[Federal Register Volume 59, Number 222 (Friday, November 18, 1994)] [Unknown Section] [Page 0] From the Federal Register Online via the Government Publishing Office [www.gpo.gov] [FR Doc No: 94-28506] [[Page Unknown]] [Federal Register: November 18, 1994] ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES [Docket No. 92N-0434] Citizen Petition Regarding the Food and Drug Administration's Policy on Promotion of Unapproved Uses of Approved Drugs and Devices; Request for Comments AGENCY: Food and Drug Administration, HHS. ACTION: Notice; request for comments. ----------------------------------------------------------------------- SUMMARY: The Food and Drug Administration (FDA) is requesting comment on a citizen petition from the Washington Legal Foundation (WLF). The petition requests that FDA withdraw the document entitled, ``Draft Policy Statement on Industry-Supported Scientific and Educational Activities,'' (hereinafter referred to as the draft policy statement) which was published in the Federal Register on November 27, 1992. The draft policy statement was intended to provide guidance concerning educational and scientific activities that may be supported by industry without causing them to be regulated as advertising or promotional labeling. The draft policy statement was intended to facilitate the flow of reliable information about FDA-regulated products. Nonetheless, the petition claims that the draft policy statement and FDA's regulation of the promotion of unapproved uses generally are contrary to the First Amendment's protection of speech and interfere with health care professionals' provision of effective medical care. The petition requests that FDA formally adopt a policy stating that, while drug and medical device manufacturers should not label their products for unapproved uses, they will not be subject to regulatory action for facilitating the dissemination of ``truthful'' information about such unapproved uses. This notice requests comments on the petition and certain questions regarding the draft policy statement and FDA regulation of promotion of unapproved uses. DATES: Submit written comments by February 16, 1995. ADDRESSES: Written comments to the Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857. FOR FURTHER INFORMATION CONTACT: Ilisa B. G. Bernstein or Philip L. Chao, Office of Policy (HF-23), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-2831. SUPPLEMENTARY INFORMATION: I. Background Traditionally, FDA has regarded industry-supported communication, including scientific and educational activities on human and animal drugs, biologic products, and medical devices for health care professionals, as activities subject to regulation. In general, under the Federal Food, Drug, and Cosmetic Act (the act) and the Public Health Service Act, any person who wishes to introduce or deliver for introduction into interstate commerce any new drug, biological product, or new animal drug must demonstrate that the product is safe and effective for its intended uses (see sections 505(a) and 512(a) of the act (21 U.S.C. 355(a) and 360b(a)) and section 351 of the Public Health Service Act (42 U.S.C. 262)). Any person who wishes to introduce or deliver for introduction into interstate commerce a new medical device must either demonstrate that the device is safe and effective for its intended uses or that it is substantially equivalent to another device for which such a showing is not required. (See sections 510(k), 513(f), and 515(a) of the act (21 U.S.C. 360(k), 360c(f), 360e(a)).) Such demonstrations of product safety and efficacy usually consist of data and information derived from clinical investigations and presented as part of a marketing application. The marketing application also contains information regarding the product's intended uses, the patient population (including any special conditions, restrictions, or limitations for segments of the population, such as children, pregnant women, or the elderly), potential adverse events associated with the product's use, and technical information about the product (see, e.g., 21 CFR 314.50, 514.1, 601.25, and 814.20). If FDA agrees that a product is safe and effective for its intended use, as reflected in the marketing application, it approves the application and the product's professional labeling.\1\ The uses that are approved by the agency are sometimes referred to as ``labeled'' uses because they appear in the product's approved labeling. Uses that do not appear in the labeling and are not approved by the agency are referred to as ``unapproved,'' ``unlabeled,'' ``off-label,'' or ``extra-label'' uses. --------------------------------------------------------------------------- \1\In the case of biologic products, the firm must initially file both an establishment license application and a product license application. Upon simultaneous approval, the firm is granted a U.S. license. Once licensed, the firm may enter the licensed product into interstate commerce. --------------------------------------------------------------------------- If labeling for a drug or device fails to contain adequate directions for use, the drug or device may be deemed to be misbranded under section 502(f) of the act (21 U.S.C. 352(f)) and subject to seizure and other penalties.\2\ Prescription drugs, prescription medical devices, and restricted medical devices are also misbranded unless ``all advertisements and other descriptive printed matter issued or caused to be issued by the manufacturer, packer, or distributor'' contain a brief summary or statement of the product's effectiveness or intended uses, side effects, and contraindications (see sections 502(n) and 502(r) of the act (21 U.S.C. 352(n) and 352(r))). A drug or device is misbranded in accordance with section 502(a) of the act (21 U.S.C. 352(a)) if its labeling is false or misleading. Additionally, medical devices are considered to be misbranded under section 502(o) of the act (21 U.S.C. 352(o)) if a notice or other information was not provided in accordance with the provisions of section 510(k) of the act. The listing of unapproved uses in the labeling or advertising of an approved device results in an adulterated medical device under section 501(f)(1)(B) of the act (21 U.S.C. 351(f)(1)(B)). --------------------------------------------------------------------------- \2\Biological products are also drugs or devices and, therefore, subject to regulation under the misbranding provisions of the act. --------------------------------------------------------------------------- FDA has long regulated drugs and devices (including biological products and animal drugs) based on the intended uses for the products. Under section 201 of the act (21 U.S.C. 321), which defines the terms ``drug'' and ``device,'' the intended use of an article determines whether the article is a drug or a device. The package insert or product manual (approved professional labeling) which, for approved and/or licensed products, physically accompanies the approved product, sets forth the uses for which the product has been demonstrated to be safe and effective. The package insert and product manual are not, however, the sole means by which manufacturers provide information on their products to health care professionals and consumers. The agency thus regulates products based not only on information provided ``with'' the product, but also based on information disseminated by manufacturers in other contexts, such as scientific and educational meetings and symposia, books, and articles, in part because all of these materials can create new intended uses for the products, which must be reflected in the labeling of the products. This longstanding regulatory scheme has been challenged in a citizen petition filed by the WLF on October 22, 1993 (Docket No. 92N- 0434/CP1). The petitioner asks FDA to adopt a formal new policy that: * * * recognizes the important role played by off-label uses of approved drugs and medical devices in the proper administration of health care * * * and that declares that FDA will not interfere in non-labeling activities of drug and medical device manufacturers whose effect is to promote--through the dissemination of truthful medical information--off-label [unapproved] uses of approved drugs and medical devices. (See petition at page 3.) The petitioner requests specifically that the agency withdraw its Draft Policy Statement on Industry-Supported Scientific and Educational Activities (57 FR 56412, November 27, 1992), see petition at page 3, and acknowledge that manufacturers can provide information on unapproved uses through the dissemination of books and through scientific and educational activities for health care professionals. (See petition at pages 7 through 12, and 17.) In support of this position, the petitioner argues that the agency's policy on promotion of unapproved uses is detrimental to patient care. The petitioner asserts that oncologists and orthopedic physicians commonly use approved drugs and devices for unapproved indications and believes that the public interest is best served by the widest possible dissemination of accurate information about unapproved uses. The petitioner views FDA's policy as contrary to this interest and asserts that FDA intends to prevent the dissemination of information on unapproved uses and eliminate all unapproved uses of approved drugs and medical devices. (See petition at page 11.) The petitioner also argues that FDA's policy is legally unsound. The petitioner asserts that the act does not provide authority for such a policy and that the policy violates the First Amendment to the Constitution. The petition is based, in part, on erroneous interpretations of FDA policy. The petitioner asserts, without basis, that FDA fails to acknowledge the importance to physicians of reliable information on unapproved uses, that FDA seeks to eliminate all dissemination of information on unapproved uses, and ultimately, that FDA intends to eliminate all unapproved uses of FDA-regulated products by physicians. FDA disagrees with the petition's characterization of FDA policy. The draft policy statement does not prohibit discussion of unapproved uses. However, based on its experience, FDA has found that the promotion of unapproved uses by manufacturers of the promoted products can subject patients to unnecessary and dangerous risks. Nevertheless, because the petition raises fundamental questions regarding FDA's regulation of the safety and effectiveness of therapeutic and diagnostic products, FDA believes that a full airing of these issues, with an opportunity for all interested parties to comment in writing, will be useful to the agency, the regulated industry, and the interested public. II. FDA Policy on Promotion of Unapproved Uses Over a decade ago, the FDA Drug Bulletin informed the medical community that ``once a [drug] product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens of patient populations that are not included in approved labeling.'' The publication further stated that: `unapproved' or, more precisely, `unlabeled' uses may be appropriate and rational in certain circumstances, and may, in fact reflect approaches to drug therapy that have been extensively reported in medical literature * * * Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations, subsequently confirmed by well-planned and executed clinical investigations. (See FDA Drug Bulletin 12:4-5, 1982.)\3\ --------------------------------------------------------------------------- \3\Similarly, the agency does not intervene in unapproved use of devices in the absence of a significant public health concern or significant risk to the patient. --------------------------------------------------------------------------- The agency and its representatives have restated this policy on numerous occasions.\4\ --------------------------------------------------------------------------- \4\FDA representatives have described the policy in professional journals, e.g., Nightingale, S. L., ``Use of Drugs for Unlabeled Indications,'' American Family Physician, 269, September 1986, Nightingale, S. L., ``Unlabeled Use of Approved Drugs,'' Drug Information Journal, 26:141-147, 1992, and in public meetings, e.g., Young, F. E., ``Paying for Progress: Reimbursement and Regulated Medical Products: Speech for the Blue Cross and Blue Shield Association,'' Technology Management Conference, Chicago, November 1, 1988. --------------------------------------------------------------------------- At the same time, FDA recognizes the need to ensure that data are generated from adequate and well-controlled studies to determine a product's safety and effectiveness for its intended uses and that the label of the product can be updated to reflect the new uses. Promotion of unapproved uses can encourage physicians and patients to make decisions based on statements or claims that are, in many cases, supported by little or no data. Thus, FDA's position is that the promotion of unapproved uses, either by companies or other parties that benefit by the promotion, can place physicians and patients in positions where they cannot make an informed, unbiased decision. It can also decrease the incentive of sponsors to conduct the well-controlled clinical investigations that are necessary to demonstrate whether the products are safe and effective for their intended uses. Without well- controlled trials, physicians will not have the information needed to optimally use the product. A product's intended use is usually primarily a function of the manner in which a company characterizes its product in the marketplace. The agency's focus on the company's characterization of its product in the marketplace leads naturally to an examination of information disseminated by or on behalf of a company, in addition to the approved labeling that physically accompanies the product. The indications for use set forth in the approved labeling provided with the product may not necessarily reflect the uses for which the company is actually marketing its product. The agency's experience over the years in regulating drug and device safety and effectiveness has demonstrated that regulatory control over package inserts, user manuals, and traditional advertising formats may be rendered meaningless if the company is free to engage in aggressive promotion outside of these formats. The agency has thus traditionally evaluated the promotion of drugs and devices through various other avenues of communication, including books, reprints of articles from scientific journals, and scientific and educational symposia, to determine whether the products are being improperly promoted with respect to the approved labeling for the product. This longstanding policy is best reflected in the agency's application of the statutory requirement that the labeling of drugs and devices bear adequate directions for use. (See section 502(f)(1) of the act). The courts have agreed with the agency that this provision requires information not only on how the product is to be used, but also on what the product is to be used for. In Alberty Food Products Co. v. United States, 185 F.2d 321, 325 (9th Cir. 1950), the United States Court of Appeals for the Ninth Circuit found a product to be misbranded because its labeling failed to bear a description of therapeutic uses suggested by the company in newspaper advertisements. Following the Alberty case, the agency promulgated a regulation providing that the company's responsibility to provide labeling for all intended uses is broad and objective, and reaches uses suggested outside of traditional labeling and advertising formats. The regulation provides, in relevant part, that the term ``intended uses'' refers to: * * * the objective intent of the persons legally responsible for the labeling of drugs. The intent is determined by such persons' expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised. * * * (See 21 CFR 201.128. See also 21 CFR 801.4; United States v. Three Cartons, More or Less, ``No. 26 Formula GM etc.,'' 132 F. Supp. 569, 574 (S.D. Cal. 1952).) Information disseminated by companies in contexts such as scientific and educational meetings, symposia, books, and articles may provide evidence of a regulated product's intended use. If these formats include statements promoting a use that is inconsistent with the product's approved labeling, the product is misbranded for failure to bear labeling with adequate directions for use. FDA also finds support for its policy of examining a broad array of information disseminated by companies in the general grant of authority over labeling and advertisements. Section 201(m) of the act defines the term ``labeling'' to include all ``written, printed, or graphic'' materials ``accompanying'' a regulated product. The Supreme Court has agreed with the agency that this definition is not limited to materials that physically accompany a product. ``Labeling'' may include materials that supplement or explain a product that are disseminated in direct mail, and/or otherwise distributed by or on behalf of the company. The Court has deemed the textual relationship between the materials and the products to be fundamental. (Kordel v. United States, 335 U.S. 345, 349-350 (1948).)\5\ --------------------------------------------------------------------------- \5\See also United States v. Urbuteit, 335 U.S. 355 (1948); United States v. Articles of Drug * * * ``Cal's Tupelo Blossom U.S. Fancy Pure Honey,'' 344 F. 2d 288 (6th Cir. 1965); United States v. Articles of Drug, 32 F.R.D. 32 (S.D. Ill. 1963); United States v. Eight Cartons Containing ``Plantation `the Original' etc., Molasses,'' 103 F. Supp. 626, 627 (W.D. N.Y. 1951). --------------------------------------------------------------------------- The agency has adopted a similar interpretation of the term ``advertisement,'' which appears in section 502(n) of the act (prescription drugs), and in section 502(q) of the act (restricted devices). Although the act does not define the term ``advertisement,'' section 502(n) of the act indicates that ``advertising'' does not include materials regulated as labeling. In addition, the legislative histories of the 1938 act and the 1962 amendments to the act support a broad construction of what constitutes ``advertising.'' Thus, the agency interprets the term advertisement to include information (other than labeling) that originates from the same source as the product and that is intended to supplement or explain the product. (See also 21 CFR 801.109(d) that states a prescription medical device must bear, among other things, labeling containing adequate directions for use for all advertised uses or it may be considered to be misbranded.) The statutory requirement of adequate directions for use and the statutory concepts of labeling and advertisements limit the ability of companies to disseminate information on unapproved uses. However, because the agency recognizes the importance of dissemination of reliable scientific information on both approved and unapproved uses, it has developed a number of policies related to dissemination of such information. In October 1991, FDA informally released an early draft document called ``Drug Company Supported Activities In Scientific or Educational Contexts: Draft Concept Paper'' (hereinafter referred to as the draft concept paper). The draft attempted to clarify FDA's position on industry-supported scientific and educational activities. Certain elements of the draft concept paper met some resistance from the regulated industry, health care professional organizations, and academic communities. With substantial input from these and other interested parties, FDA developed the draft policy statement which was published in the Federal Register on November 27, 1992, for public comment, and which is now one of the subjects of the WLF Petition. The draft policy statement is part of an effort to produce a policy statement that reasonably accommodates the need for industry-supported scientific and educational activities and the need to regulate industry labeling and advertising in accordance with the act and the Public Health Service Act. (See Draft Policy Statement on Industry-Supported Scientific and Educational Activities at 57 FR 56412.) The draft policy statement distinguishes between company-supported scientific and educational activities that are independent of the influence of the supporting company and those that are not. The content of independent activities would not be regulated by FDA. The purpose of the draft policy statement is to clarify this distinction. The draft policy statement focuses largely on the relationship between the supporting company and the independent provider responsible for developing the activity in which information is disseminated. The agency generally seeks to determine whether the activity is designed to be a promotional vehicle for the supporting company's products or an independent educational program. The draft policy statement recommends that the supporting company enter into a written agreement with the provider, making clear that the funded event is not to be a promotional program for the supporting company, but rather is intended to be an independent scientific or educational activity, controlled in content and format by the provider and characterized by balance, objectivity, scientific rigor, and appropriate disclosure of financial support or conflicts of interest. The draft policy statement states, in part, that: [i]f the company abides by such a written agreement and does not otherwise circumvent its purpose, the agency does not intend to regulate the activity under the labeling and advertising provisions of the act, nor under the reporting requirements related to labeling or as advertisements. (57 FR 56413.) Under the draft policy statement, companies could provide financial, logistical, and technical support for the program without being held responsible for the program's content for regulatory purposes. In preparing the draft policy statement, FDA conducted an extensive outreach effort with scientific and health care professionals, industry, consumer groups, and other government agencies. FDA proceeded in this fashion because it recognized the delicate balance required to accommodate the need for industry-supported scientific and educational activities and the statutory mandate that products be safe and effective for their intended uses. In developing the draft policy statement, senior agency officials met with representatives from the American Medical Association, the Accreditation Council for Continuing Medical Education, the Pharmaceutical Manufacturers Association (now called the Pharmaceutical Research & Manufacturers of America), the Association of American Medical Colleges, the Health Industry Manufacturers' Association, the Pharmaceutical Advertising Council, the American Osteopathic Association, the American Council on Pharmaceutical Education, and others. Written comments submitted to the agency after publication of the draft policy statement were predominantly supportive. Those supporting the draft policy statement included, among others, the American Medical Association, the Pharmaceutical Manufacturers Association, the American Dental Association, the Accreditation Council for Continuing Medical Education, the American Nurses Association, the American Academy of Family Physicians, the University of Arizona Health Sciences Center, the University of Kentucky, the MOET Institute, and the American Association of Dental Schools. Most comments supported the draft policy statement and sought only minor changes or clarifications. Some comments said that the draft policy statement was not sufficiently restrictive. One comment said that the draft policy statement ``represents a cave-in to drug industry/organized medicine pressures.'' Other comments argued that the policy exceeded FDA's authority under the act or unjustifiably expanded FDA's legal authority. Some comments claimed FDA's authority in this area is limited by the First Amendment's protections afforded to commercial speech or that the draft policy statement restricts a company's ability to engage in free scientific exchange. Several comments sought clarification of the draft policy statement's application beyond live presentations. Certain comments requested that the draft policy statement exempt written or other enduring materials from its scope. In addition to dissemination through live, oral, independent and nonpromotional educational activities, such as certain symposia, information on unapproved uses may be disseminated through the submission of original research to peer-reviewed publications. The agency has recognized the need among health care professionals for peer review and dissemination of the latest significant scientific data and information on drugs and devices in scientific journals. The agency has thus followed a course under which it may refrain from regulating the dissemination of information on unapproved uses if the dissemination involves submission of original research to peer-reviewed journals. Under current FDA policy, companies may also disseminate information on unapproved uses in response to unsolicited requests for scientific information from health care professionals. Scientific departments within regulated companies generally maintain a large body of information on their products. When health care professionals request such information, companies can provide responsive, nonpromotional, balanced, scientific information, which may include information on unapproved uses, without subjecting their products to regulation based on the information. This policy permits companies to inform health care professionals about the general body of information available from the company. Companies may also disseminate independently prepared educational materials that contain product information. As discussed above, the agency's general exercise of regulatory authority over company dissemination of books and similar materials containing product information is well established in the case law. However, agency policy is to permit dissemination of materials that are independently prepared, are prepared solely for educational use, are in the form of balanced educational material, are not promotional in nature, cover a number of different products, and are not associated in any way with a promotional campaign for a specific product. Although recognized medical textbooks have been disseminated by companies under this policy, dissemination of materials that are not recognized by health care professionals or are not independently prepared may lead to agency regulation. Thus, as in the matter raised by the petitioner involving ``edited'' versions of a recognized textbook, the agency has informed companies that their products may be subject to regulation based on the dissemination of books that are designed or edited by or for the company (so-called ``custom'' textbooks). FDA has met with the American Medical Writers Association and the American Medical Publishers regarding FDA's development of a policy clarification that specifically addresses ``enduring materials.'' (The term ``enduring materials'' refers to items such as books, reprints of articles, and other printed material, as well as programmed course materials and electronic or recorded material such as computer disks and videotape.) These groups voiced concern that application of the draft policy statement to enduring materials would impede their distribution and the free flow of information. FDA reiterates that it does not wish to regulate either oral presentations or enduring materials that are independent and nonpromotional in nature. FDA has also taken steps to obtain more information on unapproved uses of approved drug products to facilitate approval of important unapproved uses that are supported by adequate data. In April 1993, the agency invited several organizations to identify prevalent unapproved uses that have therapeutic significance, and that may be supported or partially supported by published or unpublished clinical data. The agency indicated that it would encourage manufacturers of the identified products to submit supplemental applications for those uses. FDA received over 40 comments and is presently reviewing the information that it has received. III. Risks Associated With Unregulated Promotion of Unapproved Uses Although agency policy has allowed companies several avenues for disseminating scientific information concerning unapproved uses of their products, FDA has not abandoned its general position prohibiting the promotion of unapproved uses. The agency has seen numerous examples of risks associated with the promotion of unapproved uses in a variety of contexts. A. Post-Infarction Anti-Arrhythmic Agents It is known that patients after an acute myocardial infarction (AMI, or heart attack) who have a high rate of ventricular premature beats (VPB's) have a higher mortality, especially sudden death, over the year following the heart attack, than patients with fewer VPB's. There are, moreover, plausible relationships between ventricular premature beats and death; e.g., a ventricular premature beat at the wrong time can trigger ventricular tachycardia (VT), a poorly functional rhythm that tends to degenerate ventricular fibrillation, which is always fatal if not reversed. Still, regardless of whether the relationships are plausible, the question is whether lowering the rate of ventricular premature beats will, in fact, lead to fewer deaths. FDA has never accepted decreased rate of ventricular premature beats as a surrogate for improved survival. In fact, labeling of anti-arrhythmics in the late 1970's and 1980's began to emphasize that information on post-AMI use was not available and that there was no evidence in any situation that anti-arrhythmics improved survival. No sponsor ever asked for a survival claim, but many practitioners continued to use anti-arrhythmics because they had the impression (which was unsubstantiated) that survival would be favorably affected by VPB suppression. Early attempts in controlled studies to see whether post-AMI anti- arrhythmic therapy improved survival showed no benefit and tended to show an adverse effect of the treatment, but the studies were flawed, mainly because they did not choose a population with enough VPB's to benefit. The Cardiac Arrhythmia Suppression Trial (CAST) was an attempt to get a definitive answer by selecting patients with high VPB rates, showing that a drug suppressed VPB's, and then randomizing the patients to either that drug or placebo to examine survival. The initial drug screening period also allowed exclusion of patients whose rhythm was made worse by the drug (pro-arrhythmic effect), a recognized potential problem with these drugs. This trial showed a highly unexpected result. Rather than helping patients, the drugs studied (flecainide and encainide) caused a 2.5- fold increase in mortality compared to placebo. A second part of the trial also showed an adverse morbidity effect of moricizine, another anti-arrhythmic agent. Meta-analysis of studies of anti-arrhythmic drugs in the post-AMI setting also show adverse trends. There is no anti-arrhythmic agent, except beta blockers, that has had a favorable effect on post-AMI survival. Indeed, when these agents have been properly studied in the post-AMI setting, they have taken, not saved, lives. Despite the absence of evidence showing the value of post-AMI VPB suppression, use of anti-arrhythmic agents for that unapproved indication was substantial even though drug companies could not legally promote antiarrhythmic drugs for the unapproved use. Given the greater mortality in those patients who received the drug, this was an imprudent claim, but it reflects the potential power of plausible, but under-documented claims in difficult situations, e.g., where there is no good treatment for a condition. B. Post-Infarction Calcium-Channel Blockers Calcium-channel blockers are effective anti-anginal drugs that are generally well tolerated. Despite animal data that suggest potential benefit during and post-infarction, many studies of post-AMI calcium- channel blocker use have failed to show benefits, and some studies suggest that they may cause harm, particularly in patients with poor heart function. There is, therefore, no basis for recommending calcium- channel blockers for routine post-infarction use. In contrast, several beta-blockers (such as propranolol, timolol, metoprolol, and atenolol) have unquestionably been shown to improve survival when given prophylactically to people who have had an AMI. Use of beta-blockers and calcium-channel blockers together can lead to problems, and, especially in patients with poor heart function, the combination could worsen the patient's condition. Physicians are aware of this and tend not to use the drugs together although there are many exceptions to this. To the extent, however, that physicians perceive calcium-channel blockers as a substitute for beta-blockers to reduce post-AMI morbidity and leave patients off beta-blockers, patients would be denied the benefits of the beta-blocker. On average, beta-blockers produce an approximately 25 percent reduction in annual mortality. In the past, several manufacturers of calcium-channel blockers attempted to encourage their use in post-AMI situations, and the agency successfully rejected these attempts. Extensive promotion of calcium- channel blocker's for post-AMI use could have been extremely damaging because the use of calcium-channel blocker's in the population of post- AMI patients, or segments of that population, appears to be harmful. More importantly, however, increased use of calcium-channel blocker's due to the mistaken impression that they have the same effect as beta- blockers for post-AMI use would have inevitably decreased use of beta- blockers for this purpose and had a very substantial adverse effect on post-AMI survival. Given the many patients who sustain an AMI each year, the loss of life would surely be in the thousands. In this instance, promotion of an unapproved use would have been lethal. C. Botulinum Toxin Type A and Cosmetic Use ``BOTOX'' (botulinum Toxin Type A) is a licensed biologic product for use in the treatment of ``strabismus and blepharospasm associated with dystonia.'' Currently, these are the only approved indications for use of this very deadly botulinum toxin. Nevertheless, a patient information/education bulletin announced new therapies and treatments using BOTOX strictly for cosmetic purposes. The bulletin claimed, ``NEW WRINKLE REMEDY * * * SAFE * * * SIDE EFFECTS * * * ARE MINIMAL * * * .'' This promotion of an unapproved use is an egregious example of promoting a potentially toxic biologic for cosmetic purposes. D. Unapproved Uses of Approved Devices Unnecessary risks can also result from the promotion of unapproved uses of approved medical devices. For example, one manufacturer's promotion of such unapproved uses encouraged physicians to extend the use of the device beyond that which has been proven to be safe and effective. Other promotions of unapproved uses for approved medical devices have involved claims for specific diseases or conditions that go beyond the general claims that FDA cleared or approved. Under the act, manufacturers must obtain new marketing approvals or clearances when they promote an approved or cleared device for a new intended use. Since the public controversy surrounding silicone gel breast implants, some entrepreneurs have promoted various devices, such as a ``breast coil,'' as effective in detecting leakage of the inner gel component of the implant to bodily tissues. In addition, some in vitro diagnostic tests, involving the examination of blood and serum samples, have been illegally promoted as capable of detecting silicone gel migration. To date, no evidence has been presented to validate the efficacy of either of these products for this unapproved use. The unapproved use of these devices may result in a misdiagnosis of leaking breast implants, thereby leading to unwarranted surgery to remove the implant. Left unchecked, the promotion of unapproved uses not only can expose patients to unnecessary risks, but also has the potential to undermine the product approval process. If a manufacturer were free to promote its product for any use, the manufacturer would have little or no incentive to conduct the necessary clinical trials to demonstrate that the product is safe and effective for its intended uses. As a result, consumers would be exposed to products whose safety and effectiveness for the unapproved uses are unknown. In addition, consumers and health care professionals may avoid or delay using known, effective therapies or products as a result of the attention given to unapproved uses. Moreover, distinctions between approved and investigational products would also be blurred, and the protections associated with the use of investigational products (such as obtaining informed consent from research subjects and institutional review board approval to ensure that the rights and welfare of research subjects are protected) would be easily circumvented. IV. Striking the Proper Balance: Issues Presented for Comment Striking the proper balance between the need to regulate the promotion of unapproved uses for drugs and devices and the need for reliable scientific data and information on unapproved uses of approved products has long been a difficult and controversial challenge for the agency. FDA has given serious consideration to these issues over the years and has worked with health professional organizations and other outside parties to develop policies that facilitate company-supported dissemination of reliable scientific information in a manner that is consistent with the statutory mandate that products be safe and effective for their intended uses. Nonetheless, the pending WLF petition raises issues that merit consideration. FDA's policies allow for industry-supported scientific and educational activities and free exchange of information in a manner consistent with the statutory and regulatory goals. Because drugs and devices are regulated based on their ``intended use'' (as previously discussed), the agency's policies may have an unavoidable effect on the dissemination of information regarding unapproved uses for approved products. However, FDA emphasizes that these policies are narrowly drawn and are intended to further describe FDA's regulation of drugs and devices (not speech), to ensure that sponsors demonstrate that their drugs or devices are safe and effective for their intended uses, and to protect consumers from the risks associated with the unapproved use of drugs and devices whose safety and efficacy for the unapproved use have not been established. However, the WLF citizen petition asserts that the draft policy statement, and FDA's regulation of the promotion of unapproved uses generally, interfere with the First Amendment rights of physicians and consumers to receive information regarding unapproved uses. Consequently, FDA invites comments on the WLF citizen petition and on the following questions: 1. FDA has long recognized that physicians and other health care professionals may prescribe approved therapies for unapproved uses. FDA's experience, as previously described, demonstrates that promotion of unapproved uses may subject patients to serious and unnecessary risks and may cause health care professionals to refrain from using other products that may represent first-line therapy or present less risk. Given the current amount of information available to health care professionals, what are the added benefits, if any, of allowing manufacturers to promote unapproved uses of approved products to health care professionals? What are the additional risks, if any? 2. The WLF petition argues that the draft policy statement and FDA's regulation of the promotion of unapproved uses are not authorized by the act, violate the First Amendment, and prevent health care professionals from providing ``the best possible medical care.'' The agency believes that the draft policy statement and FDA's regulation of the promotion of unapproved uses are consistent with its authority and responsibilities under the act, do not violate the First Amendment, facilitate dissemination of accurate product information, and as noted above, prevent patients from being exposed to products whose safety and efficacy for an unapproved use have not been demonstrated. Given these different considerations, the amount of scientific and educational information available to health care professionals, and the sources of information (other than industry-supported activities) available to health care professionals, does the agency's implementation of its statutory authority significantly limit health care professionals' access to current, scientifically valid information regarding unapproved uses for approved products? Does the draft policy statement restrict or facilitate access by health care professionals to current, scientifically valid information regarding unapproved uses for approved products? How might the involvement of device or pharmaceutical manufacturers in the preparation or dissemination of information on unapproved uses affect that information? 3. The draft policy statement acknowledges that discussion of unapproved uses can be an important component of scientific and educational activities. The draft policy statement does not prohibit such discussion, but encourages disclosure of the fact that a product is not approved in the United States for the use under discussion. In addition, company-supported activities that do not relate to the company's product, a competing product, or suggest a use for the company's product would not be regulated as promotional activities under the draft policy statement. Given its narrow scope, how might the draft policy statement preclude health care professionals and patients from receiving important scientific information regarding unapproved uses for approved products? 4. The WLF petition suggests that FDA adopt a formal policy stating that FDA will not interfere in company-supported, ``non-labeling activities'' whose effect is to promote--through the dissemination of ``truthful'' medical informatio--unapproved uses of approved drugs and medical devices. However, FDA's broad experience reviewing promotional materials and scientific data suggests that determining whether information is ``truthful'' may depend on a variety of factors, including time, context, publication bias, lack of stringent review before publication, whether a published article appeared in a journal or in a purchased ``supplement'' to a journal, etc. For example, a preliminary study may suggest a result that appears ``truthful'' at the time the preliminary study is first announced, but subsequent studies may fail to reproduce those results, disprove the preliminary result, or even show that the preliminary study was flawed. Given the wide variety of factors, how should one determine whether the information in question is, indeed, ``truthful?'' The draft policy statement and WLF citizen petition, as well as comments on the draft policy statement and petition, may be seen at the Dockets Management Branch (address above). Requests and comments are to be identified with the docket number found in brackets in the heading of this document. Copies of the draft policy statement and the WLF citizen petition may be requested in writing from the Freedom of Information Office (HFI-35), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Dated: November 8, 1994. William K. Hubbard, Interim Deputy Commissioner for Policy. [FR Doc. 94-28506 Filed 11-17-94; 8:45 am] BILLING CODE 4160-01-F