercial speech that is false or deceptive. Similarly, there may be restrictions on advertisements for transactions or products which are illegal. See ~g., Pittsburgh Press Company v. Human Relations Comm'n., 413 U.S. 376 (1973). None of those justifications for regulation of conanercial speech ap- plies to aspirin advertising. Aspirin is not illegal, nor is aspirin adver- tising inherently misleading or deceptive. Likewise, the approach of H.R. 1381 is not a time, place or manner restriction. Instead it mandates publica- tion of required content. In Central Hudson Gas & Electric Corp. v. Public Service Cotanissiom of New York, 447 U.S. 557 (1980), the Supreme Court struck down a New York reg- ulatory ban on promotional advertising by electric utilities. In his concur- ring opinion in that case, Justice Blackmun expressed concern about regulating speech that is not deceptive or misleading "... in order to manipulate a pri- vate economic decision that the state cannot or has not regulated or àutlawed directly". The Court recognizes that we have never held that commercial speech may be suppressed in order to further the State's interest in discouraging pur- chases of the underlying product that is advertised. Permissible restraints on commercial speech have been limited to measures designed to protect consumers from fraudulent, misleading or coercive sales techniques. 447 U.S. at 574. It may be argued that the warning message required by H.R. 1381 is simply an example of the kinds of warnings and disclaimers that the Supreme Court, in several of the recent commercial speech cases such as Virginia Pharma~y and In Re R.M.J., has indicated may be permissible forms of regulation. Uniformly, however, references to the possibility of requiring such disclaimers occur in PAGENO="0692" 686 the context of a discussion of commercial speech that is deceptive or mislead- ing. For example, in Virginia Pharmacy, Justice Blackmun notes that The [attributes of commercial speech such as its greater objectivity and hardiness] nay also make it appropriate to require that a commercial mes- sage appear in such a form, or include such additional information, warn- ings, and disclaimers, as are necessary to prevent its being deceptive. 425 U.S. at 771, n. 24 (Emphasis added). There is no suggestion that aspirin advertising is so inherently decep- tive or misleading as to require the mandatory inclusion of a specifically- worded warning message. This is not t~ say that aspirin advertising which is deceptive or misleading is immune from challenge. Under Section 5 of the Federal Trade Commission Act, (15 U.S.C. Sec. 45), the FTC clearly has the pm~er to deal with such advertising. Absent such a specific finding, it should not be assumed that aspirin advertising per se is deceptive without a health warning, any more than automobile advertising would be deceptive with- out a warning about the dangers of driving. In the Central Hudson case decided in 1980, the Supreme Court outlined a four-step analytical framework for examining restrictions on commercial speech: In commercial speech cases, then, a four-part analysis has developed. At the outset, we mast determine whether the expression is protected by the First Amendment. For commercial speech to come within that provision, it at least must concern lawful activity and not be misleading. Next, we ask whether the asserted governmental interest is substantial. If both in- quiries yield positive answers, we must determine whether the regulation directly advances the governmental interest asserted, and whether it is not more extensive than is necessary to serve that interest. 447 U.S. at 566. When this four-part test is applied to H.R. 1381, the first two inquiries can be answered positively: aspirin advertising, in general, is not mislead- ing and is therefore protected by the First Amendment, and the asserted PAGENO="0693" 687 governmental interest -- public health -- is substantial. It is in connection with the last two questions that LANPA and NPA believe the commercial speech provisions of H.R. 1381 do not satisfy this constitutional test: whether man- datory warning messages in aspirin advertising "directly advance[s] the governmental interest asserted," and mmre importantly, whether the govern- ment's intrusion into commercial speech "is not nore extensive than is necessary." Whether a government specified warning message carried in aspirin adver- tising "directly advances" the governmental interest in public health is open to serious question and should at least be the sub~ject of careful debate and specific factual showings. Aspirin advertising and packaging already contains certain health information. The new more prominent warnings would divert the consumer's attention from this important information and dilute the effective- ness of that information. A more critical inquiry is whether the kind of approach represented by H.R. 1381 unnecessarily involves the government in a pervasive system of reg- ulating non-deceptive commercial speech. No matter how seemingly laudable the goal, any legislation which proposes to delegate to government the power to decide what will be published and to impose criminal penalties for the failure to publish a specific statement is constitutionally most troublesome. ANPA and MPA believe this would impinge on the constitutionally-protected rights of advertisers, the press, and ultimately the public. PRACTICAL CONSIDERATIONS Dictating the use of specific colors in advertising raises many practical concerns. First, not all media are able to offer color advertising; although many newspapers offer color capabilities to advertisers, often the location of PAGENO="0694" 688 color advertising is limited to preprinted materials and special sections. Second, using two colors (red and yellow) on a black and white page may bring additional attention to the warning, but this effect would be minimized if the advertiser was able to run the entire advertisement in full color, as any legislation would certainly have to permit. Finally, requiring the use of color at all means additional expense to advertisers, an expense which has not been documented nor supported in the course of considering this legislation. CONCLUSION Commercial speech restrictions must be a "last resort" action of govern- ment. Only where there is a concrete showing that an identifiable problem cannot be solved by means other than restricting speech can the government turn to measures such as those embodied in this legislation. The process of reaching this decision must include a ~ assessment of all the informa- tion now available to the public concerning aspirin and the health issues sur- rounding them. Having taken that and all other factors into account, then, and only then, can restrictions on commercial speech be considered. It is not at all clear that this rigorous process has been followed in advancing these legislative measures. The principal concern of ANPA and MPA about this legislation is the pro- posed resort to government regulation of speech as a means of regulating a product which for whatever reason, the government chooses not to regulate directly. We believe a very troubling precedent is set whenever the federal govern- ment determines the content of the speech of private entities. H.R. 1381 pro- poses to do that. Absent compelling circumstances and clear evidence that other, less intrusive, alternatives are ineffective, this kind of governmental action is inimical to the preservation of free speech and a free press in out free society thus the case has not been articulated which would support as harsh a statutory restriction on commercial speech as that embodied in H.R. 1381. PAGENO="0695" 689 ` FOR THE RECORD "I~J A ASSOCIATION OF NATIONAL ADVERTISERS, INC. 155 EAST 44TH STREET, NEW YORK, NY 10017 (212) 697-5950 STATEMENT OF THE ASSOCIATION OF NATIONAL ADVERTISERS, INC. ON H.R. 1381 REQUIRING SPECIAL WARNINGS IN LABELING AND ADVERTISING OF SALICYLATE-CONTAINING PRODUCTS BEFORE THE SUBCOMMITTEE ON HEALTH AND THE ENVIRONMENT COMMITTEE ON ENERGY AND COMMERCE UNITED STATES HOUSE OF REPRESENTATIVES The Association of National Advertisers, Inc. (~A.N.A.") is a not-for-profit corporate trade association, organized and exist- ing under the laws of the State of New York, with offices' at 155 East 44th Street, New York, New York 10017. It is composed of approximately 400 companies, with over 2,000 subsidiaries and divisions (many of which are relatively independent advertiser entities), located throughout the United States. They sell a wide range of products and services and employ advertising as an important element of their marketing and public relations programs. Although A.N.A.'s membership includes many of the nation's largest advertisers, it also comprises a large number of smaller ones. Approximately one-third of A.N.A. members spend under $5 million annually for advertising. A.N.A. members collectively' account for over two-thirds of all national and regional advertising expenditures in the United States. It has always been a fundamental policy of A.N.A. to defend against abridgment or erosion of advertisers' right to advertise truthfully any product or service that can lawfully be sold. Inevitably subsumed under this cardinal principle is the propo- sition that truthful advertising should not be collaterally abridged by imposing upon it an emasculating requirement to warn against grave dangers from use of a product where such dangers have not, been established to exist. We believe that to be the situation with regard to the alleged association between salicylate-containing pharmaceuticals, child- ren's flu-like diseases, and Reye's Syndrome. However, we leave the arguing of that highly technical, scientific matter to others more expert than ourselves in that area. If the danger has truly been proven to be real that is one situation; but unless and until it has been, we respectfully submit that H.R. 1381 should not be enacted. Officers: Directors: SPENCER C. BOISE, MaOH, thc.-CRaiccac B. OHSDRLUN. WEISPRA CR(pONHcT DOUGLUST. MACLURE, FoR ROAR Coopacy HERBERT N. BAUM, Caopbell Soop Co-VIO'COlLFRaO VIM ARMSTRONG. AT&TComounoaSocs WILLIAM S. MCGRANAAAN. RANaotsoc-VAEo HA. E~WITT F. HELM, JR., PNSIURII SHARON E. BAUM. CBeckcaI Back JOHN J. MEAGER, JR.. Conbe Icoopooted RICHARD K. JEWETT, Pitney Boses-Tnasotet JAMES B. BLOCEI. Colt. Inc. MILESA. NELSON, 3M Coep.cy SAMUELTHURM, SecicitAne PcesiRnt JOHN H. CHILDS. Hooc AR. DON A. OSELL,The Rtsbcy Cotnpany WILLIAMS. KISTLER. Ho Pceoidect JOSEPHJ DOHERTY, Dacco-Coccaig Rbeglas Cooccason BARBARA PESIN. Hoot Pcnd~ts, Inc. BERBEETA AHLGREN, Ho Fctsidrct JOHN H. DOBBS, HoBby Foods Cc!pclabioc JOHN J. POWERS, Easteac BodakCoepacy HARRY L DAVLWG. Ho Pcesident ROBERTA. GOLDSTEIN.TAB Pmot,: B Gaoble Coccpacy ROBERTA. RECHHOLTZ, AdolpH Coos CoRpacy CLERE ROLT. Hoe Pcesidtcl and Assistant to the Pnroideto DONALD U. GO1.DSTROM. Actottoog WaRd Icdiistces, Inc. SANFORD E. REISENBACH, Waco: Bcotttecs, Ito. ANTHON C. LUNT. Ho Pteodect DAVID L EOODMAN,10, CAms Coopaey THOMAST. RYAN,THe GBHtte Coop.cy JAMES B. COSSROVE, AosistattTreasscet .odDetcetaty MICHAEL ES. EIRHC Bass Cotpoo.tiso CHARLES L. SHEMELY, CaeRe Coopacy GILBERT H. WElL. Stneol Colosel RORERTF. LAUTEROORN. IctecnaSooal P~o Cotnpacy DELHDYO THOMAS, Lack D'LakeN. Inc. PBTERW. ALIPORT. PooReR Eccenftss PAGENO="0696" 690 For virtually a decade A.N.A's policy has enjoyed constitutional recognition and backing, subject only to a narrowly confined exception (Central Hudson Gas & Electric Corporation v. Public Service Commission of New York, 447 U.S. 557, at page 564), which we shall now discuss with respect to its application to truthful advertising of salicylate-contaifling products. The three tests which all must be passed before abridging legis- lation can be constitutional, are concisely stated by the Central Hudson court: If the communication [the advertising) is neither misleading nor related to unlawful activity, the government's power [to restrict] is more circum- scribed. The State must assert a substantial interest tobe achieved by restrictions on commer- cial speech. Moreover,. the regulatory technique must be in proportion to that interest. The limi- tation of expression must be designed carefully to achieve the State's goal. Compliance with this requirement may be measured by two criteria. First, the restriction must directly advance the state in- Eirist involved; the regulation may not be sustained if it provides only ineffective or remote support for the govern nt's purpose. Second, if the gov ernmental interest could be served as well by a more limited restriction on commercial speech, the exces sive restrictions cannot survive. (Ibid.) The burden of proof is firmly on the proponents of abridging or hobbling laws. "The party seeking to uphold a restriction on commercial speech carries the burden of proving it." Bolger v. Youngs Drug products Corp., 103 S. Ct. 2875 at 2882 n.20 (1983) ~ (citing Central Hudson, 557 U.S. at 570). One need only read the Supreme Court's fine-toothed combing, and consequent rejection, of the government's assertions of substantial state interests and of their direct advancement by General Bolger's restrictions upon Youngs' advertising, to appreciate how heavy that burden of proof is. Thus, unless arid until the burden has been fulfilled of proving a causal relationship between children's ingestion of salicylates in the presence of flu-like diseases and the occurrence of Reye's Syndrome there must be a failure by the government to satisfy the first prerequisite for exemption from the First Amendment: es- tablishment of "a substantial interest to be achieved by [the) restrictions on commercial speech." PAGENO="0697" 691 Interestingly, if that causal relationship were proven, passage of H.R~l~l would be unnecessary. Section l5(a)(l) of the Federal Trade Commission Act, 15 U.S.C. S 55(a)(l), provides in pertinent part, "[I]n determining whether any advertisment is misleading there shall be taken into account . . . the extent to which the advertisement fails to reveal facts material * .. with respect to consequences which may result from the use of the commodity to which the advertisement relates under the conditions prescribed in said advertisement, or under such conditions as are customary or usual." Even if the first constitutional hurdle were cleared, moreover, the next two would be too high for the proponents to leap, at least so far as advertising is concerned. H.R. 1381 would be ineffective, or at best remote, for directly advancing the govern- ment's "warning" goal, and would excessively restrict commercial speech via advertising because labeling would be the appropriate, adequate and far less restrictive means of whatever communication might be called for. (Let us repeat that it is not advertisers' burden to prove ineffectiveness or remoteness of the proposed restrictions, but the government's to establish the converse.) There are many warnings and contraindications that are necessary to make the great and increasing variety of otc medicines safe and effective for use without medical supervision. There would be no less reason to impose restrictions upon the advertising of all of them than for those proposed in H.R. 1381. Much, if not most, otc pharmaceutical advertising would collapse under such burdens, to the frustration of the public policy manifested in the Food, Drug and Cosmetic and the Federal Trade Commission Acts of promoting lay use of such products. Self-medication with proprietary drugs is a sig- nificant factor in the U.S. health care scheme. Escalating costs of health care create a greater need for low cost self-medication than ever before. Seventy-f ive percent of all illness and injuries are initially treated through self-care and OTC medication. If only a small percentage of self- treatment was shifted to medical practitioners, the patient load would disrupt the U.S. health care system. [U.S. Department of Commerce, U.S. Industrial Outlook 19.78, at 131 (January, 1978)]. It is not surprising that the Federal Trade Commission, after studying, deeply and extensively, the voluminous data produced in a trade regulation rulemaking proceeding, concluded that generi- cally advertisements were an inappropriate medium for conveying drug warnings. While the specific product line involved was ant- acids, there was no question in anyone's mind but that the basic principle of a blanket requirement (such as H.R. 1381 proposes) PAGENO="0698" 692 was what was at test. And, there is also no question but that the proponents for the principle had a full opportunity to make their case for it. The result is understandable, and was correct. The March 15, 1985 statement of The Proprietary Association, at pages 5-6 describes it, and the relevant inadequacies of adver- tising, quite well; we need not repeat its contents here. In short, the necessity to prove that the restrictions upon com- niercial speech, especially upon advertising, proposed in H.R. 1381 are exempt from the forbiddance of the First Amendment has not been met by its proponents as to any one of the specified condi- tions. All of them must be satisfied for its restrictions upon advertising to be valid. Respectfully submitted, Dated: March 28, 1985 ASSOCIATION OF NATIONAL ADVERTISERS, INC. By: ~2~1~LLL DeWitt F. Helm, Jr president Gi4bert H. Weil ~ General Counsel PAGENO="0699" 693 STATEMENT OF THE NATIONAL ASSOCIATION OF BROADCASTERS ON H.R. 1381 "The Finergency Reye's Syndrcine Prevention Act of 1985" Mr. Chairman and members of the subcommittee. The National Association of Broadcasters ("NAB")JJ submits these comments to be included in the record of the subcommittee's hearings on H.R. 1381, a bill that proposes mandatory warnings about Reye's Syndrome for all labeling and advertising of aspirin-containing products. Because NAB represents the broadcast media, its comments address only the advertising proposals of H.R. 1381 -- and specifically speak to the unique and restrictive context of radio and television advertising. This bill has been proposed as an emergency measure to ensure that teenagers and mothers of children know about the potential risk of Reye's Syndrome associated with certain aspirin use so that those at risk can act, in an informed way, to avoid potential harm. Getting the word out about the potential risks of such a serious and often-fatal disease as Reye's Syndrome is the goal of this legislation. It is, jj NAB is a nonprofit incorporated association of radio and television broadcast stations and networks. NAB membership includes more than 4000 radio stations, 700 television stations and the major commercial broadcast networks. PAGENO="0700" 694 unquestionably, an important goal. It is a goal that surely all inVolved parties are working to achieve. And it is a goal that the National Association of Broadcasters and its member radio and television stations want to help effectuate -- just as NAB and radio and televi- sion stations across the country have worked to alert the public to other immediate potential health hazards, from toxic shock syndrome to the rash of adulterated Tylenol products. Getting the word out about an immediate danger is something broadcasters can facilitate.-- through broadcast news programs and news updates and through public service announcements, messages from aspirin manuafacturers and references by radio announcers. Broadcasters have gotten the word out many times before. And they intend to do so now with regard to the potentially dangerous association of aspirin with Reye's Syn- drome when taken by children and teens with flu or chicken pox. Broadcasters stand ready to help shore up the current voluntary warning program in this emergency situation. But NAB does not, and cannot, stand ready to sup- port government-imposed warnings on broadcast aspirin adver- tising. For NAB believes that such a government mandate would be unnecessary, unworkable, ineffective and possibly counterproductive to other important public goals. A. Broadcast &lvertising Is Neither Appropriate Nor Effective for the Task of Educating the Public on the Contraindications of Over-the-Counter Medicines. Product advertising on radio and television does convey some health-related information to the public. But PAGENO="0701" 695 the nature of broadcast advertising is not suited to the task of educating the public on the detailed contraindications of over-the-counter ("OTC") medicines. This is so because typi- cal radio and television ads are limited to 30-second spots. Such a brief exposure is hardly sufficient time to deliver usable and non-alarming information on the contraindications of OTC products -- along with the selling message for the product. And the warning suggested by H.R. 1381 would con- sume 20 seconds -- two thirds of the typical ad. While dis- closures generally, and particularly those involving warnings, may be informative and useful in labels, disclosures in broad- casting are far less effective and may in fact be unduly alarming or confusing to the consumer. Television and radio ads, typically 30 seconds long, can accommodate only a limited number of concepts. Too many ideas contained in a message would only serve to confuse the consumer and frustrate the public policy goal of consumer awareness of effective OTC self-medication.~a' Bur- dening brief broadcast ads with required disclosures increases the number of concepts presented and thus may preclude full information processing of those disclosures by the typically 2/ The Supreme Court has recognized the public policy bene- fits of informing consumers as to the availability of con- sumer-aiding products. See Virginia Citizens. Consumer Coun cil, Inc. v. State Board of Pharmacy, 373 F. Supp. 683 (E.D. Va. 1974), aff'd, 425 U.S. 748 (1976); Terry v. California State Board of Pharmacy, 395 F. Supp. 94 (N.D. Cal. 1975), aff'd ~L curiam, 426 U.S. 913 (1976). . PAGENO="0702" 696 passive viewer or listener of broadcast advertising.-~1 It is the contention of Professor Roger Blackwell that consumers might only grasp a general knowledge of product availability from broadcast advertising. In fact, because of selective perception, consumers will perceive only some of the stimuli they receive and may misinterpret that material to which they do not devote some attention. Consumers who watch or listen to advertising over the broadcast media are passive participants to the communi- cation of commercial messages. And many elements impact upon the advertiser's ability to reach consumers. For example, adjacent commercials, the nature of the advertised products and even outside stimuli may affect the manner and accuracy of consumers' perceptions. FTC Associate Director Wallace Snyder agreed with the experts in the FTC antacids warnings rulemaking that the broadcast media are inappropriate for conveying information on contraindications because it is a "low-imvolvement" med ium.-~i' It is not likely that mandated warnings about Reye's within aspirin and aspirin-containing product adver- tising will be as effective as a voluntary effort undertaken 3/ See testimony of Michael Ray, Professor of Marketing, Stanford University; Scott Ward, Professor of Marketing, Harvard Business School; and Roger Blackwell, Professor of Consumer Behavior, Ohio State University in FTC antacids warnings rulemaking, TR 1484. j/ FTC Bureau of Consumer Protection, Staff Report and Recommendatibns Advertising for Over-the-Counter Antacids, No. 215-56, at 195 (August, 1983) ("Antacids Staff Report"). PAGENO="0703" 697 by manufacturers, distributors, advertising associations, broadcasters, NAB and other organizations. Nor are mandated warnings necessary, given a voluntary multi-industry warning program. But it is likely, very likely, that passage of the proposal pending before the subcommittee would produce un- necessary and undesirable side effects. One, Congress will have taken a step seen as not sure enough by the agency expert about advertising and con- sumer perception, the FTC. That is, Congress would be legis- lating that every ad, here aspfrmn ads, must, by government order, warn consumers about a rare but possibly fatal occur- rence -- which information can be conveyed to and understood by the public in a voluntary and effective campaign -- a cam- paign to get the word out, not one to cause public questioning of reasonable self medication with aspirin products. Two, Congress would, by passage of H.R. 1381, be second-guessing the scientific judgment of the FDA processes on the medical underpinnings of contraindications. That too is unnecessary. A stepped-up voluntary program can and will get the necessary word of caution out and will do so immedi- ately. Meanwhile the expert agency, the FDA, will come to some solid conclusions about the association of aspirin and Reye's and about contraindications required in labeling. Three, passage of advertising provisions like those in H.R. 1381, by itself or by its prpgeny, may reduce consumer reliance on labeling and may scare of f consumers PAGENO="0704" 698 who overgeneralize advertising warnings from appropriate aspirin self-medication. B. Once a Voluntary Warning Program Has Alerted the Public About Reye's Syndrome, Labeling Becomes the Appropriate and Effective Method of Conveying Consumer Information on the ContraindicationS of Aspirin and Reye's. The FDA has found OTC aspirin products "generally safe and effective." Mandatory inclusion in advertising of aspirin label cautions may reduce the effectiveness of label warnings and, at the same time, may discourage OTC aspirin use by consumers who overgeneralize the warnings in adver- tising, Those consumers would lose the benefits of effective aspirin self-medication. The proposed legislation would extend label warnings (not yet required by the FDA) to aspirin advertising. But automatic application of label warnings to advertising is not justified simply by the fact of labeling restrictions. Pro- duct labeling serves a wholly different role from that of advertising. Advertising functions to awaken a general con- sumer awareness of the product and of the product's intended use. Some advertising also manages to distinguish a product brand from other similarly-used products. For the ad to be the most effective, the consumer must be both attracted to and interested in the simple information presented. By contrast, product labels function to explain in greater detail the particular characteristics of a product and thus go fa~ beyond piquing consumer awareness. Labeling PAGENO="0705" 699 is an effective medium for providing important health infor- matior~ because labels may be reread for clarity and because they are reviewed at the point of the purchase where the con- sumer may make the best decision based on thoughtful consid- eration of the information on hand. The role played by pro- duct labeling is complementary to, but distinct from, the role of advertising. Requiring warnings in advertising, particularly broadcast advertising, may in fact serve to reduce consumer reliance on effective labeling information -- to the consumers' detriment. FTC associate Director Snyder, in the antacids warnings rulemaking, cites two FDA studies, done in the early l970s, which found that substantial numbers of consumers read labels for safety information.-~1 Labeling is an effective method through which consumers properly and adequately receive FDA cautionary information. The mandated inclusion of any warnings in aspirin advertising itself likely would reduce con- sumer reliance on label information and encourage consumers to depend on advertised warnings as the last word in information. C. Aspirin Warnings in Broadcast Mvertising May Mislead and Unnecessarily Alarm Consumers. Even the most attentive of listeners and viewers may be both confused and alarmed by the warnings proposed for aspirin advertising. Broadcast commercials simply cannot 5/ Antacids Staff Report, supra, Snyder Memorandum at 40-41. 52-266 0-85-23 PAGENO="0706" 700 accommodate additional clarifying information and still pre- sent a selling message in a 30-second spot. And a barrage of information would cause either inattention or confusion. The potential for consumer confusion from brief warnings should not be understated. Nor should the potential impact on advertising decisions be overlooked. Confusion created by warnings may in fact discourage broadcast adver- tisements for OTC medications. Reduced advertising may re- sult where broadcast messages cannot accommodate lengthy dis- closures and effective selling messages -- or where selling messages are rendered ineffective by required disclosures.-~! Reduced broadcast aspirin advertising would unquestionably lessen consumer awareness of effective OTC products. Aspirin use is generally safe and effective for the vast majority of consumers in the vast majority of uses. But those same consumers, passively involved with broadcast advertising, likely may overgeneralize the warnings in aspirin. Required disclosures may serve to mislead and alarm consumers about the potential risks of OTC aspirin. Required advertising warnings simply would mislead consumers about the risks of OTC aspirin use. D. Conclusion NAB believes that the immediate need to alert mothers and teenagers to the potential risks of youngsters' 6/ See Thanscrip~ of the antacids rulemaking, TR 1484, Dr. Larry Light's testimony. PAGENO="0707" 701 taking aspirin for flu and chicken pox can be met and will be met through a stepped-up voluntary warning program. NAB and the nation's broadcasters stand ready to help get that word out. But NAB believes that reaching beyond a voluntary warning program and beyond labeling to mandated warnings in aspirin advertising, particularly for radio and television advertising, goes well past effective and needed measures and would disserve the public interest. PAGENO="0708" 702 OUTDOOR ADVERTISING ASSOCIATION OF AMERICA, INC. March 28, 1985 Honorable Henry A. Waxman Chairman Subcommittee on Health and the Environment Committee on Energy and Commerce 2415 Rayburn House Office Building Washington, D.C. 20515 Dear Mr. Chairman: The following statement is submitted by the Outdoor Advertising Association of America, Inc. for inclusion in the official hearing record of the March 15, 1985 hearing on H.R. 1381 -- the "Emergency Reye's Syndrome Prevention Act of 1985." The Outdoor Advertising Association of America, Inc. (OAAA) is the trade association of the standardized outdoor advertising industry. The Association is comprised of one hundred and seventy member companies that serve 7,900 dis- tinct local advertising markets throughout the United States. The OAAA understands the concerns evident in H.R. 1381 to make the public aware of the potential association between the use of aspirin and the development of Reye's Syndrome. Nevertheless, the advertising disclosures proposed in Section 2 of this bill are very poorly conceived. A 48-word boilerplate warning is not going to be effective when inserted into adver- tising. The proposed warning is so ponderous and unsuitable that it cannot be adapted to most advertising for salicytate products. The simple fact is that this bill would destroy all incentive to advertise these products. The advertising provisions of H.R. 1381 are, therefore, counterproductive since there will be few if any advertisements to carry the warnings if the bill is enacted. There is a superficial appeal in the proposed statutory scheme. Nevertheless, it is based upon the flawed premise that a lengthy and technical label warning will be communicated effectively through advertising. The bill reflects a wholesale misunderstanding of how information is conveyed in advertising and ignores the basic fact that a message must be tailored National Headquarters SUITE 403, 1899 L STREET, N.W., WASHINGTON, D. C. 20036-3881 (202) 223-5566 PAGENO="0709" 703 Honorable Henry A. Waxman March 28, 1985 Page Two for the precise medium in which it is disseminated. The manner in which this bill would impact on aspirin advertisements in the outdoor medium provides a good case study of how H.R. 1381 fails in this regard. It is generally understood that complex and comprehensive disclosures are not an effective method for conveying information in advertising. The most basic problem is that every medium imposes unique constraints on the manner in which information is communicated. For example, a standard outdoor advertising poster is 12 feet by 24 feet in size. This may seem like a large area. Certainly a 48-word warning could be accommodated physically within that space. But the size of the lettering would have to be relatively small for the warning to fit and, even then, the warning would occupy so much space that there would be little useable area remaining for the advertiser's message. Moreoever, there is no likelihood that such a warning could be read by a motorist. This problem is not confined to the outdoor medium alone. Theoretically, a 48~word warning could be recited within the confines of a 30 second radio or TV spot. Nevertheless, the warning message would have to be read very quickly to allow any time at all for the principal message. Beyond these practical limitations, the mere fact that the warning is incorporated in an advertisement does not mean that it will be understood. The proposed warning is too long and too complicated to convey the desired information. Adver- tising for consumer products, such as aspirin, generally relies on simple, evocative messages specifically designed for the particular medium through which they are disseminated. Even a single, well conceived warning would notbe effective in all media because each medium is different. This fundamental principal has been recognized in other regulatory contexts where affirmative disclosure requirements have been adapted to the specific media involved. For example, in 1978 the Federal Trade Commission issued guidelines for the inclusion of fuel economy disclosures in automobile advertising. The Commission recognized the different constraints imposed by each medium and incorporated separate disclosures for broadcast, print and outdoor media. Likewise, during the last Congress, this Subcommittee enacted the Comprehensive Smoking Education Act of 1984 which establishes separate cigarette health warning systems for package labeling, print advertising and outdoor advertising. The simple fact is that the advertising provisions of H.R. 1381 cannot achieve their ostensible purpose. In the OAAA's view, this warning scheme, however well intentioned, will not work. The development of an affirmative disclosure system should be left to the FDA and FTC which have the requisite expertise in this area. In a real sense, this bill would have the perverse effect of preventing those agencies from implementing a truly effective disclosure system to deal with the Reye's Syndrome problem. For these reasons the OAAA urges the Subcommittee to reject the advertising provisions of this bill. S in~74Z~ Vernon A. Clark, President PAGENO="0710" 704 L~JtLL. ~ L~\/ S1~it~ ThI~T r( ~, ~Xfl&Ev~iLY ~IFHC~L.1~LT i'b ~r~z-r Th \~ ThQ. f~Vf~)1S i~4~j~L'f ~~cshu~, ~iy cii~ ~L1\TR, JDj~i~y ~ ~ ~ i'ri2~ p~t~ ~3~t&LL ~ ~ ~ `~f~J~ o~ P~, ~ik.i~/ bt~ o~ IV17'ft~-44 P.2'-~ t~3 AFr~c&. ~ ~T~)o !~/~y BATTLE t'OtTH ~gyEs, S\~j~0~, ~ ~To SA)' , f~t'~t~)T ~LC..(-4 ~c,oLZ~~ ~ ~ t~k~~S ~g~mk1~Ly ~ ~ Su 1~t~'i v, N c~ S~1~ 7 LL~J ~ N~ ~Ri~I,~i .~f»=~31~s, ~ ~ `~-~ ~- ~ ~ ~ P~ Vfl~y CP~tI~J(~' S~i ~A4~C J\ (4,4 LL1~ LOH c Li~ lo (~S U~T, Si-iQ~ L~-e~~ `f~'~ `j'o i~P~~f~L ~J1~ Ls~vft~ ¶_~1 ~ ~I~? ~Ay~c~1~ ~-~-) ~ Th~F~~JF~ ~ 1\ £)4~tL~. ~ (P~ 1~ ~ H~4~ `-~-~ ~ M~ f~2S*~g~~ ~ 1~. ~C~4~c~L ..SM~ ~ 1~.) ~T~&c~j~y ~tc~-i~' 1~c~ ~ ~ ~ PAGENO="0711" 705 J~'t~ tLA)~C~~ )~Co~L) o3 U~3eSI~Ay. ~ ~Y~t~IL~I ~I- -rk~i~,t~y WI H~4~ SH~ ~ Ia ~ c~-rttL~& `~1M~k LQ )JO 1~~I~*1~ c?*~c cD~) t~Rsb$~y ~ i~ Ot4R Pi~c&. C1PL4~&f~j~. o1~S J~: ~4v~44 ~&~Q~O,~-) MO~ilt~)Cz7 S'it. 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O~1OLT~ kS ~fl~i I~Y1~ `~ ~*,.. `~ i~ f~I~iY~ ~ i~T v~ l-1i4~ ~ ~ ~3 ~t~fW~~J Si?~ o~k ~ ~4~Q1M ~ ~.R ~ ~ ~ ~ ~ ~ I ~k) ~ ~o(~-iJt'~C~ JY1Af~M ~2~5 ~ ~ ~bL~ ~ ~ tx~ ç~ u4 &~f ~ i~S ~PN~$iYiS ~ R~ Y4S)~) Th t~ * > * ~44~ ~ * .1~g , V~Vt~&. ~`IVtbJ 1k~%~t'~) * C~4tL,t~ tA*11~ W1M~~' ~ CpiJ ~Ri * ~ t~kV~' -fl~j *u~) ~ ci~t~ PAGENO="0713" 707 i~v1 V~~H1' c~-r ~ 13i~ 1~~!:L~1~ ~ `~ i~i1 P6'I'~ ?_I ~)& i~t~ ~ -Th'~P ~A3~ ~ c~k~i( LOj~ t~$ AL~Y«=.. ~i R~L ~tt~ )S 1~T d~t~) ~41 ~-i cMk~ ~1A1L4~ I~ ~i' ~ ~ W~H~ ~ w1~ ~ ~3~I9~5 ~ cj,~c,c i~ PAGENO="0714" PAGENO="0715" ORPHAN DRUG ACT REAUTHORIZATION WEDNESDAY, MARCH 20, 1985 HOUSE OF REPRESENTATIVES, COMMITTEE ON ENERGY AND COMMERCE, SUBCOMMITTEE ON HEALTH AND THE ENVIRONMENT, Washington, DC. The subcommittee met, pursuant to notice, at 10:30 a.m., in room 2322, Rayburn House Office Building, Hon. Henry A. Waxman (chairman) presiding. Mr. WAXMAN. The meeting of the subcommittee will please come to order. One year ago, the subcommittee conducted the first oversight hearing on the Orphan Drug Act. We found that we had made an excellent beginning and created high expectations. Our goal for this past year was to sustain our early success. Today we are pleased to be able to say that we are living up to those high hopes. The pharmaceutical companies, both large research-intensive firms, and small biotechnology and~ generic firms, are stepping for- ward to sponsor drugs for rare disorders. The Food and Drug Ad- ministration, particularly its Office of Orphan Products Develop- ment, has shown the American public that we are going to keep our promise to make orphan drugs available. Independent scien- tists have taken the challenge to be more attentive to orphan drug research, and the voluntary organizations like the National Orga- nization for Rare Disorders, continue to remind us of the need for ever greater success. They are our standard bearers and our inspi- rational leaders. For too many years, the story of orphan drugs has been one of hopelessness. After only 2 years of the Orphan Drug Act, we have proven that the story can be rewritten. The orphan drug problem can be solved, and for an increasing number of drugs, is being solved. Congratulations for a good year are in order today. We must re- member that it will never be profitable to conduct research on an orphan drug or to market one. No matter how much we have done, each new orphan drug is a challenge. Every year we must ask our- selves how we can improve our effort and whether additional re- sources are warranted. At our current pace, pharmaceutical companies will soon have adopted all those orphan drugs which do not require a lot of new research. Will we be able to get pharmaceutical companies to spon- sor orphan drugs at an earlier stage when original research is nec- (709) PAGENO="0716" 710 essary? Will we need additional Government funds to support human and animal research because companies are not willing to conduct it? Many people tell us the problem with orphan medical devices is as great as with orphan drugs. Should the act be expanded to in- clude medical devices? These are some of the questions we want to explore today. We have an impressive list of witnesses, all of whom are actively ad- dressing the problem of orphan drugs and medical devices. We look forward to hearing from them. Our first witnesses are the Commissioner of the Food and Drug Administration, Dr. Frank Young, and the Director of the Office of Orphan Products Development, FDA, Dr. Marion Finkel. We would like to ask them to come forward. And as they come forward, I would like to call on any of my colleagues who wish to make an opening statement. If not, we want to welcome Dr. Young and Dr. Finkel to this hearing today. We are pleased to have you with us. Your prepared statements will be made part of the record in full. We would like to ask you to summarize those statements so we will have a full op- portunity for questions and answers. STATEMENT OF FRANK E. YOUNG, M.D., PH.D., COMMISSIONER, FOOD AND DRUG ADMINISTRATION, PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES, ACCOMPA- NIED BY MARION FINKEL, M.D., DIRECTOR, OFFICE OF ORPHAN PRODUCTS DEVELOPMENT, FOOD AND DRUG ADMIN- ISTRATION; TOM SCARLETT, GENERAL COUNSEL Dr. YOUNG. Thank you very much. It is, indeed, a pleasure and an honor to be here today to discuss this program with you. I be- lieve that the accomplishments have been great over the past 2 years, but as you pointedly reminded us, we cannot rest at this point. There are substantial issues that must be faced and new dis- eases that must be dealt with. I am also very proud to have Dr. Finkel on the staff who has done an exceptionally fine job not only in administering this pro- gram, but in working with members of the academic and industrial communities, as well as consumer and patient representatives, to bring this program to fruition. Perhaps I can best summarize in a short period of time by calling our attention together to the chart that is over there. Basically, we have attempted to outline for you the program, the dates that it occurred, and the orphan designations; the sponsor commitments; the drug device marketing applications; the exclusivity applications approved; and the number of grant applications. The baseline is the period from May 1982 to December 1982 where we are begin- ning to get activities in place but do not yet have the act there. As you can see, there is a progressive increase in the number of orphan designations as time progresses. Particularly important was the passage of the amendment, and you can see, as in the prepared comments, that there was a marked increase in the number of designations following the amendment. That removed the sole responsibility to deal with fi- PAGENO="0717" 711 nancial issues and enabled us to use a 200,000 patient population as a criterion. The sponsor commitments have also continued to grow over this period of time. Looking at the next column, the drug and device marketing ap- plications, you can see that we received a total of 13 and corrected for 4 as shown in the footnote, as a function of time of submission. And then we had a progressive increase in the number that had been submitted. Probably the most important figure for our attention is the number of approved devices and drugs. Moving from what was one to three approvals per year prior to the enactment of the act, there has been a substantial increase reaching a peak of seven in the last full year. And you can see the one at the bottom refers only to the year to date. Important in our total program is the ability to have grant appli- cations. I should say, Mr. Chairman, that these grant applications are somewhat different than the grant applications at the National Institutes of Health. These are designed to take the identified projects, as you pointed out in your opening statement, to do the appropriate research, examinations and to then convert these into orphan products. During this period of time, we have been able to fund 19 grants. This will be augmented substantially by an additional million dol- lars that we received this year from one of the National Institutes of Health, enabling us to go further with the research grant ap- proach. It is estimated that at least 50 percent of these grants will yield products that can be brought to the marketplace under the Orphan Drug Act. That's an extremely important conversion factor, and I must emphasize that unlike the very important basic research pro- grams that are sponsored by the National Institutes of Health, these research programs are product-specific and designed to bring products to the market. And as you will see from the material that we submitted for the record, the vast majority of these are to uni- versity faculty members who are doing fundamental and applied investigations that are designed to bring these products further, and eventually to bring them to the marketplace. We feel that great diligence must be taken to be sure that the act is not violated or misused. It is important to remember, in our opinion, the very goal of this; to bring products that would not heretofore be brought to the American public. And it is not de- signed primarily to be profitable. We have some concerns for which we would be delighted to answer questions in regard to some of the patent provisions of the act. There has been a much greater experience with patent exten- sion over a period of time, and my testimony focuses on that. If I could read my conclusion, Mr. Chairman, it might be helpful for those that are listening to our testimony today. It is evident, Mr. Chairman, that the Orphan Drug Act is serving the purposes that you intended. We are gratified by the response of the pharmaceutical industry, clinical investigators and the volun- tary and professional organizations to the needs of patients with rare diseases. Through such cooperation, we can predict continued PAGENO="0718" 712 success in this field and thereby aid members of the American public who have rare but significant disorders. Particularly important is our research program that has stimu- lated interest in this important class of drugs and devices. An ex- ample of that comes to mind involving the drug mesna to prevent severe inflammation and bleeding of the urinary bladder in pa- tients receiving high doses of the anticancer drug, cyclophospha- mide. Although preclinical studies were performed by another drug company, Adria Laboratories is now sponsoring clinical trials with support from FDA under its grants program. Recently, the Nation- al Cancer Institute has expressed interest in participating in the development of the drug in order to facilitate its availability. The bottom line is, of course, the number of orphan drugs that have been marketed and are likely to be marketed in the next few years. Prior to the act and our program, in most years about one to three of the orphan drugs were approved for marketing annually. In 1982, four drugs were so approved, and you can see the in- crease that we have seen in that particular program. In addition, in 1983, there were five drugs an4 one medical device, and in 1984, seven drugs were approved including pentami- dine for P. Carinii pneumonia, the most common cause of death in patients with AIDS, and naltrexone for treatment of drug addic- tion. We anticipate that the total yearly number will continue at least at that level or rise as applications are received and approved for the products that have already been adopted. In addition, an increased focus on orphan drugs can be anticipat- ed in view of the needs in the areas of cancer chemotherapy and biotechnology. Thank you very much. [The prepared statement of Dr. Young follows:] PAGENO="0719" 713 STATEMENT BY FRANK E. YOUNG, M.D., Ph.D. COMMISSIONER OF FOOD AND DRUGS FOOD AND DRUG ADMINISTRATION Mr. Chairman: I am pleased to have been given an opportunity to appear before the Subcommittee to describe the results of FDA' s Orphan Products Development Program and the activities of the Department of Health and Human Services' Orphan Products Board. With me today is Dr. Marion Finkel, Director of Orphan Products Development at the Food and Drug ~drninistration. When the former Assistant Secretary for Health, Dr. Edward Brandt, appeared before the Subcommittee a year ago, he stated that the Orphan Drug Act and the climate it created had stimulated the development and marketing of orphan drugs by the pharmaceutical industry. At that time, he indicated that the industry had cooperated fully by `adopting" all the orphan products that were available for adoption, so to speak, by virtue of conplete or nearly corrplete investigations. I am delighted to say that this cooperation continues and that the interest of drug and device manufacturers has out waned. I will outline first what has been accortplished under each new section of the law that was added by the Orphan Drug Act. Section 525: Protocol Assistance N~i section 525 of the Federal Food, Drug, and Cosmetic (FD&C) Act states that a sponsor of an orphan drug may request written recommendatior.~ for the ounclinical and clinical investigations that PAGENO="0720" 714 stist be conducted with the arug before it can be approved for marketing. We have received nine requests for protocol assistance. This is a small n~nber in coitparison with the large n~ber of requests received for orphan designation under section 526 but it is r~t surprising in view of the effort that goes into preparing a request for protocol assistance. In order to provide cur reviewing divisions with the information they need to make a written recorrrnendation, a sponsor nust suirrnarize all available pertinent information, provide the clinical protocols it plans to use, state what it believes are appropriate studies to be performed for market approval and formulate specific questions it s~uld like FDA to address. Most sponsors prefer, instead, to meet with FDA periodicalJ~y cm an informal basis to discuss the corapleted researdi and their proposed plans for further study. Nevertheless, this ssction of the Act is useful for those who prefer to obtain a written recormut~ndation on the appropriateness of their research plans. Section 526: Orphan Drug Designation New section 526 of the FD&C Act provides for the designation of drugs as ormhans in order to render the~i eligible for the financial incentives of the Act. FDA has granted 53 requests for orphan drug PAGENO="0721" 715 designation since November 1983 when our designation guidelines were made available to sponsors. Six requests have been disa~roved, either because of an inadequate pharmacologic rationale or because the drug was not considered to be an orphan. The October 1984 amendment to the definition of an orphan drug had a significant ii~act on receipt of requests and designations. The new definition permits sponsors to aPply for designation without submitting projected costs of development and distribution and projected return from sales for drugs intended for patient populations in the U.S. of feaer than 200,000 patients. In the 12 month period prior to the aer~irent, 22 designation requests were granted. In the 4 1/2 month period since the amendrr~nt 31 requests were granted. The vast majority of designated drugs are intended for diseases with fewer than 50,000 patients in the TJ.S. I have supplied for the record a list of designated orphan drugs. Section 527: Exclusive Approval N~q section 527 provides a seven year period of marketing exclusivity for the first sponsor of an unpatentable orphan drug who receives marketing approval from FDA. This section provides important PAGENO="0722" 716 advantages over the exclusivity provisions of the Drug Price Coispetition and Patent Term Restoration Act in that an additional t'~ years of marketing exclusivity is offered and protection is granted against toth full and abbreviated new drug applications. In the 5 1/2 months that we have been providing information to sponsors on h~'i to submit a request for marketing exclusivity, we have received 17 requests and have granted 11 so far. These approvals are contingent upon the sponsor's obtaining marketing approval and being the first to do so. New drug applications have been approved for ts~v of these products and their sponsors are cperating under the exclusivity provisions of the Act. Section 528: Open Protocols for Investigational Drugs New section 528 encourageS sponsors of designated investigational orphan drugs to make those drugs available f or treatment purposes while the controlled trials needed for marketing approval are being conducted. FDA's policy with respect to these `treatment investigational new drug applications" (treatment IND's) is to permit distribution of the orphan drug for treatment purposes after preliminary evidence of safety and effectiveness for the intended use has been accumulated; distribution can then be made to patients with serious illness for whom other therapy is rot available or appropriate. PAGENO="0723" 717 Distribution of an orphan drug under section 528 is generally preceded by a request from FDA to the drug's sponsor to establish a treatment IND. ~en a corrpany agrees to distribute an orphan drug under section 528, we publish a notice in the Federal Register and an article in the FDA Drug Bulletin informing physicians about the availability of the drug and h~z it nsy be cbtained. Additional avenues for informing physicians are also being considered. I'~ cospanies are distributing orphan drugs under our formal treatment IND policy and another will do so later this year. ~any other con~anies, h~ever, are already making their drugs available without a request from us. In these cases, treatment INDs may be held by independent investigators as well as by the drug sponsor. Of 28 additional drugs and medical devices on the sponsor coimnitment list, which I shall describe in a norrent, 13 are or were being distributed by drug corrpanies or by the Centers for Disease Control. Section 227: Orphan Products Hoard The Orphan Drug Act also added section 227 to the Public Health Service Act which provides for the establishment of an Orphan Products Board within the Department of Health and Human Services. The Board meets approximately everj ts~o months. It has, in addition, held three public meetings. The Board concerns itself with broad issues, such as PAGENO="0724" 718 factors that might serve as disincentives to orphan drug development, the extent to which orphans exist in the medical device area, and methods for dissemination of available information on orphan diseases and orphan drugs. The first annual report of the activities of the Board, required under the Orphan Drug Act, was transmitted to the Congress in October 1984 and the second report is in preparation. ~kfter holding a public hearing and considering written corstents, the Board authorized the establishment of a new entity to provide information to patients and their families, physicians, clinical researchers, and the general public on rare diseases and the availability of orphan drugs to diagnose or treat these diseases. The National Information Center on Orphan Drugs and Rare Diseases was thus established in September 1984 through a contract funded by FDA. The existence of the Center was publicized by a press release and a brochure distributed to voluntary rare disease associations. The Center currently receives oore than 150 inquiries per rronth, primarily from patients o~ the general public. An article intended for health professionals that describes the Center will soon be published in the FDA Drug riulletin. This should increase physician and clinical investigator participation. The Center, in cuoperatiori with voluntary rare disease associations, will prepare approximately 30-50 fact sheets this year on specific diseases. PAGENO="0725" 719 It also is preparing a directory of educational materials on orphan drugs and rare diseases that are available from the voluntary rare disease organizations. Sponsor C~nitrnents I ~uld like to describe briefly other activities FDA conducts under its Orohan Products Develomiient Program. Under cur program, we identify drugs, medical devices and medical foods that appear to be useful for an uncormm~n or comim~n disease but that have no coimnitted sponsor to -complete development and submit a marketing application. Depending upon the circumatances, we seek sponsors by several mechanisms: for examele, we publish notices in the Federal Register and make presentations to the Corrninissicn on Drugs for Rare Diseases of the Pharmaceutical Manufacturers Association or the Institute of Orphan Drugs of the Generic Pharmaceutical Industry Association. Since May 1982, 31 orphan products have been adopted as a result of our efforts to seek sponsors through these procedures. Three of these are medical devices. Three adopted products have been approved for PAGENO="0726" 720 marketing and marketing applications for 12 others are under review. All products for which we have sought sponsors have teen adopted. I have provided a list of the sponsor cormnitments for the record. Some of the sponsors of these products have requested orphan designation. During the past three years 66 distinct orphan products have been adopted formally by the pharmaceutical and rredical device industries, as manifested by beth the sponsor comaitrrents to marketing that we have obtained and by the requests for orphan designation that have been received. In addition, over 30 orphan drugs are being studied by drug cortpanies independent of the Orphan Drug Act provisions. Grant Awards Under its appropriations, PDA received increases for orphan product developrrent that resulted in distribution of $500,000 in F~ 83 and $1 million in FY 84 for support of research on orphan drugs and madical devices. These funds enabled us to support 19 grant aoolications. I have provided a list of these applications for the record. FDA will use $1.4 million of its appropriations for fiscal year 1985 to fund orphan drug qrants; in addition, the National Institute of Child Health and Human Development has transferred $1 million to us for this year only to support research related to its mission. In addition, the Pr's Budget for fiscal year 1986 includes $1 .5 million to continue FDA' s reseach grants and contracts for orphan drugs. PAGENO="0727" 721 Conclusion In ~nclusion, Mr. Chairman, it is evident that the Orphan Drug Act is serving the purpose that you intended. We are gratified by the res~nse of the pharmaceutical industry, clinical investigators and the voluntary and professional disease organizations to the needs of patients with rare diseases. Through such rooperation we can predict continued and sustained success in this field arid thereby aid meirhers of the Amerian tublic who have rare bet significant disorders. Particularly iirmortant is our research program that has stimulated interest in this irrportant class of dtugs and devices. An exarple that comes to mind involves a drug, Mesna, to prevent severe inflartri'ation and bleeding of the urinary bladder in patients receiving high doses of the anticancer drug, cyclophosphamide. Although preclinical studies were performed by another drug corrpany, Adria Laboratories is ri~w spDnsoring clinical trials with sup~rt from FDA under its grants program. Recently, the National Cancer Institute has expressed interest in participating in development of the drug in order to facilitate its availability. The bottom line is, of course, the number of orphan drugs that have ceen marketed arid are likely to be marketed in the next few years. Prior to the Act and our program, in most years about one to three orphan drugs were approved for marketing annually. In 1982 four drugs were approved; in 1983 there were five drugs and one medical device; and in 1984 seven drugs were aoproved, including pentamidine for P. Carinii pneumonia, the most ooirrron cause of death in patients with AIDS, and Naltrexone for treatment of drug addiction. We anticipate that the yearly total will continue at least at that level or rise as applications are received and approved for the products that have already been "adopted." In addition, an increased focus on orphan drugs can be anticipated in view of needs in the areas of cancer dierrotherapy and biotechnology. PAGENO="0728" 722 Mr. WAXMAN. Thank you very much, Dr. Young, for your testi- mony. Let me address a question to Dr. Finkel, if I might. Did you have grant applications last year, and do you have grant applications this year which are worthy of funding but cannot be funded because you don't have enough funds? Dr. FINKEL. Yes, Congressman Waxman. Each year we have a few additional applications that are worthy of funding, and we hold them over and use the funds from the next year. And we expect to do the same this year. Mr. WAXMAN. Would it be helpful if your grant awards could cover the cost of preclinical animal studies? Under current law, grants may only be made for human testing. Dr. FINKEL. Well, under the FDA appropriations, there is no stip- ulation that the testing must be only for clinical studies. We have elected, because of the sum, to devote the money to clinical testing. Mr. WAXMAN. So you don't feel that you need a change in order to be involved in the preclinical part of the activities for the devel- opment of orphan drugs? Dr. FINKEL. No. Mr. WAXMAN. Should the Orphan Drug Act be expanded to in- clude medical devices? Dr. YOUNG. We feel that the act already enables us to begin to focus on a few medical devices. We feel that with increasing fre- quency, particularly in the area of diagnostic kits, there will be a need for devices. We would support such an action. Mr. WAXMAN. Should they be eligible for grants for human test- ing, and should they be eligible for the provision which grants 7 years of exclusive marketing rights for nonpatentable orphan drugs? Dr. YOUNG. We would prefer at this time to be as flexible as pos- sible with regards to the designation. As Dr. Finkel said, we al- ready have the ability to do both preclinical and human studies. That flexibility is extremely helpful for us. I believe the extension of patent exclusivity would also stimulate support in this important area. Mr. WAXMAN. Have there been any problems with the 7-year ex- clusive marketing provisions for nonpatentable orphan drugs? Dr. YOUNG. I would like Dr. Finkel to answer that, as she can speak most clearly to this. And we do have some problems, as I mentioned. Marion, would you comment, please? Dr. FINKEL. The most common problem is the situation where either an unmarketed product or a marketed product with a new use has some type of patent. It might be a product patent or a proc- ess patent. And at the time that the drug would be approved for the new use, there might be 1 or 2 years remaining of that patent. At that point, we could not grant 7 years' exclusivity since the patent was in existence. And the firms have told us that without those 7 years they would not go ahead. On the other hand, it would be a detriment to the public if firms waited until the patent expired before marketing the drug so they could get the 7 years. Another problem relates to the language of the act. It says that exclusivity can be granted if a U.S. Letter of Patent cannot be issued, but it doesn't say what kind of patent cannot be issued. PAGENO="0729" 723 If the language said, "if a use patent cannot be issued," which is the case in most of these situations, regardless of the fact that they might have other patents, then most of our problem would be obvi- ated. Dr. YOUNG. Mr. Waxman, I do have Tom Scarlett, our general counsel here. We have been looking into the question of that very important point that Dr. Finkel raised in regards to the last few years of a patent, and we would be interested in exploring this fur- ther. But perhaps Mr. Scarlett could provide some additional informa- tion on that. Mr. WAxMAN. Or perhaps we could suggest that Mr. Scarlett work with our staff to see if we could come up with language to resolve those difficulties. If you want to make any comments, we welcome them. Mr. ScA.iu~rr. We are looking into the question of whether the language can be interpreted, if it cannot be, we will work with the staff. Mr. WAx~,tA.r~. Mr. Whittaker. Mr. WHITTAKER. I have no questions. Mr. WAxi~.N. Mr. Leland. Mr. LELAND. Thank you, Mr. Chairman. Dr. Young, I understand that the regulations that establish an orphan drug tax credit still have not been issued by the Treasury Department. At a press conference to announce the approval of the drug, primozide, for Tourette's Syndrome on August 7, 1984, Secre- tary Heckler said she would be in touch with Secretary Regan about the tax credit regulations. be? you know why they haven't been issued and when they will Dr. YOUNG. The information that we have is that the Depart- ment will be issuing them soon. We have our guidelines out that complement those, and we hope within the not too distant future, measured in days and weeks, not months and years, the tax credit regulations will be forthcoming. Mr. LELAND. It's also my understanding that the orphan drugs which pharmaceutical companies have agreed to sponsor usually* have complete or nearly complete human testing. Are companies as willing to sponsor orphan drugs when very little testing has been done, so that the company will be responsible for conducting the necessary tests? if not, why not? And what should we do to get greater cooperation? Dr. YOUNG. We have, as shown over there, 54 designations. Ap- proximately half of the designations come from major companies that would be able to support such studies. To date, we have found that there has been good cooperation through Dr. Finkel's office in stimulating these events. In each of the oversights, if. there is any flagging of this atten- tion, I believe that further stimulation might be developed. But it seems to be working quite well at this time. Dr. Finkel, did you wish to add to that? Dr. FINKEL. Of the 54 designations, about half of that research is in the early stages, and there are both large companies and small companies that are developing new orphans PAGENO="0730" 724 Mr. LELAND. Do you think, Dr. Finkel or Dr. Young, that we will soon find that the Government must fund the initial research before pharmaceutical companies will get involved and sponsor a drug? Dr. YOUNG. It is a very important question of the total funding. In the aggregate, in biomedical funding, approximately 85 percent of the total research efforts throughout the Nation are supported by the Federal Government. This primarily is related to basic re- search, and the Congress has been very helpful in providing the sustained support. There are also, based on what we know from the National Insti- tutes of Health, substantial support in various activities of orphan drugs. The key issue will be what will happen in the future. It appears at the moment that industry is putting substantially increased dollars into research, particularly in the field of biotech- nology and some of the device areas. If this trend continues and if it can be stimulated through the good efforts of Dr. Finkel's office calling attention to this, we may be able to get an ever-increasing amount of funds developed for these projects. We cannot let, though, research support flag; otherwise, we would not bring these important medicines to the American people. We intend to watch that very carefully. Mr. LELAND. The National Information Center on Orphan Drugs and Rare Diseases was set up to provide information to patients, doctors, researchers, and the public about the availability of orphan drugs and rare diseases. Dr. Finkel, it's my understanding that the contract for the center was not done by competitive bids and was awarded to a company which has not computerized the in- formation. Why did you select such a company, and does it duplicate what the National Organization for Rare Disorders was already doing? Dr. FINKEL. Well, this organization has already had a contract with the Department of Health and Human Services to provide in- formation on diseases, most of which have been common diseases. And we thought they were very well set up to add the orphan dis- eases to the program. They are working very closely with the National Organization for Rare Disorders to gather information from the organizations, and also, to transmit queries back to the organizations. Mr. LELAND. Well, what about the information being computer- ized? The state-of-the-art should be in place, shouldn't it? Dr. FINKEL. Eventually, yes. They are just really starting up, and when they get everything together they will computerize it. Mr. LELAND. Thank you, Mr. Chairman. Mr. WAXMAN. Thank you, Mr. Leland. Mr. Nielson. Mr. NIELSON. The only comment I would have is to congratulate the chairman for his farsightedness in this particular area, and also the FDA for doing as well as you have so far. I'm supportive of the act and the efforts that the chairman has made in this respect. Mr. WAXMAN. Thank you very much, Mr. Nielson. Mr. Sikorski, any questions? Mr. SIK0R5KI. No, sir. Mr. WAXMAN. Well, Dr. Young, Dr. Finkel and Mr. Scarlett, we thank you very much for your participation in this hearing. We are PAGENO="0731" 725 going to work with you on these few issues that are outstanding and stand shoulder to shoulder and continue our efforts. Dr. YOUNG. Thank you very much, Mr. Chairman, we look for- ward to that. [Testimony resumes on p. 745.] [The following letter was submitted for the record:] PAGENO="0732" 726 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville MD 20857 MAR 2 1 ~85 The Honorable Henry A. Waxman Chairman, Subccxttstittee on Health and the Environment Committee on Energy and Commerce House of Representatives Washington, D.C. 20515 Dear Mr. Waxman: The enclosed material is being submitted for the record of the hearing conducted by the Subcommittee on Health and the Environment on March 20, 1985 on the Orphan Drug Act: (1) A list of orphan drug and biological product designations through 1984; (2) A list of sponsor commitments; (3) A list of orphan drugs and devices approved from June 1982 through Decertber 1984; (4) Ts~ lists of grant awards: (a) September and November 1983, and (b) September 1984; (5) The Executive Summary of the Annual Report to Congress for 1983 of the Orphan Products Board; (6) A chart shoaing the number of designations, sponsor cctstiitments, marketing applications, marketing exclusivity applications and funded grant applications in six nonth increments from 1982 to the present. In addition, s~ are submitting to the Subcommittee a list of designations that also contains estimated patient po~a.ilations considered to be confidential and not releasable to the ~itblic under FDA's Freedom of Information regulations. We therefore request that the Subccastitittee not release or otherwise make this document piblic without first notifying the Agency. Sincerely yours, Henry H. Dausch Director, Legislative Affairs Staff Enclosures PAGENO="0733" Name of Drug/Biological Product Generic-alpha-i-anti- trypsin (recombinant DNA origin) Trade-not estabi ished Generic-alpha-l-proteinase T~Tbitor (Alpha-i PD) Trade-not established Generic-antimelanoma i~T~ooy XllDIE-OO1-DTPA- III IN Trade-Same as generic Generic-antimelanoma 9~fl8oy X1iiltiE-OOI-RTA Trade-Same as generic Generic-antithrombin III ThrT!T) Trade-ilot established Sponsors Uarne and Address Cooper Biomedical, Inc. 3145 Porter Drive Palo Alto, CA 94304 Cutter Laboratories P.O. Box 1986 Berkelby, CA 94701 Xoma Corporation 3516 Sacramento Street San Francisco, CA 94118 Xoma Corporaticn 3516 Sacramento Street San Francisco, CA 94118 Cutter Laboratories P.O. Box 1986 Berkeley, CA 94701 727 SUBMISSION FOR THE RECORD/ORPHAN DRUG HEARING 3/20/85 ORPHAN DRUG AND BIOLOGICAL PRODUCT DESIGNATIONS THRU 1984 (Approved for ilarketing*) (Exclusive Approval **) BIOLOGICAL PRODUCT DESIGNATIONS Proposed Use Supplementation therapy for alpha-i antitrypsin deficiency in the ZZ phenotype population Replacement therapy in the Alpha 1 P1 congenital deficiency state Diagnostic use in imaging systemic and nodal melanoma metastasis Treatmemt of Stage III mela- noma not amenable to surgical. resection. For use as replacement therapy in congenital deficiency cf AT-Ill for prevention and treatment of thrombosia and pulmonary emboli PAGENO="0734" Name of Drug/Biological Product Generic-amSaCrifle `~~~msidyl Generic-bacitracin, U.S.P. T~not established ORPHAN DRUG AND BIOLOGICAL PRODUCT DESIGNATIONS THRU 1984 (Approved for ?lerketing*) (Exclusive Approval **) ORPHAN DRUG DESIGNATIONS Proposed Use Treatment of patients with acute adult leukemia Antibiotic-associated pseudomembranous entero- colitis caused by toxins A and B elaborated by Clostridium difficile Sponsors Name and Address Warner-Lambert Co. 201 Tabor Road Morris Plains, NJ 07950 A.L. Laboratories, Inc. 452 Hudson Terrace P.O. Box 1021 Englewood Cliffs, 13 07632 Generic-chenodiol ~8~henix*/~ For patients with radiolucent stones in well opacifying gallbladders, in whom elective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. Rowell Laboratories, Inc. 210 lain Street West Baudette, linnesota 56623 Generic-clofaZimine i~8-tamprene Treatment of leprosy resistant to Dapsone and the ENL and lepra reaction Pharmaceuticals Division Ciba-Geigy Corporation 556 Morris Avenue Summit, New Jersey 07901 ~enerjc-cromolyn sodium Tã~-~romoral ilastocytosiS Fisons Corporation 2 Preston Court Bedford, lA 01730 Generic_Cyproterofle acetate Trade-Cyproteron Gener ic-diaziquofle Trade-not established Treatment of severe hirsutism Treatment of primary brain malignancies (Grade III-IV astrocytomas) Berlex Laboratories, Inc. 110 East Hanover Avenue Cedar Knolls, NJ 07927 Warner-Lambert Co. 201 Tabor Road Morris Plains, NJ 07950 728 PAGENO="0735" BIOLOGICAL PRODUCT DESIGUATIONS (Continued) Proposed Use Treatment of selected cases of strabismus and blepharospasm strabismus - 14,700 patients blepharospasni - 1,500 Treatment of potentially life- threatening digitalis intoxi- cation in patients who are refractory to management by conventional therapy. Amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women and similar symptoms which occur in other patients with acute inter- mittent porphyria, porphyria variegata and hereditary coproporphyria. Sponsors Name and Address Alan B. Scott, 1.D. 2232 llebster Street San Francisco, CA 94115 Burroughs-Wellcome Co. 3030 Cornwallis Road Research Triangle Park North Carolina 27709 Abbott Laboratories Pharmaceutical Products Division North Chicago, IL 60054 729 Name of Drug/Biological Product Generic-botulinum A toxin 1F9~9~culinun Generic-digoxin-specific 9~Th~Iy fragments Trade-Dig ib md Generic-hemin 19~9~anhematin* PAGENO="0736" 730 ORPHAH DRUG DESIGHATIOUS (Continued) lame of Drug/Biological Product Generic-epoproStenOl ~~6~cyclin, PGI2, PGX Trade-Flol an Generic-epoprostenol Trade-Cycl o-Prostin Gener ic-ethanolaroine Trade-not established Replacement of heparin in certain patients requiring hemodialysis Replacement of heparin in certain patients requiring hemodialysis Bleeding esophageal varices Treatment of advanced adenocar- cinoma of the ovary Acceleration of corneal epithelial regeneration and healing of stromal incisions from corneal transplant surgery Genetic carnitine deficiancy Sponsors lane and Address Burroughs Weilcome Co. 3030 Cornwallis Road Research Triangle Pork lorth Carolina 27709 The Upjohn Co. 301 Henrietta Street Kalamazoo, ill 49001 Glaxo, Inc. P.O. Box 13960 Five bore Drive Research Triangle Port North Carolina 27709 Ivas Laboratories 685 Third Avenue New York, bY 10017 Chiron Corporation 4560 Horton Street Emeryville, CA 94603 American bcGaw Division of Americsn -bos:~:a1 Supply Corporstion 2525 ilcGaw Avenue Irvine, CA 92714 Sigma Tau, Inc. 723 North Beers Street Holodel, Hew Jeroey 07733 Dolor Pharnscestical Cc, 130 Lincoln Street Copiague, bY 11720 Proposed Use Generic-hexamethYl- ~T5~ine Trade-HexaStat Generic-human epidermal growth factor (urogastrone) Trade-not established Generic-L-carflitine Trade-not established Generic-L-Carnitine TPD~8Hot establiuhed Generic-L-5 Hydroxytryp- Ri~(L-5HTP) Trade-Not established Primary and secondary carnitine deficiency of genetic origin Treatment of postanoxic intention nyoclonus PAGENO="0737" 731 ORPHAN DRUG DESIGNATIONS (Continued) Name of Drug/Biological Product Generic-roonooctanoin `a~TIoctan Gener ic-PEG-adenosine ~iã~T~ise (PEG-ADA) Trade-Imudon Dissolution of cholesterol gallstones rotained in the cocoon bile duct For use as enzyme replacement therapy for ADA deficiency in patients with severe combined iromssodeficiency (SCID) Pneuviocystis carinii pneumonia Pneumocystis carinii pneumonia Prevention of calcium renal stones in patients ~iith hypo- citraturia and for the avoidance of the complication of calcium stone formation in patients with urate lithissis. For use in the prevention of recurrence of pneumothorax in patients at high risk of recurrence, e.g., patients with cystic fibrosis Adjuvant to levodopa or lays- dopa and carbidopa treatment of selected cases of idiopathic Parkinsons disease (paralysis agituns), postencephalitic parkinsonism, and symptomatic parkinuonism. Lypholled, Inc. 2020 Ruby Street Melrose Park, IL 60150 Rhone-Poulenc, Inc. 52 Vanderbilt Ave. New fork, NY 10017 Charles Y. C. Pak, 1.0. The Univ. of Texas Health Science Center at Dallas 5323 Harry Hines Blvd. Dallas, Texas 75235 Lypholled, Inc. 2020 Ruby Street llelrose Park, IL 50150 Farmacon, Inc. P.O. Box 586 Westport, CT 06881 Proposed Use Sponsors Name and Addrenn Ascot Pharmaceuticals Inc. 7701 11. Austin Avenue Skokie, Illinois 60077 Enzon, Inc. 300C Corporate Court South Plainfield, NJ 07080 Generic-pentamidine TE~6Tonate**/* Trade-Pentam 300 Generic-pentamidine T88ElFTonate rrade-not established Generic-potassium citrate T~DtTrocit Generic-quinacrine HCI `rFi~iNot established Generic-selegiline HCI ãRfleprenyl 52-266 0-85-24 PAGENO="0738" 732 ORPHAN DRUG DESIGNATIONS (Continued) Name of Drug/B iolog ical Product Generic-sodium rsonooercap- toundecahydro-~i2.~-dOdeca- borate Trade-Borol ife Treatment of glioblastoma muitiforme as an alternative to conventional photon therapy Sponsors lame and Address Nuclear Medicine, Inc. 900 Atlantic Drive, IN. Atlanta, GA 30332 Generic-spiramycin Trade-Rovanyci ne For use in the uymptsnatic relief and parasitic cure of chronic cryptosporidiouis in patients with immunodeficiency Rhone-Poulenc, Inc. 52 Vanderbilt Ave. New York, flew York 10017 Generic-tenipouide (VM-26) TFD8DiTot established Treatment of refractory childhood acute lympho- cytic leukemia (ALL) Bristol-Myers Co. Pharmaceutical Research & Developcient Division P.O. Box 4755 Syracuse, MY 13221-4755 Generic-triethylene ~Th~aFochloride Trade-Cuprid Treatment of patients with Wilson's disease who are intolerant, or inadequately responaive to, penicillamine Merck Sharp and Dchoe Research Laboratories Division of Merck and Co., West Point, Pa 19486 Generic-viloxazine hydrochloride Trade-Viva lan Treatment of narcolepsy and cataplexy Stuart Pharmaceuticals Division of DCI Americas ~ Wilmington, Delaware 19097 Gener ic-13 1lmeta- T~ooenzy1guanidine Trade-Not establ ished Generic-131 I-SB-iodornethyl- T~i~Eholesterol Trade-Not established Diagnostic adjunct in patients with pheochrsrnocytcma Adrenal cortical imaging lillian 11. Beierwaltes, 1.7. Physician-in-charge, Nuclear Medicine, University of Michigan Medical Center 1405 E. Ann Street Ann Arbor, Michigan ~6109 William H. Deierwaltes, M.D Physician- in-charge Nuclear Medicine University of Michigan Medical Center 1405 E. Ann Street Ann Arbor, Michigan 48109 Generic-2 ,3-dimercaptosuc- ~ThT~7~cid (DMSA) Trade-not established Treatment of lead poisoning in children Johnson and Johnson Baby Products Co. Grandview Road Skillman, law Jersey 08868 Proposed Use PAGENO="0739" Same of Biological Product Generic-Antithrombifl III ~~ç~n) Trade-Anti thrombin Generic-Erwinia t~ã~ag i nasa Trade-Sot established Generic-Factor XIII TFDX8Fibrogammin Acute lymphoblastic leukemia Congenital Factor XIII deficiency Sponsors lame and Address Kabi Vitrum Inc. 600 Steamboat Road Greenwich, CT 06830 Lypho fled, Inc. 2020 Ruby Street lelrose Park, IL 60160 Hoechst-Roussel Pharoaceuticals, Inc. Route 202-206 lorth Somerville, I.J. 08876 Generic-sheep antidigoxim Trade-Digidota Life-treatening acute cardiac glycoside intoxication canifested by conduction disorders, ectopic ventricular activity and (in uomè cases) hyperkalemia Boehringer iannheim Corporation 1301 Piccard Drive Rockville, Ilaryland 20850 733 ORPHAN BIOLOGICAL PRODUCT DESIGNATIONS January 1, 1985 through Narch 15, 1985 (Approved for :larketiny*) (Exclusive Approval **) BIOLOGICAL PRODUCT DESIGNATIONS Proposed Use Hereditary AT-Ill deficiency PAGENO="0740" lame of Drug Generic-antipyrine iP569-not established Gener ic-flumecinol Trade-Zixoryn Gener ic-glucocerebros idase/ 8B6R~lucosidase (placenta- derived) Trade-not established Generic-human epidercial ~F3~E, factor (urogastrone) Trade-not established Generic-human superoxide 3T68O6aue (hSOD) Trade-not establ ished Antipyrine test as an index of hepatic drug-metabolizing capacity Hyperbi I irubinernia in newborn infants unresponsive to phototherapy Replacement therapy in patients with Gaucher's Disease Type I Promotion of cutaneous wound healing in extreme burn treatment protocols Protection of donor organ tissue from damage or injury mediated by oxygen-derived free radicals that are generated during the necessary periods of ischemia (hypoxia, anoxia), and especially reperfusion, associated with the operative procedure Treatment of heroin addicts suitable for maintenance on opiate agonists Sponsor's Name and Address Upoher-Snith Laboratories, Inc 14905 23rd Avenue North Minneapolis, MN 55441 Farmacon, Inc. P.O. Box 536 Westport, CT 06381 Genzyme Corporation 75 Kneeland Street Boston, MA 02111 Chiron Corporation 4560 Horton Street Erneryville, CA 94608 Chiron Corporation 4560 Horton Street Emeryville, CA 94608 Dixon and Williams Pharmaceutical Cs, Inc. 43 Old (sod Road Bernardsville, N.J. 07924 734 ORPHAN DRUG PRODUCT DESIGNATIONS 1985 (Approved for Marketing*) (Exclusive Approval **) ORPHAN DRUG DESIGNATIONS Proposed line Generic-l-al pha-acetyl- i6~tlli08l (LAAM) Trade-not established PAGENO="0741" 735 ORPHAN DRUG DESIGNATIONS (Continued) Prooosed Use Sponsors Name Name of Drug and Address Generic-naltrexone HC1 Blockade of the pharmacological Du Punt Pharmaceuticals, Inc.. TBBTrexan effects of exogenously 1000 Stewart Avenue administered opioids as an Garden City, New York 11530 adjunct to the maintenance of the opioid-free state in detoxified formerly opioid-dependent individuals Generic-oxymorphone For severe intractable pain Du Pont Pharmaceuticals, Inc. ~i~tency in narcotic-tolerant patiento P.O. Box 12 Trade-Dilaudid H.P. !anati, Puerto Rico 00701 Generic-physostigmine Friedreicho and other ONeal, Jones and Feldman iBTTE~Tate inherited ataxias Pharmaceuticals Trade-Antilirism 2510 Hetro Doslevard lIaryland ieighto, 10 54043 Generic-sodium garna Narcolepsy and the auxiliary Sigma F end 0 ~a~butyrate (GHB) symptoms of cataplexy, sleep Division, Ltd. Trade-not established paralysis, hypnagogic Sigma Chemical Co. hallucinations and automatic 3050 Spruce Street behavior St Louis, 110 53103 Generic-thyrotropin- Amyotrophic lateral Abbott Laboratories F5T~ing hormone (TRH) sclerosis (ALS) North Chicamo, CL 60054 Trade-not established PAGENO="0742" 736 SUBMISSION FOR THE RECORD/ORPHAN DRUG HEARING 3/20/85 ORPHAN DRUGS AND DEVICES SPONSOR COMNITMENTS DRUG SPONSOR DISEASE DATE OF COMMITMENT Trien MSD Wilson's Disease October 1982 (triethylene tetramifle dihydrochloride) NP-59 Mallinckrodt Adrenal Cortical June 1982 (6-beta-l9- Imaging (Presentation to PMA iodonorcholesterol) Commission Hematin Abbott Hepatic Porphyria May 1982; (licensed July 1983) Amiodarone Ives Cardiac Arrhythmias October 1982 Indium1~ Amersham Platelet Imaging December 1982 Oxine Methacholine Cl Roche Diagnosis of March 1982 occult bronchial asthma Pimozide McNeil * Tourette's November 1982 (Approved Syndrome for marketing July 1984) Bacitracin A.L. Labora- Pseudomembranous August 1982 tories Enterocol itis Hydroxy-Ethyl American WBC Harvesting August 1982 starch Critical Care L-5 Hydroxy- Bolar Postanoxic June 1982 tryptophan Myoclonus Vitamin E Roche Neuromuscular October 1982 Disorders secondary to cholestatic disease in Vitamin £ deficient patients Pentamidine LyphoMed P. Carinli Approved for marketing Pneumonia October 1984 L-Carnltlne McGaw Carnltine July 1982 Deficiency Ethanolamine Glaxo, Inc. Bleeding December 1982 Oleate Esophageal Varices PAGENO="0743" i131_~i_ I odobenzyl- guanidine (I 13l-tIIBG) Moctan (monooctanoin) Confidential Citric acid, gluconic acid, magnesium hydroxy- carbonate, mag- nesium acid citrate, calcium carbonate solution Furamide (diloxide furoate) Mitronal (cinnarlz me) Confidential Lamprene (clofazimine) Glycopyrrolate Ismel in (guaneth idine) IV Quinacrine HC1 SPONSOR DISEASE Confidential Certain patients with Parkinson's disease Confidential Confidential Confidential Confidential Hall inckrodt Adrenal medullary imaging agent Ascot Cholesterol gallstone dissolution Confidential Dissolution of urinary tract calculi and preven- tion and treatment of encrusted in- dwelling urinary tract catheters Boots Pharma- Asymptomatic ceuticals Inc. intestinal amebiasis G.D. Searle Hereditary angloneurotic edema Confidential Pain Ciba-Geigy Leprosy A. H. Robins Ciba-Geigy LyphoMed (Sterling Drug will provide Information for product development) Upsher-Smith Laboratories Chelsea Laboratories Confidential Tn Hawk Inter- national Inc. 737 DRUG Deprenyl Confidential Confidential Confidential Guardian Chemical DATE OF COMtIITtIENT January 1983 January 1983 December 1982 March 1983 July 1983 September 1983 November 1983 January 1984 January 1984 January 1984 February 1984 March 1984 July 1984 September 1984 October 1984 Frey syndrome Causalgia Prevention of recurrence of pneumothorax in patients at high risk of recurrence Use of oral anti- pyrine in the Antipyrine Test in patients to monitor the drug-metabolizing capacity of the liver Confidential Selected cases of corneal perforation Antipyrine Confidential Histoacryl January 1985 January 1985 PAGENO="0744" 738 SUBMISSION FOR THE RECORD/ORPHAN DRUG HEARING 3/20/85 ORPHAN DRUGS AND DEVICES APPROVED JUNE 1982 - DEC. 1984 HEMATIN - ERYTHROPOIETIC PROTOPORPHYRIA AFP DIAGNOSTIC KIT FOR TESTICULAR CARCINOMA ORAP (PIMOZIDE) - TOURETTE~S DISORDER GONADORELIN - DIAGNOSTIC FOR EVALUATION OF HYPOTHALMIC-PITUITARY GONADOTROPIC FUNCTION ACETOHYDROXAMIC ACID - FOR UREASE SPLITTING URINARY TRACT INFECTIONS HYDROMORPHONE HIGH POTENCY - CHRONIC PAIN CHENODEOXYCHOLIC ACID - DISSOLUTION OF RADIOLUCENT GALLSTONES IN POOR-SURGICAL-RISK PATIENTS ETOPOSIDE - TESTICULAR CANCER CYCLOSPORINE - IMMUNOSUPPRESSANT TO PREVENT ORGAN TRANSPLANT REJECTION DESMOPRESSIN - MODERATE HEMOPHILIA SODIUM CELLULOSE PHOSPHATE - HYPERCALCIURIA AND RECURRENT CALCIUM NEPHROLITHIASIS PENTAMIDINE ISETHIONATE - P. CARINII PNEUMONIA NALTREXONE - NARCOTIC ADDICTION MODRASTANE (TRILOSTANE) - GUSHING'S SYNDROME PRISCOLINE (TOLAZOLINE HCL) - PERSISTENT PULMONARY HYPERTENSION IN THE NEWBORN PAGENO="0745" 739 SUBMISSION FOR THE RECORD/ORPHM DRUG HEARING 3/20/85 Grant Awards Office of Orphan Products Development Food and Drug Administration September and November 1983 The amounts listed are for first year funding. ROCKEFELLER UNIVERSITY (New York) - $112,109 - Dr. 0. Martin Carter Phenytoin for Recessive Dystrophic Epidermolysis Bullosa ROCKEFELLER UNIVERSITY (New York) - $60,575 - Dr. Charles Peterson Evaluation of WR 2721 as Treatment for Cystinuria UNIVERSITY OF MICHIGAN (Ann Arbor) - $65,952 - Dr. Jess Thoene Pantethine Therapy of Nepropathic Cystinosis UNIVERSITY OF ~1ICHIGAN (Ann Arbor) - $45,235 - Dr. Brahm Shapiro 131 I-MIBG: Evaluation of Efficacy in Diagnosis and Therapy ADRIA LABORATORIES, INC. (Columbus, Ohio) - $50,362 - Dr. James Luce Mesna to Prevent Cystitis from High Dose Cyclophosphamide NYS PSYCHIATRIC INSTITUE (New York) - $92,000 - Dr. Joaquim Puig-Antich Imipramine in Pre-Pubertal Major Depression UNIVERSITY OF CALIFORNIA (Los Angeles) - $50,417 - Dr. Edward Ritvo Safety & efficacy of Fenfluramine in Autism MT. SINAI SCHOOL OF MEDICINE (New York) - $22,350 -. Dr. Melvin Van Woert Therapeutic Trial of Harmaline in Cerebellar Disorders UNIVERSITY OF IOWA (Iowa City) - $79,967 - Dr. Daniel Furst Analysis of Controlled Trial of Chiorambucil vs Placebo in Progressive Systemic Sclerosis CHILDREN'S HOSPITAL RESEARCH FOUNDATION (Cincinnati, Ohio) - $50,625 - Mrs. Helen Berry - VIL - A Hew Treatment for Phenylketonuria CASE WESTERN RESERVE UNIVERSITY (Cleveland, Ohio) - $44,776 - Dr. Gary Brittenham - Carbonyl Iron Therapy for Iron Deficiency Anemia JOHN F. KENNEDY INSTITUTE (Baltimore, MD) - $54,555 - Dr. Julian Chisholm Efficacy of DMPS in Therapy of Childhood Lead Poisoning PAGENO="0746" 740 GRANT AWARDS Office of Orphan Products Development Food and Drug Administration (September 1984) CHILDREN'S HOSPITAL, Buffalo, New York, Clara Ambrus, M.D., Ph.D. Use of Enzyme-Reactors for Management of Phenylketonuria BOSTON UNIVERSITY, Boston, Massachusetts, Michael E. Osband, M.D. Treatment of Histiocytosis-X with Suppressin A THE WISTAR INSTITUTE, Philadelphia, Pennsylvania, Stanley A. Plotkln, M.D. Live Attenuated Cytomegalovirus Vaccine in Patients Receiving Renal Transplants BAYLOR COLLEGE OF PIEDICINE, Houston, Texas, Earl J. Brewer, M.D. Methotrexate in Severe Juvenile Rheumatoid Arthritis UNIVERSITY OF FLORIDA, Gainesville, Florida, William N. Williams, Ph.D. Treating Palatal Insufficiency by Teflon A. L. LABORATORIES, INC., Englewood Cliffs, New Jersey, Bernard B. Brown, Ph.D. Bacitracin for Therapy of Pseudomembranous Colitis JAYE-BOERN LABORATORIES, INC., Northbrook, Illinois, Joel E. Bernstein, M.D. Topical Capsaicin Treatment of Post-Herpetic Neuralgia PAGENO="0747" 741 SUBMISSION FOR THE RECORD/ORPHAN DRUG HEARING 3/20/85 I. EXECUTIVE SUMMARY BACKGROUND Orphan Drugs is the first annual report on the status of orphan drug development as coordinated within the Department by the Orphan Products Board (OPB). This report Is submitted by the Secretary of the Department of Health and Human Services to the Committee on Labor and Human Resources of the Senate and the Committee on Energy and Commerce of the House of Representatives, pursuant to Section 227 of the Public Health Service Act. This report is due on June 1, 1984. It was prepared at an estimated cost of ~75,SOO. It presents the results of a survey of all Department activities with respect to the development of orphan drugs. As specified by statute, the report is organized around four major themes: o ActIvities of the Orphan Products Board o Orphan Product Development Activities of the Department o Marketing Commitments by Sponsors of Orphan Drugs o Rare Disease Research Activities of the Department Fourteen tables and five appendices on orphan product research and development activities are also presented. FINDINGS Orphan drugs are drugs or biological products for the diagnosis, treatment or prevention of a rare disease or condition which occurs so infrequently in the United States that there is no expectation that the cost of developing the product and making it available in the United States will be recovered from the sales of that product in the United States. The Orphan Drug Act (Public Law 97-414) establIshed within the Department of Health and Human Services (OHHS) the Orphan Products Board (OPB). The Orphan Products Board is chaired by the Assistant Secretary for Health. It includes members representing those agencies within the Depamtment which function to develop, identify, approve, distribute, or provide reimBursement for drug products. At the Board's regular meetings and the two public hearings, it identified and developed positions on major policy issues that affect orphan product availability. These areas of interest are presented below. Product Liability Related to Orphan Products Development Concern has been expressed that increased product liability costs would prevent the development of orphan drugs. To explore this concern, the Orphan Products Board conducted a brief survey of the Chief Zxecutive Officers or Presidents of several Pharmaceutical Manufacturers Association (PHA) member firms and the President of the Generic Pharmaceutical industry Association (GPIA). The results of this survey indicated that most firms are not deterred from developing and marketIng orphan drugs by liability considerations. Also, firms that have marketed orphan drugs have had no increase in insurance costs as a result of this activity. The Bcard will continue to monltcr the ava:labillty of orphan urugs aid determine if liability Is a major obstruction to the development of orpnan drugs. PAGENO="0748" 742 Orphan Drug Designation FDA developed interim procedures to implement Section 526 of the Federal Food, Drug and Cosmetic Act to designate drugs for rare diseases or conditions. These interim procedures will help speed up the development of orphan products by encouraging research activities with the availability of incentives after a drug receives the orphan designation. The requirements in a request for designation as an orphan drug include information on the estimated costs for the development and distribution of the drug as well as the expected sales in the U.S. This information is necessary to Indicate there is no reasonable expectation that the total costs for drug development and distribution will be recovered from sales of the drug. Assistance to Soonsors on Orphan Drug Research Protocols To assist In the development of research protocols and provide guidance to these sponsors FDA developed interim procedures to implement Section 525 of the Federal Food, Drug and Cosmetic Act. These procedures require FDA to provide written reconmmendations for the pre-clinical and clinical investigations that are required prior to marketing approval to those sponsors of drugs who submit a request for assistance in the design of the study protocol. Information Center for Rare Diseases and Orphan Dr'~gp The possibility of developing an improved mechanism for disseminating informatibn about orphan drugs and rare diseases or conditions to patients, physicians and voluntary patient associ~tions was discussed at the first publlc.meeting of the OPB. A public meeting was held in December, 1983 to discuss this in greater detail. Participants at the public meeting were asked to identify information gaps in the area of orphan drugs or rare diseases ano possible sources of information for patients and their families, physisiars, or researchers. Existing clearinghouses, information centers and voluntary associations discussed their activities with respect t3 the transfer of information to requestors. The Board continues to work on this issue. CHHS ORPHAN PRODUCTS DEVELOPMENT ACTIVITIES Introduction The 0P8 conducted a survey of the 12 research Institutes and Divisions that comprise NIH, the three ADA~fl~A Institutes, FDA, CCC, and HCFA to determine the extent of research activities with respect to orphan drugs. Ten Federal agencies reported direct involvement in research and/cr distribution activities to increase the availability of over 80 products. The FDA reported that aoproximately 300 products are currently under study, either within the Federal government or in the private sector. Sixty percent of these drugs are available to patient populations through treatment and compassionate Investigational New Drug (IND5) exemptions. The drugs represent treatments for a broad range of rare conditions, including neurologic, hematologic, metabolic and oncologic disorders, as well as infectious diseases. PAGENO="0749" 743 Some important indicators of specific orphan drug development efforts among the surveyed organizations follow: o Nine organizations and CCC are involved to varying degrees in the development of orphan products. In addition CDC and Nd selectively distribute several of these drugs, and FDA performs a monitoring role. Twenty-one products are available to physicians and patients through treatment INDs. o Eleven NIH Institutes have issued an omnibus grant announcement - requesting for ap~plications to conduct research projects on orphan products; o Ten organizations have funded research projects for orphan drugs; while some products required no Federal funding, the expenditures for others have ranged as high as 3 million dollars; o Six organizations engaged in activities to seek sponsors for the development and/or marketing of orphan products; and o Six organizations currently pursue and/or plan future intramural research activities to support the development of orphan products. ORPHAN DRUG DEVELOPMENT AND MARKET!NG COMMITMENTS BY SPONSORS OF ORPHAN CRUGS Many orphan drugs are without a commercial sponsor to guarantee the continued availability of the product to the general public or clinicians involved in the treatment of a rare disease or condition. The Act provides incentives such as tax credits for expenses incurred by required clinical studies, exclusive marketing privileges and assistance in developing a protocol for the study of a particular product. In spite of inducements made available by the Act, many products remain unavailable. Sponsor commitments are obtained in several ways. Most are the result of a direct approach by means of invitations for sponsorship published in the Federal Register, or requests to firms that are making a drug available under a compassionate IND or that have specific expertise in the manufacture of a certain type of product. The remainder are obtained by working with the PMAs Commission on Drugs for Rare Diseases or S?!As Institute- for Orphan Drugs. Twenty-one products received commitments in l983 from sponsors to pursue further investigations prior to submitting a New Drug Application. The work on orphan drugs in the private sector has been augmented by the efforts of the PMA Commission on Drugs for Rare Diseases and the G?IA Institute for Orphan Drugs. Each of these associations has workeo with ADAIO-iA, CCC, FDA, and NIH to identify potential treatments for rare diseases and then to Identify sponsors of these drugs, thus allowing the treatments to become more readily available to the patient popula~ions. RARE DISEASE RESEARCH ACTIVITIES OF THE DEPARTMENT The Act directs the Secretary to make grants to and enter into contracts with public and private entities mo individuals to assist ~n r~ducirg the cc~ts of clinical testing expenses incurred in the development of drugs for rare PAGENO="0750" SUBMISSION FOR THE RECORD/ORPHAN DRUG HEARING 3/20/85 ORPHAN DRUGS AND MEDICAL DEVICES Drug and Device Exclusivity Grant Orphan Sponsor Marketing Applications Approval Applications Program Designations Coniuitments Submitted Approved Applications Funded 5/82 - 12/82 0 14 (13)4* 2 0 0 Orphan Drug Act 1/83 - 6/83 0 3 5 2 0 0 7/83 - 12/83 1 3 5 5 0 12 1/84 - 6/84 16 5 3 2 1 0 Act Amended 7/84 - 12/84 23 3 6 5 6 7 1/85 - Present 15 3 2 1 10 0 * 4 submitted between 5/82 - 12/82 9 submitted before 5/82 PAGENO="0751" 745 Mr. WAXMAN. I would like to now call forward Dr. Jess G. Thoene, president-elect, National Organization for Rare Disorders, who will be accompanied by Abbey S. Meyers, chairperson, Govern- ment-Industry liaison committee, National Organization for Rare Disorders, director, Family and Professional Services, Tourette Syn- drome Association; and Dr. Dilip P. Shah, vice president, regula- tory affairs, LyphoMed, and Mr. William Baird, president of the American Narcolepsy Association. I want to welcome you to our subcommittee hearing today and tell you that your prepared statements will be made a part of the record in full. We would like to ask you to summarize those statements in around 5 minutes if you could possibly do it. Dr. Thoene. STATEMENTS OF JESS G. THOENE, M.D., PRESIDENT-ELECT, NA- TIONAL ORGANIZATION FOR RARE DISORDERS, ACCOMPANIED BY ABBEY S. MEYERS, CHAIRPERSON, GOVERNMENT-INDUS- TRY LIAISON COMMITTEE, DIRECTOR, FAMILY AND PROFES- SIONAL SERVICES, TOUREVfE SYNDROME ASSOCIATION; DILIP 0. SHAH, PH.D., VICE PRESIDENT, REGULATORY AFFAIRS, LYPHOMED, INC.; AND WILLIAM BAIRD, PRESIDENT, AMERI- CAN NARCOLEPSY ASSOCIATION Dr. THOENE. Thank you, Mr. Chairman, and my thanks to the members of this committee for giving us this additional opportuni- ty to address you on this important issue. As you know, the Orphan Drug Act has been a vital first step in the struggle to provide the fruits of the American biomedical-indus- trial complex to sufferers of rare disorders. The committee knows that until the institution of this act, there was little interest on the part of industry in developing treatment for these diseases. Since passage of the act, the Office of Orphan Products Develop- ment of the Food and Drug Administration has made a number of research grants to investigators attempting to develop treatment for rare diseases. We are delighted with this first step and pleased with the results of some of these investigations which have led to the availability of treatment for rare disorders which otherwise have no hope of ame- lioration. It is essential, therefore, that the act be reauthorized and that continuing research funds be made available for preclinical trials and clinical investigations in the treatment of rare disorders. In responding to the conversation just a moment ago, these funds are essential, in my view, because without them the data necessary to generate interest on the part of industry for the development of treatment for rare disorders will not be available. The National Organization of Rare Disorders therefore requests that the $4 million appropriation for the Orphan Drug Act be reau- thorized but with the following change: that funding for Orphan Drug research grants should be appropriated by the Agricultural Subcommittee directly to the Food and Drug Administration's Office of Orphan Products Development. PAGENO="0752" 746 This is because the Orphan Products Board is not funded by any congressional committee, and during the past 3 years, funding for orphan drug research grants has been appropriated through the House Agricultural Subcommittee. This resulted in some confusion and dilution of funding efforts. In 1985, as was noted, an additional $1 million was appropriated through the National Institute of Child Health and Human Devel- opment and then transferred to FDA's Office for Orphan Products Development. Language in the reauthorization should restrict the use of the funds to extramural research grants, and the money should not be used for FDA's intramural research, administrative costs, or other ongoing projects. Insofar as it is possible in these times of domestic budgetary re- striction, the National Organization of Rare Disorders would like to emphasize that this $4 million appropriation for rare disorder re- search should not be obtained at the expense of funding for the Na- tional Institutes of Health. I echo Dr. Young's statement. The National Organization of Rare Disorders recognizes the essential nature of the infrastructure pro- vided by basic research funded by the National Institutes of Health. To subtract moneys from these vital research efforts to fund the Orphan Drug Program would only rob Peter to pay Paul. Our feeling is the entire research enterprise must go forward with augmented funding. The National Organization of Rare Disorders notes that under current regulations, during the time a drug is approved for market- ing but not actually released to the market, the drug may not be distributed to consumers. We believe that the act should allow for drug companies to continue distribution of an orphan drug which was under IND status during the transition between approval for marketing and actual licensing. In some cases this period can last between 6 months to a year. We feel it unconscionable to allow patients with rare disorders to suffer for lack of a drug they were previously receiving just be- cause of the way a regulation is written. The National Organization of Rare Disorders also supports inclu- sion of medical devices within the purview of the act insofar as these devices will truly benefit persons with orphan conditions. We believe that the 7-year exclusive marketing rights provision of the act is essential to encourage corporations to undertake orphan drug development. However, we also feel some abuse of this exclusive marketing period may occur, conceivably, if a company holding a patent for a given agent continually pursues, under pro- visions of the act, a marketing application for an orphan indica- tion. Serial repetition could provide an unfair advantage to the patent holder for an indefinite amount of time. We suggest a limit of no more than 1 year during which the Secretary cannot issue approv- al for a generic form of the drug. Finally, the NORD is concerned that the Department of the Treasury be directed to publish tax incentive regulations of the act within 6 months of enactment. Both patients with rare disorders and those of us in this field of research are heartened by the con- PAGENO="0753" 747 tinued interest of this committee-and I mean that sincerely-and we hope that the recommendations made today will further en- hance the prospects of sufferers of rare disorders to obtain treat- ment. Thank you. Mr. WAXMAN. Thank you very much. Dr. Shah. STATEMENT OF DILIP P. SHAH, PH.D. Mr. SHAH. Thank you, Mr. Chairman and members of the sub- committee. I am indeed honored today to have this opportunity to share with the committee a view of the Orphan Drug Program from the per- spective of the small pharmaceutical company. I would like to use my allotted time today to mention briefly Ly- phoMed's experience with orphan drugs and also to focus on specif- ic suggestions which I feel would serve to advance this worthwhile program. LyphoMed, Inc., is headquartered in a suburb 25 miles outside of Chicago and employs approximately 420 persons. Sales for fiscal year 1984 have reached $31.4 million. We are a leading producer and distributor of critical care micronutrients in small volume par- enteral dosage form. These micronutrients consist of a wide range of multivitamins, trace elements and electrolytes. In addition, we manufacture anti- biotics, anticoagulants, diuretics, steroids and hormones. In the near future, we will enter the anticancer market, which will serve to strengthen our leadership position in the area of critical care parenteral drugs. In 1983 the Centers for Disease Control, CDC, approached several pharmaceutical companies, including LyphoMed, with the purpose of securing a manufacturer for the drug Pentamidine Isethionate. This product is used in the treatment of an often fatal pneumonia in patients with suppressed immune system, including those with acquired immune deficiency syndrome, commonly known as AIDS. Due to the dramatic increase in the number of requests for Pent- amidine and the uncertain availability of the overseas supply, the CDC found it necessary to recruit a domestic manufacturer. In view of LyphoMed's commitment to and concern for the specialized needs of the critically ill, we agreed to produce and distribute the drug. Since there are less than 7,000 AIDS patients in the country, a fact that would make commercial success unattainable, we sought and received orphan drug status for Pentamidine. A decision was then made to file a new drug application with the FDA. Within a remarkably short time of 6 months, the drug was ap- proved. Along with that approval, I am very proud to say, the first 7-year manufacturing and marketing exclusivity for an orphan drug was granted to our product, Pentam 300. Presently we are the sole supplier of this critical drug to virtual- ly every major medical institution in the country. A 24-hour hot- line has been instituted to ensure product distribution within a matter of hours. The hotline is also an effective channel of commu- PAGENO="0754" 748 nication for disseminating clinical and technical information to the health care professional. Pentam 300 can, no doubt, be called an orphan drug success story. Through the combined efforts of the CDC, various divisions of the FDA, and especially the Orphan Drug Division of Dr. Finkel, and LyphoMed, the ultimate goal of providing a life-saving drug to AIDS victims was accomplished. From our vantage point, both agencies offered invaluable support and guidance throughout this project, and for that, we at Ly- phoMed are most grateful. Our positive experience with Pentam 300 has served to reinforce the company's commitment to the Orphan Drug Program. Within the last 5 months, LyphoMed has filed and received orphan drug designations for two more drugs, and several others are now being considered as possible candidates. As LyphoMed becomes more involved with the activities of the program, we have perceived that certain improvements can be made in order to assist those already involved in the program and, at the same time, help in attracting additional participants. These suggestions are as follows: One, increase the amount of funding to support clinical trials regarding safety and efficacy of orphan products. To obtain a new drug approval for our orphan drug quinacrine hydrochloride, LyphoMed will need to finance clin- ical studies. Although expected sales of the drug over a 7-year period would total $350,000, the cost for the required studies alone would amount to well over half a million dollars. To a company of our size, the loss of revenue from such an undertaking is difficult to justify. Presently the maximum amount of funds through the grant pro- gram for the purpose of clinical investigation is $70,000 per year per grant. An increase in available moneys would serve a dual pur- pose. First, it would help offset the high cost of the required safety and efficacy studies, and second, help to encourage additional par- ticipation from small pharmaceutical companies like ours. Second, once orphan drug status is granted, certain funds could be earmarked for clinical studies for the specific drug. In this way, availability of funds to finance the study would be guaranteed. This would make disbanding of a study due to lack of funds less likely. Perhaps a matching fund program would be one means of provid- ing this type of specific funding. Third, the greatest obstacle we encountered recently with the Orphan Drug Program was finding researèhers who were interest- ed and qualified to undertake clinical studies. After numerous phone calls, false leads and negative responses, sponsorship was eventually acquired. We suggest that, along with publication of the list of orphan product designation in the Federal Register, an invitation for par- ticipation in specific clinical studies be extended. In this manner, interested parties would have the opportunity to contact the spon- sor directly, serving to expedite the entire process. LyphoMed has been given this opportunity to make a significant contribution to the area of critical care medicine. Without the vari- ous incentives offered through the program, a company of our size PAGENO="0755" 749 would not have been able to develop and make available a life-ex- tending drug such as Pentam 300. We are most eager to continue our involvement in the develop- ment of orphan products, and therefore, we wholeheartedly support reauthorization of the Orphan Drug Program. Thank you. Mr. WAXMAN. Thank you very much, Dr. Shah. Mr. Baird. STATEMENT OF WILLIAM BAIRD Mr. BAIRD. I would like to give you a demonstration of your suc- cess. There was a police officer, a motorcycle cop, going down the highway, and he spied a woman driving a station wagon. Believe me, this is relevant to why I am here. In the back of the station wagon were a bunch of penguins, so he pulled the station wagon over and he said to the lady, "What's with all the penguins?" She says, "Nothing, officer. I'm just out for a drive." He says, "This is not the thing you should be doing with pen- guins. Now, going down the highway here, there is a zoo. I want you to take the penguins to the zoo." So she went off and he went off, and the next day he is going down the highway and he spies the same station wagon, and in the back, a bunch of penguins, and they are all wearing sunglasses. So he pulls her over, and he said, "Lady, I thought I told you to take those penguins to the zoo." And she said, "I did, and they enjoyed it so much, today we are going to go to the beach." I have told that so many times that by now, I am feeling like everyone in the world must have heard that joke, but a year ago I couldn't have told it. Just thinking about telling it to someone would have triggered a cataplectic attack because I have narcolep- sy. That cataplectic attack would have caused my eyes to be a little difficult to focus. My muscles would have been hard to maintain. I would have sort of slumped down slowly until I actually slid off the chair onto the floor, and as long as I continued to think about trying to tell that joke, as long as I still had that emotional feeling, I would be awake but unable to move, unable to control my mus- cles. Now, as part of a drug being tested because of the orphan drug legislation, I can do that. I can have those emotions. I can experi- ence humor, laughter, joy, anger, elation, all the things that we value most highly because they make life really why life is worth living because of its emotional content. At this point, we still need well-controlled clinical trials, I under- stand, to demonstrate the effectiveness of this particular medica- tion, and I understand that. For me, I don't need any proof. I just don't fall down. I tell jokes and I am still standing. I know that it works for me. But I recognize that you can't do things that way. The áontinu- ation of the orphan drug legislation and the continuation of fund- ing, though, becomes ever more vital and important to me and to the hundreds of people that I know. PAGENO="0756" 750 I am president of the American Narcolepsy Association, I get to write in our newsletter, and I get to do newspaper interviews. I got to be on 60 Minutes. For 60 Minutes, I just fell down to show them what happens, and they thought I did well enough so they let me talk on Nightline. But I am afraid to mention that I've got a medication that's doing well because of what it would do to the expectations of all those people who have narcolepsy and have suffered the symptom of cataplexy. Just to tell them that there's something that's work- ing for me and that it might not be made available to them would be a very cruel thing to do. I have talked to people in Canada who have used it. They have said great things about it. I have talked to other people in the United States. I mean, this really looks like it's going to be some- thing special. But then, of course, not all jokes are equally funny. And the setting here today might have been such that I would have been too tense to really enjoy telling the joke. So maybe it's a bit misleading to say that I couldn't have told it. It might have gotten me by here, but I couldn't have told it with the confidence that I can get through the entire joke, and hit the punch line and not hit the floor. So from a very personal standpoint, and for the thousands of people who suffer from this, the continuation of the program and continuation of the funding is absolutely vital. And I think it would be tragic if we didn't look at the success that we have al- ready had and attempt to build upon that, and the potential for the future. Mr. WAXMAN. Thank you very much, Mr. Baird. Your testimony and your story is very heartening, and I want to thank you very much for it. I think also, Dr. Thoene and Dr. Shah, let me ask the four of you this question. Do we have sufficient funds for grants? If not, do you know what types of applications are not being funded? Ms. MEYERS. Yes; the $4 million appropriation was never fully appropriated. In the first year or two, we had less than $1 million, and this year there will be more money because of the National In- stitute of Child Health and Human Development which is transfer- ring $1 million to FDA. We know that every year Dr. Finkel gets a substantial number of research proposals and she can only fund a small amount. And in the 3 years since the Orphan Drug Act became law, I believe ac- cording to that chart, only 19 grants have been funded so far. Dr. Finkel told me that she felt that 18 of those grants would lead to the approval of new drugs, and that's really quite a mark. But of course, more money is needed, and some of these studies like the narcolepsy drug, if there was more money the two con- trolled studies could have been funded this year, and maybe 2 or 3 years from now the drug would be approved. But with only one study funded, we have to wait another few years to start the second controlled study. Mr. WAXMAN. Should FDA have the discretion to award funds for animal studies in addition to its current authority to fund human testing? PAGENO="0757" 751 Ms. MEYERS. I think the basic need right now has been in the clinical studies because so many orphan drugs are out there and we had substantial evidence that they would be safe and effective. But in future years, the toxicology and the animal studies will be absolutely essential for the drugs which are not yet fully developed. So we have really been touching the top of the iceberg, and in order to get further down on the iceberg we need money for pre- clinical testing. Mr. WAXMAN. Should the act be expanded to cover medical de- vices? Members of the panel, anybody who wants to respond. Ms. MEYERS. Yes; I would like to respond. FDA has done some- thing with two or three devices without statutory authority to do so, and we are absolutely delighted that they have. But I think to clarify, in the future, since the act is up for reauthorization, de- vices should definitely be added to the act so there is no question in the future. And of course, they should be eligible for the clinical research grants. Mr. WAXMAN. Mr. Whittaker, any questions? Mr. WHIrFAKER. No questions. Mr. WAXMAN. Mr. Leland. Mr. LELAND. Thank you, Mr. Chairman. Dr. Shah, are these incentives in the Orphan Drug Act sufficient to tempt companies to sponsor orphan drugs? Mr. SHAH. That definitely helps to make a decision to take the project. Mr. LELAND. Let me ask all of you, would you comment on the capabilities of the National Information Center on Orphan Drugs and Rare Diseases? Ms. MEYERS. Well, we are absolutely delighted that this clearing- house was funded by the Government because certainly, the worst problem with~ having a rare disease is that you can't get any infor- mation about it. And even your doctor tells you that he doesn't know much about it. So it's important to have some central area to do this. Of course, NORD is a voluntary agency and has been doing this, and we saw how it is agonizingly slow to get information. Some- times it takes 2 or 3 weeks to find information about a disease. We were hoping when the clearinghouse was funded that it would be computerized so that it could be speeded up, and we could not only find information on the disease but where the current re- search projects are being conducted. And we were quite disappoint- ed in the way the project was awarded. There was no competition for the contract. And we knew at least two universities and one corporation that would have applied for it. And I'm sure that if there was competition, probably a better clearinghouse would have been set up. But we have no complaints about the current clearinghouse right now. We just feel that it could have been computerized. Mr. LELAND. Anybody else? Mr. SHAH. As I mentioned in the testimony, we had a difficult time finding the clinical researchers for the quinacrine hydrochlo- ride. Some kind of funding should be available to centralize the data and really be available, which would help expedite the proc- ess. PAGENO="0758" 752 Mr. BAIRD. We have been receiving the transmittal of requests, and we answer as quickly as we can but it does take some time. But I had been surprised at the number that we have suddenly been getting on their forms. Mr. LELAND. Very good. Thank you. Thank you, Mr. Chairman. Mr. WAXMAN. Thank you, Mr. Leland. Mr. Nielson. Mr. NIELSON. No questions. Mr. WAXMAN. Well, let me thank the members of this panel very much for your testimony, and we look forward to working with you on the reauthorization of this legislation. I would like to now call forward Dr. John Simon representing the American Academy of Ophthalmology and assistant professor, ophthalmology and pediatrics, Albany Medical College of Union University, Albany, NY; and Larry Martin, president, Florida Med- ical Device Association, general counsel, Neuromed, Inc., Fort Lau- derdale, FL. STATEMENTS OF JOHN W. SIMON, M.D., ON BEHALF OF AMERI- CAN ACADEMY OF OPHTHALMOLOGY; AND LARRY H. MARTIN, PRESIDENT, FLORIDA MEDICAL DEVICE ASSOCIATION, AND GENERAL COUNSEL, NEUROMED, INC. Dr. SIMoN. Good morning, Chairman Waxman and members of the subcommittee. My name is John W. Simon, M.D. I am assistant professor of ophthalmology and pediatrics at the Albany Medical College in Albany, NY. I am pleased to present the views of the American Academy of Ophthalmology regarding the need to amend the Orphan Drug Act of 1983. Let me summarize a few key elements of my written testimony, which I believe you have. The American Academy of Ophthalmolo- gy is the largest national professional society of medical doctors specializing in medical and surgical care of the eyes. Our 13,500 members include not only the vast majority of all board-certified ophthalmologists in this country, but also a significant proportion of the leading researchers in virtually every subspecialty of eye re- search and eye care. The academy has worked closely with the Office of Orphan Prod- ucts in the Food and Drug Administration to designate and obtain sponsorship for a number of ophthalmic products which meet orphan product criteria under the act. Most of these ophthalmic products are classified as devices. Because of this classification, these products do not enjoy the ease of orphan product designation or the incentives for sponsor- ship accorded drugs under the act. These two factors have ham- pered the approval process and have evoked considerable frustra- tion, some examples of which I will describe. We hope that the Congress will be able to address this inequity. Cyanoacrylate is one such ophthalmic device. The academy has issued a policy on cyanoacrylate tissue adhesive which is attached to my statement. Briefly, cyanoacrylate tissue adhesives appear to be a useful, safe method of treatment of corneal perforations and impending perforations, common complications of injuries and in- fections. PAGENO="0759" 753 These require immediate treatment to preserve sight. The use of cyanoacrylate provides a safer alternative to standard surgical treatments. Application of the tissue adhesive results in closure of the perforation site and reformation of the anterior chamber. The Academy has recommended that this product be made available under the Orphan Drug Act because a true medical need exists for this product for a very limited number of patients. The develop- ment of this product will require considerable cost, and the antici- pated profit will be small. Under present provisions of the Orphan Drug Act, efforts to clas- sify this ophthalmic device as an orphan product have been bur- densome. Last year, Congress amended the Orphan Drug Act to es- tablish a presumption that drugs intended for diseases or condi- tions with a prevalence of less than 200,000 patients in the United States are orphans. Unfortunately, because devices were not in- cluded under this amendment, designation of orphan status re- mains cumbersome and time consuming. In addition, sponsorship for devices remains difficult to obtain. I would like now to relate my own personal and professional ex- perience with another ophthalmic orphan device: A specific kind of contact lens designed for children. I am a pediatric ophthalmol- ogist. That means that I care for the medical and surgical condi- tions affecting infants and children. As a pediatric ophthalmologist, I have a special interest in child- hood cataracts. Now, cataracts are a condition that most of us are attuned to thinking occur only in old people, but in fact, they rep- resent the most common treatable cause of childhood blindness. Fortunately, they remain uncommon with an incidence of approxi- mately 3 in 10,000 births, accounting for perhaps 1,200 new cases each year in the United States. We have made impressive surgical advances during the past 10 years, but it is important to realize that refractive correction is es- sential if these babies are going to be able to obtain and maintain clear vision. Unfortunately, there have been insurmountable prob- lems with most available types of optical correction, including glasses and conventional contact lenses. Especially in monocular cases, babies with only one eye involved, we have come to expect failure in the treatment of the refractive error that always happens after we remove a cataract in a baby. Until about 2 years ago, the situation was grim. About that time, we began in Albany and in other centers around the country to work with a silicone contact lens that was specifically made for babies. The long and short of it is that it works. Perhaps because of the specific material that's involved in the manufacture, with its en- hanced oxygen transmissability, we have been able, in my own per- sonal praétice, to fit successfully 59 of 60 children, that we have at- tempted. The superiority of this particular lens was recognized at a na- tional meeting of pediatric eye surgeons just last week in a unani- mous resolution, which I think you have a copy of. Again, let me emphasize the importance of refractive correction. If one of the members of the committee or anyone else in this room were to remove his glasses or his contact lenses for a day or a week PAGENO="0760" 754 or a year and then replace that optical correction, the vision would return immediately. Not so in babies. Because of the condition technically known as amblyopia and commonly referred to as "lazy eye," visual loss without correction occurs daily. And within a short time, it can become permanent. It had been common to see eyes which had excellent surgical re- sults which were nevertheless, unfortunately, legally blind because of amblyopia. We thought we had that problem solved because of the silicone contact lens. In December and January, however, the Dow Corning Corp. an- nounced that they had decided, because the lens was not profitable, that they were going to discontinue production of the silicone con- tact lens. That decision was a blow to me and, more important to the parents of the children I care for. With their help, we were able to mobilize a media and letterwrit- ing campaign announcing publicly that this decision would consign children to a lifetime of blindness. That campaign was finally suc- cessful, and Dow Corning, under pressure, agreed temporarily to continue production of the contact lens. The decision was limited, however, and the lenses that they agreed to continue making will not be applicable for children with high degrees of nearsightedness or with certain other parameters that used to be available. We are particularly concerned that Dow Corning, when they do finally get out of the contact lens business, which they certainly intend to do as soon as they can, will simply dump this technology onto the shoulders of a smaller or less image- conscious company who will not be amenable to this kind of public pressure. The Academy sees its role in this matter as an advocate for our patients. In our estimation, the need is clear. We must provide companies with sufficient economic incentives to maintain the supply of these sight-saving devices. I thank the subcommittee for your attention. Mr. WAXMAN. Thank you very much. [The prepared statement of Dr. Simon follows:] PAGENO="0761" 755 ® AMERICAN ACADEMY OF OPHTHALMOLOGY Testimony of The American Academy of Ophthalmology Before the Subcommittee on Health and the Environment of the U.S. House Committee on Energy and Commerce on The Orphan Drug Act March 20, 1985 Good Morning, Chairman Waxman and members of the Subcommittee. My name is John W. Simon, M.D. lam Assistant Professor of Ophthalmology at the Albany Medical College of Union University, Albany, New York. I am pleased to present the views of the American Academy of Ophthalmology regarding the need to amend the Orphan Drug Act of 1983. My Curriculum Vitae is attached to this statement. However, please allow me to summarize at the outset a few key elements of the Academy's collective experience, and my own experience, with this issue. The American Academy of Ophthalmology is the largest national professional society of medical doctors specializing in medical and surgical care of the eyes. Our 13,500 member physicians include not only the vast majority of all board certified ophthalmologists in the country, but also a significant proportion of the leading researchers and virtually every 1833 Fillmore / P.O. Box 7424 / San Francisco / California 94120-7424 / (415) 921-4700 52-266 0-85-25 PAGENO="0762" 756 subspecialty of eye researôh and eye care. As Director of the Pediatric Ophthalmology and Strabismus service of the Department of Ophthalmology at the Albany Medical College, I have been intimately involved with infants and children whose sight depends on an ophthalmic product - pediatric high-powered contact lenses following cataract removal - whose manufacture and production has been threatened with termination because the process has not been profitable. I will address this acute problem later in my testimony. The Academy has worked closely with the Office of Orphan Products in the Food and Drug Administration to designate and obtain sponsorship for a number of ophthalmic products which meet orphan product criteria under the Act. Most of these ophthalmic products are classified as devices. Because of this classification, these products do not enjoy the ease of orphan product designation nor the incentives for sponsorship accorded drugs under the Act. These two factors have hampered the approval process and have evoked a great deal of frustration, some examples of which I shall describe. We hope Congress will address this inequity. Cyanoacrylate is one such ophthalmic device. The Academy has issued a policy on cyanoacrylate tissue adhesive which is attached to this statement. Briefly, cyanoacrylate tissue adhesives appear to be a useful, safe method of treatment of PAGENO="0763" 757 corneal perforations and impending perforations. These perforations, which are common complications of infective processes, require immediate treatment. The use of cyanoacrylate provides a safer alternative to standard methods of treatment which include conjunctival flaps, patch grafts and penetrating keratoplasty. Application of the tissue adhesive results in closure of the perforation cite and reformation of the anterior chamber. The Academy has recommended that this product be made available under the Orphan Drug Act because a true medical need exists for this product for a limited number of patients. The development of this product will require considerable cost and the anticipated profit will be small. Under present provisions of the Orphan Drug Act, efforts to classify this ophthalmic device as an orphan product have been burdensome. Last year Congress amended the Orphan Drug Act to establish a presumption that drugs intended for diseases or conditions with a prevalence of less than 2ø~,SøG patients in the United States are orphans. Unfortunately, because devices were not included under this amendment, designation of orphan status remains cumbersome and time consuming. In addition, sponsorship for devices remains difficult to obtain. Present incentives under the Act to attract sponsors for orphan products include special tax credits for clinical trials, a seven year period of marketing exclusivity for a non patentable product and a grants program. Except for the grants program offered by PAGENO="0764" 758 the FDA these incentives are not now available for devices under the Act. I would like to relate my personal and professional experience with an ophthalmic product which would be a likely candidate for orphan status under the Act. Like cyanoacrylate, the high powered contact lens for pediatric aphakic patients is a medical device. These lenses may represent the only viable alternative to a lifetime of legal blindness for infants and children who have undergone cataract surgery. The corrective surgery and lenses provide immediate restoration of a clear, focused image and have given pediatric ophthalmologists hope that we may be able to improve our results in unilateral congenital cataracts where deprivation amblyopia has been such a problem. These lenses have been manufactured and distributed by one company which until recently held a patent on the silicone which comprises the lens material. The company notified the ophthalmic community in December, 1984 that it intended to discontinue the production and manufacture of the silicone contact lens. Although there are alternative corrections for adults on the market, infants and children with cataracts and high degrees of nearsightedness have come to rely on this product. The reaction from the ophthalmic community, particularly among pediatric ophthalmologists, was rapid and intense. (We would be pleased to furnish materials relevant to this situation to the Committee). As a result of intense lobbying on the part of the pediatric ophthalmology community, the company has temporarily rescinded PAGENO="0765" 759 its decision and instead is continuing the manufacture and production of these lenses on a limited basis. I again emphasize that this solution is temporary. The tenuous nature of the decision has resulted in a "run" on the lenses with the result that not all lens powers are now available. Interesting another company in assuming the manufacture of this lens may be difficult because the company announced that the lens is not a commercially profitable product. The lens would appear to be an appropriate product for orphan status under the Act. However, the present Act does not contain incentives to encourage this particular company to continue sponsoring this device. It is the hope of the Academy that Congress will address the issue of what incentives are appropriate in order to encourage sponsorship of these products and others, so necessary for a small portion of our population. The Academy sees its role in this issue as an advocate for the medical needs of our patients in order to encourage and stimulate the availability of these necessary medical products. Thank you for your time and attention. PAGENO="0766" 760 Attachment I ® AMERfCAN ACADEMY OF OPHTHALMOLOGY CYANOACRYLATE TISSUE ADHESIVE I. INTRODUCTION Perforations and impending perforations (desmetoceles), which are common complica- tions of infective processes and melting conditions, require immediate treatment. Standard methods of treatment include conjunctival flaps, patch grafts and penetrating keratoplasty. However, such surgery on these inflamed or infected eyes, has a poor prognosis because of the risk of infection, synechiae formation, and/or graft rejection. The use of adhesives with, or without, a bandage contact lens provides a safe alternative. The application of the tissue adhesive results in closure of the perforation site, and reformation of the anterior chamber. Sometimes this is all that is needed. However, if surgery (conjunctival flap or penetrating keratoplasty) is necessary, it can be done at a later time under more optimal conditions. Unfortunately, the investigational status of the material has prevented its widespread use so other methods of treatment of corneal perforations continue to be used. II. ETIOLOGY OF CORNEAL PERFORATIONS Over half of the cases of corneal perforations are due to herpes simplex ulcers, bacterial ulcers, and corneal melting syndromes associated with rheumatoid arthritis. These are common conditions, in which treatment is not always effective, so one can anticipate an increasing incidence of comical perforations. 111. TYPES OF TISSUE ADHESIVES The first tissue adhrive that was introduced in ophthalmology was Eastman 910 (methyl 2-cyanoacrylate). Initially there was much enthusiasm because of its rapid bonding action quickly sealed perforations; the liquid monomer polymerized within a few seconds ~fJer contact with the cornea. However, it was associated with mild ocular toxicity. ` Following topical application, hyperemia of the conjunctive, and a transient mild stromal haze, occurred. When injeete~I intralamellarly into rabbit corneas, after two weeks, corneal neovascularization occurred. New materials, which are less toxic have been introduced.5'6 These include isobutyl cyanoacrylate~ and n-butyl cyanoacrylate**. Isobutyl is distributed by Ethicon* as "Bucrylate", and n-butyl cyanoacrylate is distributed by Trikhawk as "Histacryl". Isobutyl 2-cyanoacrylate (IBC) is also referred to as "Bucrylate". It does not have a pharmacologic action; it does not react with tissues. Upon polymerization, it simply acts as a physical barrier. It c~oes not have a bacteriostatic or bactericidal action. When first introduced, one study demonstrated that cyanoaci~rlate, when added to blood agar plates, inhibited the growth of bacteria. A later study indicated that the cyanoacrylate monomers are neither bacteriostatic nor bacteriocidal regardless of the form of the bacteria, whether vegetative or spore. *Ethiocn Company, Somerville, New Jersey, USA **T1.ihawk, Montreal, Quebec, Canada 1833 Fillmore / P.O. Box 7424 / San Francisco / California 94120-7424 / (415) 921-4700 PAGENO="0767" 761 IV. METHOD OF ACTION Unlike most conventional adhesives that function by the application of heat and pressure, addition of a polymerization initiator ("catalyst"), or evaporation of a solvent, the cyanoacrylate tissue adhesives are converted from a liquid to a solid ~tate by polymerization when simply pressed into a thin film between moist tissue. When Bucrylate is spread on corneal tissue, at room temperature, the monomer very quickly (15-30 seconds) polymerizes to a water proof film. This results in a reasonably strong bond between the tissues that. maintain wound apposition while stromal healing occurs. Often a free tissue patch is placed over the perforations, and then the adhesive is applied. The use of a soft b~nfl~ge lens over the adhesive protects the patch from lid trauma and holds it in place. V. RESULTS Recent studies have conclusively dem1~strated the efficacy of this mode of treatment. In a study by Hirst LW, et al, the authors contrasted the experience at their institution prior to 1974, and after 1974 (when tissue adhesives were introduced). Prior to 1974, the enucleation rate for perforations was 19%. After 1974, when corneal perforations were treated by tissue e~hesives, the enucleation rate had decreased to 6%. In another study by Weiss JL, et al, the use of tissue adhesives lowered the enucleation/evisceration rate to 7%. VI. COMPLICATIONS It is difficult to determine if complications ~e due to the adhesive or to the disease process. In the study by Weiss JL, et al, complications occurred in nine of eighty (11%) of patients. The complications included a significant increase in intraocular pressure (2 patients) and corneal infiltrates (7 patients). The cases of elevated intraocular pressure were easily controlled by antiglaucoma medication. Of the cases of corneal infiltrates, 5 were proven by culture to the bacterial infections. These infections could have been a complication of the tissue adhesive, the extended wear bandage lens, or the disease process itself. As mentioned previously, the tissue adhesive is neither bacteriostatic or bacteriocidal, but it appears unlikely to be a source of infection. These complications did not affect the eventual outcome. All nine eyes eventually had a satisfactory result. VII. SAFETY Ocular toxicity has not proven to be a significant problem with the newer tissue adhesives. Conjunctival hyperemia has not been a significant problem. Anterior chamber reaction has been minimal. (Due to the very rapid polymerization, in all likelihood very little, or no, monomer enters the anterior chamber.) The tissj~e 1~dhesives have been used for sealing corneo-s~eral wounds,15 chloriodal holes, scleral ` buckling procedures, eye muscle operations, etc. There have been no instances of ocular toxicity when cyanoacrylate comes into contact with choroidal, scleral, or muscle tissue. VIII. SUMMARY Cyanoacrylate tissue adhesives, as presently available, appear to be a useful, safe method of treatment of corneal perforations and impending perforations. The small complication rate is of little importance as contrasted to the lower enucleation/evisceration rate. It behooves the FDA to make this material available for general use. Furthermore, since the development of this product has considerable cost, and the anticipated profit will be small (because only a small number of patients will require this treatment), companies that distribute such tissue adhesives should be permitted to participate in the available tax incentives for "orphan drugs" Developed by: Research and Regulatory Agencies Committee Reviewed by: Committee on Ophthalmic Procedures Assessment Approved by: Board of Directors, June 1, 1984 PAGENO="0768" 762 REFERENCES 1. Bloomfield S, Barnett A, Kanter PD: The use of Eastman 910 monomer as an adhesive in ocular surgery. Biological effects on ocular tissue. American Journal of Ophth. 55:742, 1963. 2. Straatsma BR, Allen RA, et al: Experimental studies employing adhesive compounds in ophthalmic surgery. Trans. Am. Acad. Ophth. Otolarng. 67:320, 1963. 3. Refojo Miguel, MS.: Surgical adhesives in ophthalmology. Journal Macro- molecular Science and Chemistry 3:667, 1970. 4. Hanna C, Shibley S: Tissue reaction to intracorneal silicone rubber (sliastic ARTV 382) and methyl 2-cyanoacrylate (Eastman 910 adhesive). American Journal of Ophth. 6:323, 1965. 5. Gasset AR, Hood CI, Ellson ED, Kaufman HE: Ocular tolerance to cyanoacrylate monomer tissue adhesive analogs. Investigative Ophth. 9:3, 1970. 6. Refojo MF, Dohlman DH, Koliopoulus J: Adhesives in ophthalmology: A review. Surgery of Ophthalmology 15:217, 1971. 7. Lehman RAW, West RL, Leonard F: Toxicity of alkyl 2-cyanoacrylate U Bacterial growth. Archives of Surgery 93:447, 1966. 8. Matsumoto T, Dobek AS, Paul KC, Kovaric JJ, Hamit HF: Bacteriological study of cyanoacrylate tissue adhesives. Archives of Surgery 97:527, 1968. 9. Ginsberg SP, Polack FM: Cyanoacrylate tissue adhesive in ocular disease. Ophthalmic Surgery 3:126, 1972. 10. Hyndiuk RA, Hal DS, Kinyoun JL: Free tissue patch and cyanoacrylate in corneal perforations, Ophthalmic Surgery 5:2, 1974. 11. Boruchoff SA, Refojo MF, Slansky HH, et al: Clinical application of adhesives in corneal surgery. Trans of American Acad. of Ophth. & Otolaryn. 73:449, 1969. 12. Fogle JA, Kenyon KR, Foster CS: Tissue adhesive arrests stromal melting in the human cornea. American Journ. of Ophth. 89:795-802, 1980. 13. Hirst LS, Stark WJ, Jensen AD: Tissue adhesive: New prospects in corneal perforations. Ophthalmic Surgery 10:58, 1979. 14. Hirst LW, Sinitty WE, Stark WJ: Corneal perforations. Changing methods of treatment 1960-1980. Ophthalmology 89:630, 1982. 15. Weiss JL, Williams P, Lindstrom RL, Doughman DJ: The use of tissue adhesives in corneal perforations. Ophthalmology May 610, 1983. 16. Price JA, Wadsworth JAC: The evaluation of adhesive in cataract wound closure. American Journal of Ophth. 68:663, 1969. 17. Calabria GA, Pruett RC, Refojo MF: Further experience with sutureless scleral buckling materials 11. Cyanoacrylate tissue adhesive. Arch. Ophth. 86:82, 1971. 18. Vygantas CM, Kanter PJ: Experimental buckling with homologous sclera and cyanoacrylate. Arch. Ophth. 91:126-129, 1974. 19. Dunlap EA, Dunn M, Rossomondo R: New uses of ocular adhesives. Archives of Ophthalmology 82:756, 1969. PAGENO="0769" Board of Directors Forrest D. Ellis, M.D. Eugene R.. Folk. M.D. Thomas D. France, M.D. Hiram H. Hardesy. M.D. John Prsts'Johnson. MB. Arthur L. Rosenbaum. M.D. Wjlljasn E. Scott. M.D. President Eugene R. Folk. M.D. President.EIecz Thomas D. France. M.D. Secietary.Treasarer Arthur L. Rosenbaum. M.D. Jules Stein Eye Institute UCLA School of Medicine Los Angeles, CA 90024 Telephone (213) 823-2572 At the annual business meeting of the American Association of Pediatric Ophthalmology and Strabismus held in Dorado, Puerto Rico on March 4, 1985, the complex problem of production of soft lenses for aphakic children was discussed by Dr. John Simon. Dr. John Baker mode the following motion: Moved. Whereas there remain substantial difficulties and concerns with the availability of pediatric silicon contact lenses, the American Association of Pediatric Ophthalmology and Strabismus resolve the following: 1. That extended wear silicon contact lenses of both high plus and high minus powers must be available to infants and children with special problems to allow normal visual development. 2. That there must be an adequate supply of necessary powers while other manufacturing arrangements are mode. 3. That a dependable long-term supplier must be developed or found. Lure! .4#onerenrrnz Chatnegn. 1905 Secrrrgeyfar P96gtoth. 190546 Roe Vauqude. M.D. WOtison B. Sooct. M.D. Thou Sto'ons.Posrat. Coordinator Doparonsoc of chulmolouy P.O. Son 13132 Uojenuiy tdosp6als Rhihenood, VA 23225 teen Oct. *52242 416)997.6225 Tdopboom (319) 336.2215 763 THE AMERICAN ASSOCIATION FOR PEDIATRIC OPHTHALMOLOGY AND STRABISMUS Resolution f Lure! .4erontome,uo Chormen,r. 1906 Malcolm B. log. M.D. Kapiolnol Children, Med. Co. 1319 Puoahou In.. 11110 Honolulu, HI 96026 (000) 955.5951 PAGENO="0770" 764 4. That an Ad Hoc committee of the American Association of Pediatric Ophthalmology and Scrabismus be appointed to interact with appropriate representatives of the American Academy of Ophthalmology and can jointly meet with Dow Corning officials to resolve this crisis. 5. That the president of the American Association of Pediatric Ophthalmology and Strabismus be kept informed by the membership of other potential orphan products affecting pediatric and stràbismic eye care. A general discussion was held. The motion was passed unanimously. STATEMENT OF LARRY H. MARTIN Mr. MARTIN. Thank you, Mr. Chairman and members of the com- mittee. I would like to take this opportunity today to comment on the current status of the Orphan Drug Act with respect to the medical device industry and recommend amendments to the act that would provide the same incentives that are accorded the drug industry today. - It would appear that although the act was intended medical as- sistance for orphan diseases, using whatever medical modalities were available, drug or device, in implementation, only drug devel- opment has prospered. Sponsors of medical devices for the same diseases, at present, cannot enjoy the benefits which have been ac- corded sponsors of orphan drugs. I am confident that the intent of the legislation was to make new treatments available to the public, whether it be drug or device. There is strong evidence to support the belief that promising orphan devices will not be developed unless changes are made in the current laws to help defray costs and provide commercial in- centives for developing such devices. It is in the public interest to provide these incentives, so that the patient population can receive the same benefit of available ad- vanced technologies which could be developed and applied to medi- cal devices. The act does provide that the Orphan Product Board shall func- tion to promote the development of drugs and devices, so that it will appear that the original drafters of the act intended the de- vices to have some, if not all, the benefits. However, it is clear that the guidelines issued by the Orphan Products Board and the imple- mentation of the act, that they have overlooked the device indus- try. Medical devices were not officially designated as orphan prod- ucts under the act. Nevertheless, the orphan products may be es- sential and vital to the afflicted patient group which could benefit from their development. From my experience, both with Neuromed and as president of the Florida Medical Device Association, it is apparent that unless the same treatment is accorded the device industry, that the pre- PAGENO="0771" 765 1980 pace and experience in the drug industry with orphan product development will be fostered. Furthermore, medical device companies, different from drug companies, do not generally possess the same resources that the drug companies have established over the past decades. Very few medical device companies have other products that are, so to speak, the bread and butter of such companies to support orphan product development. In my experience, it is the smaller entrepre- neurial company, with a particular motivation, be that of a family member or friend, that is a developer of new medical technology. It is clear that high technology products will be developed by the medical industry on a fast track, as has occurred in all other forms of society today. For example, I am associated with Neuromed, whose primary focuS, is on the development of electrical neurosti- mulator devices for the treatment of some very rare diseases- namely, dystonia, tortiocollis, Friedreich's ataxia, and other motor dysfunctions. The company presently manufactures an implantable spinal cord stimulator that is being investigated for the beneficial treatment of some neurological motor dysfunctions. The broad range of stimulat- ing parameters, multichannel capability, percutaneous implanta- tion techniques are a direct result of new technologies which did not exist when the medical device amendments were enacted in 1976. How will the act spur development for the medical device indus- try? Being imminently involved in such a company and associated with many other companies in the trade association, I can speak from experience that these incentives would increase research and development substantially. For example, in a small company, you cannot afford the clinical research staff necessary to prepare and carry out more than one study at a time. Quite often, companies rely on consultants and do not have an in-house regulatory affairs person at all. The cost of device clinicals are not the same as drug trials, but in most cases, the device clinical costs far exceed the associated drug costs when taking a product to market. Many medical device clini- cals require extensive hospitalization to use and test the device. Not only is there a high cost in developing the product, but the high cost of hospital care necessary to prove the safety and efficacy of the device is an added burden as well. A comparative overview of the medical industry today will un- equivocally demonstrate that it is the device area where the great medical strides are being made today. Moreover, it's obvious from the media covering the well-publicized Jarvik-7 Heart, as compared to the Phoenix Heart, that a problem exists in funding medical device technology. There are many other devices of equal promise, including those for rare diseases, such as Neuromed's, whose growth will not be as fast as could be. When Lee Majors and Lindsey Wagner played the "Bionic Man" and "Bionic Woman" in the TV series, many people thought that to be of a futuristic world, but today the bionic persons is a reality. From artificial ears, eyes, and limbs to electrical stimulation, de- vices will be able to correct, replace, and regulate the diseased and injured. PAGENO="0772" 766 These important and relevant technologies to treat those in need cannot be ignored in today's world, especially that in the orphan product field. The chemist pioneer of yesterday has been replaced by the mechanical and electrical engineers of today. I strongly recommend that the act be amended to treat medical device companies no differently than the pharmaceutical industry. Thank you for your time. [The prepared statement of Mr. Martin follows:] PAGENO="0773" 767 TESTIMONY OF LARRY H. MARTIN I'd like to take this opportunity today to comment upon the current status of the Orphan Drug Act with respect to the medical device industry and to recommend amendments to the Act that would provide the same incentives that are accorded the drug industry. The Orphan Drug Act, Public Law 97-414, was passed by Congress over two years ago to facilitate the development of products for the treatment of rare diseases or conditions. The Act established financial and other incentives to encourage sponsors of drugs to conduct research and to pursue marketing of these drugs while failing to provide the same incentives to the medical device industry. One of the most important incentives of the Act provides that drugs designated as Orphan Drugs under Section 525. of the Act and for which a U.S. Patent may not be issued are entitled to an exclusive marketing status, 21 U.S.C. 527. Other incentives include research and development tax credits, research grants, relaxation of the Food And Drug Administration's extensive testing requirements and a procedure to determine requirements for Orphan Drug status under the Act. The Act also established a process whereby sponsors of orphan drugs may seek recommendations for the clinical and nonclinical investigations of drugs for rare diseases or conditions. Additionally, the Orphan Product Board was established under this Act to promote the development of drugs and devices for rare diseases and to coordinate the various agencies PAGENO="0774" 768 in carrying out their respective functions related to the development of such products. Unfortunately, the Act has had negligible effect on device development over the past two years. In fact, no medical device has gained recognition or assistance under the Act. It would appear that although the Act was dntended to provide medical assistance for orphan diseases using whatever medical modalities were available--drug or device--in implementation only drug development has prospered. Sponsors of medical devices for the same diseases, at present, cannot enjoy the benefits which are accorded sponsors of orphan drugs. I am confident that the intent of the legislation was to make new treatments available to the public whether it be via drug or device. There is strong evidence to support the belief that promising orphan devices will not be developed unless changes are made in the current laws to help defray costs and provide commercial incentives for developing such devices. It is in the public interest to provide these incentives so that the patient population can receive the benefit of available advanced technologies which could be developed and applied to medical devices. As referred to previously, the Act does provide that the Orphan Product Board shall function to promote the development of drugs and devices so it would appear that the original drafters of the legislation intended devices to have some, if not all, of the benefits. However, it is clear that in the guidelines issued by PAGENO="0775" 769 the Orphan Product Board and the implementation of the Act they have ignored the device industry. Medical devices, while not officially designated as orphan products under the Act, nevertheless, may be orphan products essential and vital to an afflicted patient group which could benefit from their development. The medical device industry is dramatically different in size and capability from that of the drug industry as a whole. The majority of medical device companies are small entrepreneurial businesses engaged in the development of technologies for personal medical necessities resulting from their own experiences. These companies are part of a relatively young industry and lack the capability to develop new products in the same manner required for new drugs. The Food and Drug Administration's Medical Device Act fully recognized the differing capabilities and requirements of these industries. However, it did not address the use of medical devices for orphan diseases. From my experience, both with Neuromed, Inc. and as President of the Florida Medical Device Association, it is apparent that unless the same treatment is accorded the device industry, that the same lackadaisical attitude impugned in the drug companies for orphan product development will be fostered. Furthermore, medical device companies, different from drug companies, do not generally possess the resources that the drug companies have established over the past decades. Very few medical device companies have other products that are, so-to--speak, the bread and butter of such PAGENO="0776" 770 companies to support orphan product development. In my experience, it is the smaller entrepreneurial company with a particular motivation, be that of a family member or friend, that isa developer of new medical technology. It is clear that high technology products will be developed by the medical industry on a fast track as has occurred in all other areas of society. It does not seem logical that the drafters of the Orphan Product Act would have recommended arbitrary and capricious legislation if they had been aware of the improved medical technologies that exist today. For example, I am associated with NEUROMED, INC., whose primary focus is on the development of neurostimulator devices for the treatment of some very rare diseases; namely, dystonia, torticollis, cerebral palsy, Friedreich's ataxia and other motor disorders. The company presently manufactures an implantable spinal cord stimulator system, MULTISTIM,tm that is being investigated for the beneficial treatment of such neurological motor dysfunctions. The system consists of an electrode connected to a programmable neurostimulator receiver implanted in the patient. By the use of a R.F linked transmitter, various electrical signals can be transmitted to the spinal cord. The broad range of stimulating parameters, multichannel capability, and percutaneous implantation technique are a direct result of new technologies which did not exist when the Medical Device Amendments were enacted in 1976. Implants for motor dysfunctions are presently conducted under an FDA approved investi9ational device exemption; PAGENO="0777" 771 however, due to the cost of the Medical Device Act and the requirements promulgated/thereunder, the road to developing the product and obtaining approval from the FDA continues to be a long, arduous, and expensive one. How will the Act spur development for the medical device industry? Being imminently involved in such a company and associated with other companies in the trade association, I can speak from experience that these incentives would increase research and development substantially. For example, in a small company, you cannot afford the Clinical Research staff necessary to prepare and carry out more than one study at a time. Quite often,companies rely on consultants and do not have an in-house Regulatory Affairs person at all. The cost of device clinicals are not the sane as drug trials, but in most cases, the device clinical costs far exceed the associated drug costs when taking *a product to market. Many medical device clinicals require extensive hospitalization to use and test the device; not only is there a high *cost in developing the product, but the high cost of hospital care necessary to prove the safety and efficacy of the device is an added burden as well. A comparative overview of the medical industry will unequivocally demonstrate that it is the device area where the great medical strides are being made today. Moreover, it is obvious from the media covering the well-publicized Jarvik-7 Heart, compared to the Phoenix Heart, that a problem exists in funding medical device technology . There are many other d~vices PAGENO="0778" 772 of equal promise including those for rare diseases such as Neuromed's, whose growth will be hampered due to extensive legal, financial, and regulatory requirements. These companies do not have the publicity or support that the large institutions possess. One could argue that it is not the governmental incentives that the Act provides which are necessary, but independent motivations or desires that may be even more compelling. However, if that were solely the case, it would be hard to justify the Orphan Drug Act as it relates to the drug industry. For there, it was the multimillion dollar conglomerates that were unable to justify the cost of developing such products without governmental incentives. Obviously, the medical device industry, a fledgling in comparison, has the same problems as the drug companies magnified many times over. I would venture to say that if the same incentives were available to the device industry, that the advances in technology would be faster paced than that achieved by the drug industry. When Lee Majors and Lindsey Wagner played the Bionic Man and Woman in the T.V. series, many people thought that to be of a futuristic world, but today the bionic person is a reality. From artificial ears, eyes and limbs to electrical stimulation; devices will be able to correct, replace and regulate the diseased and injured. These important and relevant technologies to treat those in need cannot be ignored in today's world. The chemist pioneer of yesterday has been replaced by the mechanical and electrical engineers of today. I strongly recommend that the Act be amended to treat medical device companies no differently than the pharmaceutical industry. PAGENO="0779" 773 Mr. WAxN. Thank you both very much. What are the most important actions that Government can take to encourage the availability of orphan medical devices? Mr. MARTIN. I think one of the biggest spurs currently could be basically in amending the act to initiate and spur the same type of incentives that the drug companies have today. I think in the medi- cal device industry, you are dealing, from my experience, with a lot smaller companies. That is not to say that there are not large med- ical device companies around, but from my experience, they are not presently interested in the smaller product for the afflicted groups. Mr. WAXMAN. Dr. Simon, have you worked with FDA on the pe- diatric contact lens that you need from Dow Corning, and if so, what has FDA done? Dr. SIMON. I have had no experience with FDA at all. Mr. WAXMAN. Why is that? Dr. SIMON. I kind of stumbled into this, Mr. Chairman. I found out about the decision that Dow Corning had made, and I, under a time pressure, acted outside of Government agencies as quickly as I could to try to reverse that decision. I did write my Congressman who did forward a copy of my. letter to the FDA, and I got a reply that said that under the current act, there was nothing they could do. Mr. WAXMAN. Well, we want to work with you on that issue. Mr. Whittaker. Mr. WHITTAKER. Thank you, Mr. Chairman. Dr. Simon, do you believe the reason the company proposed dis- continuance of the manufacturing of the silicone lens is because of the limited market that existed, as it presently stood, and if so, was that related to gaining approval for use on a wider market than just in the pediatric field? Dr. SIMON. I don't think that a major part of the problem had to do with FDA. I think that they had a great deal of difficulty mar- keting the silicone contact lens for adults. It was a big money loser for a variety of reasons. It just so happened that the part of the market which could not be supplanted by another contact lens; that is, the pediatric contact lens, was a very, very small part of the total business, and that's what allowed me to put pressure on them to continue production at all. They have made a firm decision to get out of the contact lens business in general, because it has lost money for them. They have decided to continue making a very limited number of parameters of contact lenses for babies only. What I would like to see is for Dow Corning or probably some- body else on a smaller scale to make the kinds of contact lenses that these children need. Mr. WHITTAKER. In your testimony, Dr. Simon, you indicated that until recently, they had held what would appear to be an ex- clusive patent, but now recently it is not held totally by them. Do you think that will open other markets for the silicone lenses? Dr. SIMoN. There is more than one patent involved, and I think that Dr. Finkel alluded to this kind of problem. There is a patent on the silicone material itself, which I understand has expired, and PAGENO="0780" 774 that has opened up. It's my understanding that the surface treat- ment of the lens is every bit as important in order to make the con- tact lens usable, and that there are still patent concerns in that area. Mr. WHITTAKER. Well, I would echo the chairman's sentiment. We would be most anxious to work with you. Dr. SIMoN. Thank you. Mr. WAXMAN. Mr. Leland. Mr. LELAND. I have no questions, Mr. Chairman, but I am, too, very happy that you have brought this matter before us, and I am very supportive of the chairman's leadership in this whole thing. Mr. WAXMAN. Mr. Nielson. Mr. NIELSON. I'd like to ask Mr. Martin, I guess I missed the point on the comparison between the Jarvik Heart and the Phoe- nix Heart. What point were you trying to make there? Mr. MARTIN. The point I was trying to make there is, in products that may not be considered even orphan products, you have the Jarvik Heart, which was sponsored by a substantial medical device company and outside funds, and then you have the Phoenix Heart, which is an individual who was self-motivated to develop a heart, and as was recently played in the newspaper, he was unable to carry forth his research, and the FDA requirements because of a lack of funds. It had no relevancy as to which may have been the better prod- uct, but only dealt with who had the funds to push it through, pointing out that in the medical device industry, most of the com- panies involved in it are individual entrepreneurial-type people. Mr. NIELSON. Was that because the Phoenix people did not seek FDA approval, whereas the University of Utah did? Is that the reason? Mr. MARTIN. The people that had the Phoenix heart was an indi- vidual who lacked the funds to progress down the road of FDA ap- proval. Mr. NIELSON. The University of Utah also lacked the funds, but they went through FDA approval, which took them a number of years. Mr. MARTIN. They raised a substantial amount of money through companies, I think several million dollars, to accomplish that. That's a private foundation. Mr. NIELSON. But we are talking here about which one had the approval that it be used and so on. I think one went the route, and one did not; isn't that true? Mr. MARTIN. That's correct. But I was merely using that to dem- onstrate that in the device industry, many of the small companies that are involved in it do not have the funds, as compared to the larger companies. It was merely an analogy that I was making. Mr. NIELSON. Let me ask this question: Would the Phoenix Heart ever have been developed, had there not been the primary effort at the Jarvik level? Wasn't it the fact that Jarvik-7 was acted on for a number of years; they used the caps and so on long before they used the perfected one? Wasn't the Phoenix a result of the coopera- tion between FDA and the university? Mr. MARTIN. I'm not that familiar with the Phoenix Heart. I was merely reiterating what had been recently in the media and how PAGENO="0781" 775 they were describing it as an individual who lacked the funds and capability to progress. I believe the Phoenix Heart had been around since about-I don't know the timeframe on that. Mr. NIELSON. Thank you, Mr. Chairman. Mr. WAXMAN. Thank you, Mr. Nielson. Dr. Simon and Mr. Martin, thank you very much for being with us, and we are going to work with both of you on this bill and other things we can do to be of help. That concludes our business for today. Therefore, the subcommit- tee stands adjourned. [Whereupon, at 11:25 a.m., the subcommittee was adjourned.] [The following statement was submitted for the record:] PAGENO="0782" 776 STATEMENT OF THE AMERICAN PHARMACEUTICAL ASSOCIATION The American Pharmaceutical Association, the national professional society of pharmacists, is pleased to have this opportunity to present its views on the matter of the reauthorization of the Orphan Drug Act.. A number of years ago the problem of inadequate resources and insufficent economic interest in research, development, and distribution of certain needed drugs or potential drugs was the subject of increasing public, private and professional concern. As the cost of new drug development soared, this problem grew proportionally more acute. The continually increasing economic break-even point meant that drugs needed to achieve a higher volume of usage in the marketplace than in the past in order to justify the expenditures of resources in the development process. The free enterprise marketplace was failing to operate in the case of drugs for rare diseases precisely because they were intended to treat a relatively low incidence population. With the potential market for such drugs so small, strategic decisions were made not to enter into the research and development efforts necessary to produce those drugs. As early as 1979 an Interagency Task Force to the Secretary of Health, Education and Welfare released its report titled "Sufficient Drugs of Limited Consumer Value" and in September, 1979 the Drug Regulation Reform Act carried provisions to support drugs of limited commercial value. In mid-1980 representative Elizabeth Holtzman introduced a bill to establish an office at the National Institutes of Health to assist in the development of drugs and diseases of low incidence. However, it was not .0024A/1 PAGENO="0783" 777 until the 96th Congress that consensus was reached regarding the nature of the solution. The full spectrum of view points regarding the appropriate way to address the needs of those Americans with rare diseases finally achieved consensus with the passage of the Orphan Drug Act. Since the passage of that Act we have observed a number of activities whose thrust consistently points to making available products for those with rare diseases. The activities of those involved in orphan drug development since the passage of the Act just over two years ago have been numerous and the efforts of many should be noted here. First, the pharmaceutical industry, through ~he Pharmaceutical Manufacturers Association Commission on Rare Diseases and through the Generic Pharmaceutical Industry Association have consistently sought to promote an awareness of the need for research for orphan drugs, the adoption of those products once they were developed, and the rapid distribution of those products. Second, the activities of the Federal government through the programs of the Department of Health and Human Services and especially through the activities of the Orphan Products Board have consistently sought to maintain a high level of basic and clinical research in the most promising areas. They also have addressed other needs (such as the need for increase public information and patient information) in the Orphan Drug areas. Third, Universities and individual researchers have continued their efforts, not only in the development of new knowledge through basic and clinical studies, but also by conducting seminars and conferences which sought to built networks among re2earchers to promote PAGENO="0784" 778 their knowledge of developmental efforts. Finally, and certainly among the most important, are the efforts of those patients and their families that suffer from rare diseases. These individuals and groups have been. active in maintaining th~e visibility and awareness of the nature of their diseases. On more than one occasion, they have been significant contributers to the conferences held by universities and hearings held by the Department of Health and Human Services Orphan Products Board as~~ matters of importance related to rare diseases were discussed. Now, as the committee considers the reauthorization of this legislation the American Pharmaceutical Association would like to recommend a number of items relevant to your deliberations. First, APhA supports the reauthorization of the legislation. This support is in keeping with our earlier policy statements calling for legislation or regulation to provide incentives to manufacturers, private foundations, academic and public institutions and others for the development, manufacture and distribution of needed drugs of limited commercial value. Second, APhA supports the extension of current Orphan Drug Act incentives to other therapeutic technology including those relating to medical foods and devices. PAGENO="0785" 779 Third, APhA believes that funds authorized under the Orphan Drug Act should be available for animal pre-clinical studies. The current Orphan Drug Act precludes the use of its funds for pre-clinical animal studies. It is now clear that other disincentives for animal research exist as well and that resources are needed in this area. We believe the Secretary should have sufficient flexibility in the allocation of those resources to assure that no drug limited - commercial value will fail to be developed because of an inability to conduct early clinical phase testing. APhA appreciates this opportunity to present its views before this committee, and looks forward to future opportunities to be of assistance. The American Pharmaceutical Association was among the first organizations to study this topic of needed drugs for rare diseases and adopted a policy in this regard at its House of Delegates Meeting as early as 1981. The Association will continue to press its efforts on behalf of those with rare diseases and locks forward to the day when the needs of those individuals are so sufficiently met that no special programs will be needed. PAGENO="0786" 780 STATEMENT Submitted for the Record by Dr. Theodore Cooper Chairman, PMI\ Commission on Drugs for Rare Diseases Subcommittee on Health and Environment House Energy and Commerce Committee March 20, 1985 Mr. Chairman and Members of the Subcommittee, We are pleased to have the opportunity to participate in this oversight hearing on the implementation of the Orphan Drug Act and appreciate the invitation to do so. Due to prior and firm commitments which could not be changed, neither I as Chairman of the PMA Commission, nor Dr. John Adams, Executive Director of the Commission, were able to appear at the hearing to personally present this statement and to respond to any questions you or members of the Subcommittee may have directed to us. We, nevertheless, deem it of importance to submit this statement for inclusion in the record, and I shall be pleased to respond in writing to any questions you may have concerning its content or other aspects of the Commissions activities. It is my opinion that the dialogue generated between the Commission and the Subcommittee as the result of our earlier testimony was most constructive, and it is in this spirit that we shall be pleased to personally testify at any future hearings. Based on the invitation extended to me, it is my understanding that one of the principal reasons for this hearing is to consider the need for reauthorization of the pertinent section of the Orphan Drug Act which provides for an appropriation of $4,000,000 per year for a three-year period to fund clinical research. It is our opinion as evidenced by support for the passage of the Orphan Drug Act, that this provision offers important incentives for PAGENO="0787" 781 academic investigators engaged in rare disease research. Wore importantly, this provision provides a means to encourage additional investigators to enter the field and thus increase our knowledge of the causes and possible prevention or treatment of these diseases. It is for these reasons that the Commission endorses a reauthorization of the appropriations provisions of the Act. We believe that provisions for orphan drug designation and peer review of research proposals will assure the prudent and effective use of these funds. In our testimony last March, we commented on several other aspects in the implementation of the Orphan Drug Act, some of which are worthy of repetition and further comment. To the best of our knowledge, regulations or rules to implement the tax incentive provisions of the Act have never been published. Despite this hiatus, a number of firms have applied for orphan drug designation and have undertaken the research necessary for NDA approval without any clear assurance that they will be eligible for the tax credit. We have received numerous inquiries regarding these provisions from firms who have applied for orphan product designation or are considering doing so, but we obviously cannot provide definitive answers. Our only recourse is to suggest that these firms communicate directly with the Internal Revenue Service to obtain the detailed procedures required in applying for the tax credit. One of the most frequently asked questions is whether the statutory definition of a rare disease and orphan product designation are a sufficient basis for qualifying for the tax credit, or whether IRS rules will impose additional requirements as embodied in the definition in the Act as it was originally passed. We are not aware of any PAGENO="0788" 782 firms that have filed or received a tax credit under provisions of the Act. Such information may be considered ofa confidential nature with the IRS, but it may be of interest to the Subcommittee to seek the information as a means of measuring the impact of the Act on commercial research and development. The fact that a number of firms have applied for orphan product designation is encouraging, but the number might be increased if specific IRS rules were published. We also stated in last year's testimony that there was a need for expanded sources of information on rare diseases and orphan drugs and for a system to effectively communicate such information to patients, practicing physicians, and to the scientific community. Such efforts are underway as evidenced by the Compuserve system established by the National Organization for Rare Disorders and the more recently established National Information Center on Orphan Drugs and Rare Diseases announced by the HHS Orphan Products Board. Both of these initiatives will do much to increase awareness of the needs and opportunities in the field of rare diseases. It will take some time to develop a comprehensive data base on all aspects of the problem, but an important start has been made. One of the early problems in the field of rare diseases was to assess the magnitude of the problem. Little was known concerning research in progress or available therapies. Great progress has been achieved in the past few years due in large part to the efforts of this Subcommittee, the FDA, the HHS Orphan Products Board and the voluntary health agencies such as NORD, the GPIA Institute and the PMA Commission. Much remains to be done, however, in order to expand the data base through imputs from government and voluntary health agencies, the scientific community and industry. PAGENO="0789" 783 An important corollary of comprehensive information systems will be an educational program to encourage the necessary inputs. I am pleased to report that the PMA Commission is currently considering the ways in which it can assist in such efforts. While solicitation of proposals for commercial development of promising experimental compounds remains the principal mandate of the Commission's charter, we are not unmindful of the other needs in the field, particularly the needs for information and education. We are therefore prepared to suggest changes in the charter of the Commission to the PMA Board of Directors that would authorize the Commission to engage in studies and other educational programs. There is reason to believe that the decline in the submission of formal proposals to the Comission, which we reported at the March, 1984 hearing and which has continued during the balance of 1984, may be reversed in the near future. This prediction is based on the number of grants and contracts awarded by FDA, MCI and NINCDS during the past year for early clinical evaluation of drugs for rare diseases. It is assumed that investigators will be advised to submit proposals to the PMA Comission for purposes of commercial development if the outcome of these preliminary studies is favorable. It also should be noted that contributions by industry to the commercial research and development of orphan drugs, as evidenced by the FDA lists of orphan drug designation and commercial sponsor commitments from 1982 to the present, have been impressive. In our opinion, this record presents strong evidence that the industry has been responsive to the challenge largely set in motion by this Subcommittee and by dedicated members of voluntary health organizations PAGENO="0790" 784 and other interested persons. We are confident that industry will continue to sponsor commercial development of drugs for rare diseases on its own volition or as the result of favorable recommendations by the PMI\ Commission. In closing these brief coniiients, I wish to reemphasize that commercial drug development cannot proceed in a vacuum. It is completely dependent on an infrastructure of basic and clinical science that has traditionally been provided by academic, government and private research institutions. The degree to which these institutions are funded will largely determine the quality and quantity of research on rare diseases and the concomitant increase or decrease in orphan drug development. 0