[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]


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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.

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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.
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    \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.
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    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)).
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    \2\Biological products are also drugs or devices and, therefore, 
subject to regulation under the misbranding provisions of the act.
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    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\
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    \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.
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The agency and its representatives have restated this policy on 
numerous occasions.\4\
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    \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.
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    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\
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    \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).
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    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