Citizen Petition Regarding the Food and Drug Administration's Policy on Promotion of Unapproved Uses of Approved Drugs and Devices; Request for Comments

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