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4 .0 / \ Legal Backgrounder SH TON LEGAL FOUNDATION 2009 MASSACHUSETTS AVENUE. NW • WASHINGTON, D.C. 20036 •(202) 588-0302 Vol. 9 No. 34 October 7, 1994 WHAT THE FDA DOESN' T WANT YOU TO KNOW COULD KILL YOU by Richard A. Samp Aspirin prevents heart attacks. That medical fact is widely acknowledged among medical experts. Emerging research shows that regular aspirin consumption could prevent about 20 % of all heart attacks among middle-age men. Yet, one government organization is fighting desperately to keep that life-saving information away from you: the U.S. Food and Drug Administration (FDA). But at least FDA does not discriminate on the basis of sex: it works just as assiduously to ~ prevent women from obtaining life-saving medical information. For example, authoritative medical research shows that estrogen helps to prevent ovarian cancer among post-menopausal women. FDA bureaucrats are working overtime to make sure that this research is hidden from the American people. Luckily, FDA has not yet found a way to punish doctors who discuss new, effective uses for drugs such as aspirin and estrogen, since FDA has no regulatory authority over the practice of medicine. But FDA can and has severely punished manufacturers who get involved in any way in disseminating information about new uses of their drugs. Doctors can write freely in authoritative medical textbooks on aspirin's effectiveness in preventing heart attacks, but an aspirin manufacturer cannot so much as reproduce a copy of such a textbook, or provide financial support for a medical symposium at which aspirin's benefits are discussed - even if the manufacturer had no advance warning that such discussions would occur. Similarly, although the Washington Legal Foundation is free to tout aspirin, no manufacturer of any of the drugs or medical devices mentioned in this LEGAL BACKGROUNDER would dare risk the wrath of FDA by having anything to do with the publication or distribution of the article. FDA claims to be protecting public health in its suppression of medically-accepted information about drugs and medical devices. FDA contends that until it has given its official approval to particular uses of therapeutic products, the public is best served by minimi~ing discussion of such uses. The fallacy of FDA's approach is that the medical community's knowledge o ~ Richard A. Samp is Chief Counsel of the Washington Legal Foundation. ~ W WLF publications are available on the Mead Data Central Lms/NMs* online information service. "~ ~ The Washington Legal Foundation ("WLF") is a 501(C)(3) tax exempt organization and is America's largest pro-free enterprise .., 41ir~ ..c.or. i- ., 9 rv+lfnr rantor Thic i Pr,ai Rarknrni mriar ic nna nf a ~PriPS of orioinal oacers written esoecially for and published

• regarding the safety and efficacy of FDA-approved drugs and devices inevitably outpaces FDA- approved labeling. Physicians who regularly work with such drugs and devices learn of safe and effective uses for the drugs/devices that are not included within the labeling (generally referred to as "off-label" uses). In some fields such as oncology, the great majority of treatments involve off-label uses of FDA-approved drugs and medical devices. Moreover, the medical community already has in place effective mechanisms for differentiating medically-accepted uses of therapeutic products from totally unproven uses. Three standard reference works are generally regarded as the medical bibles when it comes to off-label drug uses: (1) The American Hospital Formulary Service Drug Information; (2) The American Medical Association Drug Evaluations; and (3) the United States Pharmacopoeia Drug Information. These three works list acceptable usages for FDA-approved drugs without regard to whether FDA has approved those usages for labeling purposes.' No one disputes the propriety of FDA control of product labels or its prohibition against listing product indications on a label until FDA has approved that precise use for the product. But in its zeal to suppress the dissemination of information about off-label uses, FDA for the past several years, has wildly expanded its definition of what constitutes "labeling" by a manufacturer. A manufacturer is now said to be engaged in "labeling" if it gives a doctor an authoritative medical textbook or a reprint of an article from the New England Journal of Medicine in which an off-label use of the manufacturer's product is discussed. FDA also defines "labeling" to include a manufacturer's provision of financial support to a medical symposium at which doctors discuss off- label uses of any of the manufacturer's products -- even if the manufacturer had no indication in advance that its products were to be discussed. Unfortunately, FDA's censorship activity appears to be working. Thanks to FDA, drug companies have ended the practice (formerly quite common) of providing doctors with medical textbooks discussing the doctors' areas of specialization. Manufacturers' financial support of ~ continuing medical education (CME) activities and other medical symposia has plummeted due to FDA's crackdown; since manufacturers traditionally have been the primary source of funding for such activities, it is not surprising that the number of such activities has fallen off sharply. Medical device manufacturers are even afraid to provide CME organizers with samples of their devices; doctors attending CME activities are thus deprived of an opportunity to obtain hands-on experience in using medical devices for medically-accepted off-label uses. Incredibly, FDA has made no attempt to differentiate off-label uses which enjoy widespread support within the medical community from those whose safety and efficacy are completely untested; FDA rules against unauthorized "labeling" (as broadly defined by FDA) apply just as strongly to all off-label uses. FDA has even pursued criminal penalties against pharmaceutical company personnel (as well as private physicians thought to be acting as agents of those companies) in its effort to prevent the spread of information about off-label uses. • ' It bears repeating that no negative connotations should be attached to the phrase "off-label use. " After FDA has determined that a therapeutic product is safe, it reviews the manufacturer's proposed product labeling. The label should indicate those uses for which the product has been shown (through extensive clinical testing) to be effective. Once the product is on the market, doctors quickly discover other effective uses for the product (e.g., different dosage levels or use in combination with other drugs). Yet, due to the tremendous expense of conducting the clinical trials necessary to obtain FDA approval for those other uses (with a separate trial required for each new usage), manufacturers often determine that such expenditures are economically unjustified. Even when a manufacturer decides to make the effort to seek additional labeling authority, it takes years to conduct the requisite clinical studies and obtain FDA approval to change the product labeling. Thus, "off-label" use of a therapeutic product connotes nothing more than that FDA has not authorized the manufacturer to include that use on its product labeling. It does not necessarily mean that such usage is risky or experimental; indeed, in many situations, doctors would be guilty of medical malpractice if they failed to employ an off-label use. Copyright 0 1994 Washington Legal Foundation 2 ISSN 1056 3059

• • FDA's attempts to keep doctors and their patients ignorant about advances in medical technology might actually save a life on occasion -- as when a currently accepted off-label use is later found to be unsafe or less effective than other available treatments. But such potential advantages of censorship are far outweighed by the costs of ignorance. Medical authorities agree that countless lives would be lost if doctors stopped employing off-label uses to treat their patients; indeed, most cancer patients could not be treated at all without resort to off-label uses of FDA- approved drugs. To the extent that FDA succeeds in its effort to inhibit the flow of truthful information about off-label uses, it inevitably will sacrifice the lives of those patients whose doctors were deprived of that information. The Washington Legal Foundation would be pleased to confound the censors at FDA by doing its part to disseminate the truthful information about therapeutic products that FDA is attempting to suppress. Unfortunately, there are so many thousands of off-label uses that have become accepted by medical experts that the information cannot be conveyed in anything smaller than a full-length medical compendium. Indeed, it is the sheer volume of information on accepted off-label uses that renders so unreasonable and destructive FDA's efforts to anoint itself as the sole traffic cop for the flow of medical knowledge. What follows is a listing of some of the more widely accepted off-label uses of FDA-approved prescription drugs: Drug ame Accepted O-Labe Use ame Accep O-Labe Use Carbamazepine Restless leg syndrome Erythromycin Surgical prophylaxis colorectal Metronidazole Antibiotic assoc. pseudomembranous colitis Amphotericin B Bladder irrigations for candidal cystitis Lithium carbonate Improved neutrophil count in patients w/cancer chemo-induced neutropenia Sucralfate Prevention of stress ulcers; prevention of traveler's diarrhea Acyclovir Herpes zoster encephalitis Capesioin Phantom limb pain Reserpine Phantom limb pain Clonidine Alcohol withdrawal; pain of shingles lesions Captopril Hypertensive crises Benadryl/ Lidocaine Migraine headaches Lysine Treatment/prophylaxis; Herpes simplex infections Huozeune Obesity; Bulimia nervosa; Obsessive-compulsive disorders Trazadone Panic disorders; agoraphobia Sertraline Obsessive-compulsive disorders Cettriaxone Neurologic complications, arthritis; carditis assoc. w/Lyme disease Trimethoprim/ sulphamethoxa- zole Prophylaxis neutropenic patients w/pneumocystis carinii Chlorpromazine Migraine headaches Phenelzine Treat cocaine addiction Ketoconazole Cushing's syndrome Ovral Postcoital contraceptive Cinmonracin Pulmonary exacerbations in cystic fibrosis Allopurinol Ameliorates 5-Al granulocyte suppression Bethznachol Reflex esophagitis Clonazepane Adjunct in schizophrenia Pemoline Narcolepsy Tetracycline Nonspecific mouth ulcerations Copyright 0 1994 Washington Legal Foundation 3 ISSN 1056 3059 i14

a f There are nearly as many medically accepted off-label uses of FDA-approved medical devices. Some of the more common: (1) Bone screws are FDA-approved for several orthopedic surgical procedures, but not for a complicated surgical procedure on the spine known as pedicle fixation. Nonetheless, pedicle fixation is the state-of-the art therapy for many spinal conditions, and orthopedic surgeons use tens of thousands of bone screws for this purpose each year. (2) Fertility specialists routinely use catheters approved by FDA (but only for intrauterine insemination) when performing embryo transfer after in-vitro fertilization. (3) The medically accepted procedure for performing a hysterosalpingography (a radiological procedure for blockage of the fallopian tubes) involves use of pediatric Foley catheters --which have not been approved by FDA for that purpose. (4) Infant feeding tubes are routinely used by medical specialists to alleviate urological problems, although FDA has not approved labeling of these tubes for that purpose. (5) The New England Journal of Medicine recently reported that a combination of three assays used in laboratory testing could provide a reliable means of predicting whether a fetus has Down's Syndrome. This state-of-the-art "triple screen" technique has not been approved by FDA. • (6) Prostate specific antigen (PSA) tests have been shown to be useful in detecting prostate cancer -- one of the most common cancers in men. FDA has not approved use of PSA tests for prostate cancer screening, and thus manufacturers may not assist in publicizing the importance of such testing. Yet, state public health officials and the American Cancer Society strongly endorse screening for older men, public service announcements throughout the country urge men to get PSA tests, and even Ann Landers wrote a column this past year endorsing PSA tests. There is considerable legal authority suggesting that FDA's attempts to suppress truthful information about off-label use of FDA-approved drugs and medical devices violate the First Amendment rights both of those seeking to convey the information and those seeking to receive it. Indeed, the Washington Legal Foundation has pending a lawsuit against FDA, challenging FDA policy on First Amendment grounds. WLF v. Kessler, No. 94CV01306 (U.S. District Court for the District of Columbia). But leaving issues of constitutional law aside, one has to wonder what is going through the minds of FDA bureaucrats as they step up their efforts to suppress information about off-label use of therapeutic products. FDA readily acknowledges off-label uses as a necessary component of effective health care. Given the importance of off-label uses, it makes little sense to suppress all manufacturer-supported dissemination of information about off-label uses in the absence of some indication that the information is inaccurate. Manufacturers who peddle false or wholly unsubstan- tiated claims are appropriately subject to sanction; but truthful and potentially lifesaving information about off-label uses is far more likely to reach the doctors and patients who have need for it if manufacturers (the group with by far the strongest motivation to disseminate such information) are permitted to provide the funds necessary to ensure that independent medical specialists can spread the word. Copyright ° 1994 Washington Legal Foundation 4 ISSN 1056 3059 To receive information about previous Washington Legal Foundation publications contact Alan M. Slobodin, President, Legal -tn~tinn r1nniAI I Pnr1Pr1 ("hairm."in