Regulation of prescription drug promotion: direct-to-consumer advertising

CLINICALTHERAPEUTICSVVOL. 20, SUPPLEMENT C, 1998

Regulation of Prescription Drug Promotion: Direct-to-Consumer Advertising Minnie Baylor-Henry, RPh, JD, and Norman A. Drezin, RPh, JD US Food and Drug Administration,

Rockville, Maryland

ABSTRACT

INTRODUCTION

The US Food and Drug Administration (FDA) is responsible for regulating the information on prescription drugs disseminated by sponsors to health care providers and consumers to ensure that it is truthful and not misleading, and that it presents a fair balance of benefit and risk information. Thus the public health is both protected and promoted by the dissemination of honest, accurate information about regulated products. This paper discusses the regulatory requirements for promotional materials for prescription drugs and the standards used by the FDA to evaluate these materials. It also discusses the agency’s views on direct-toconsumer advertising, the enforcement actions that are available to the FDA, the process used by the FDA to determine what action should be taken and when, and what remedies are available. Key words: advertising, DTC, promotion, regulation.

The benefit from, and value of, prescription drugs is obtained when a drug is prescribed for, and used by, an appropriate patient. This benefit is often dependent on the quality of information disseminated by the sponsor to health care providers and consumers concerning the product’s benefits and risks. This information may affect discussions between providers and patients about treatment options and the decision to use various therapies. Such information may result in a prescription for the patient to obtain and use the product.

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LIFE CYCLE OF A PRESCRIPTION DRUG The prescription drug industry has made a considerable contribution toward improving the lives of consumers. This contribution includes growth in knowledge and technology and the development of new therapeutic agents. 0149-2918/98/$19.00

M. BAYLOR-HENRY & N.A. DREZIN

A prescription drug goes through what we would describe as three distinct stages during its life cycle. The various activities in each stage may occur at different times for different products and different companies. Stage

1

The first stage of the life cycle of a product is marked by conception and development, clinical trials, and flow through the New Drug Application (NDA) process to obtain approval of the product. This stage is governed by the Federal Food, Drug and Cosmetic (FDC) Act and regulations that require sponsors to provide substantial evidence of effectiveness (from well-controlled studies) and evidence of safety while simultaneously providing safeguards to protect patients participating in clinical trials. Each of the milestones in this first stage requires considerable resources and represents the hopes and expectations of the sponsoring company, from the marketing and planning departments to the dedicated scientists, and ultimately to the shareholders. A variety of therapeutic agents has been developed rapidly over the past 30 years. For example, 30 years ago there were no nonsteroidal anti-inflammatory agents (other than aspirin and phenylbutazone), no calcium channel blockers, angiotensinconverting enzyme (ACE) inhibitors, transdermal systems, 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibitors, pharmacologic treatments for benign prostatic hypertrophy, cephalosporin or fluoroquinolone antibiotics, histamine,-receptor antagonists, proton-pump inhibitors, antiviral agents, protease inhibitors, or selective serotonin reuptake inhibitors.

These product classes are only representative examples, but they highlight the tremendous successes of both the industry in developing these products and the US Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research (CDER) in evaluating and approving these products. These examples also emphasize the significant benefits to consumers achieved in the current regulatory environment. However, the success of the drug industry in research and development raises new issues and competitive pressures. Many of these new drug classes, such as those for use in lowering blood pressure, lowering cholesterol levels, relieving pain and inflammation, and treating infection, may contain 10 or more products. During development, most of these products were studied and compared with a placebo. Most products within the same class appear to be generally similar in benefits and risks and have similar labeling, but relatively few head-to-head comparative trials between drugs within a class have been conducted. Nonetheless, the sponsors of these products compete for the prescribers’ attention with other products in their class as well as with other classes of therapeutic agents that are indicated for the same condition. For example, an ACE inhibitor indicated for the treatment of hypertension not only competes against the other ACE inhibitors, but also against calcium channel blockers and an established base of diuretics and beta blockers. Stige 2 The second stage of the life cycle is the commercial phase and is marked by the launch of the product, product proC87

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motion, and sales. It includes the development of additional indications (as in stage 1) and dosage forms as well as new information about previously unknown risks. This stage is governed by the FDC Act and regulations to ensure that the experiences gained from the use of the drug are adequately reported and disseminated. Specific sections of the FDC Act and regulations impose requirements and standards for the advertising and promotion of these products to ensure that the information disseminated about prescription drugs is truthful, not misleading, and fairly balanced. Stage 3 The final stage marks the twilight years in a prescription drug product’s life cycle. For many products, market exclusivity is lost, bioequivalent and therapeutically interchangeable products are available, and the economic value to the sponsor of the product usually declines. It is important to note here that it is usually the “economic value” that declines and not the therapeutic or clinical value. Although these therapeutic agents usually retain their clinical value, in many cases use declines because the products become commodities, and sponsors are no longer interested in some of the commercial aspects of the second stage, such as product promotion. REGULATION OF LABELING AND ADVERTISING The prescription drug industry is a regulated industry, and the FDA’s mission is to protect and promote the health of the American people. The key phrase in this mission statement is “protect and proC88

mote.” In fulfilling this mission, the FDA reviews and monitors the development of products from early research to postmarketing experience, surveillance, and reports. The FDA’s responsibilities include ensuring that drugs, biological products, and medical devices are safe and effective, and that these regulated products are honestly, accurately, and informatively represented to health care providers and consumers. Within CDER, the Division of Drug Marketing, Advertising, and Communications (DDMAC) plays a significant role in regulating promotional representations made by sponsors during the various stages of the life cycle of a prescription drug product. DDMAC is responsible for monitoring and regulating the advertising and promotion of prescription drugs. DDMAC’s mission is as follows: ‘To protect the public health by assuring prescription drug information is truthful, balanced, and accurately communicated. This is accomplished through a comprehensive surveillance, enforcement, and education program, and by fostering better communication of labeling and promotional information to both health professionals and consumers.”

The Federal Dade Commission

Historically, the Federal Trade Commission (FTC) had primary responsibility for the advertising of drugs. However, in the 1962 amendments to the FDC Act, Congress granted the FDA the responsibility to regulate prescription drug advertising.’ The FTC retains primary responsibility for the advertising of most other products, including over-the-counter drug products.

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The materials and information disseminated to promote and sell most products are generally considered to be advertising. However, for prescription drugs, the FDC Act and regulations divide these promotional materials into two distinct categories-labeling and advertising. Although the requirements for labeling and advertising are generally the same, some differences exist. In most instances the difference between these categories is clear, but in others it is blurred. The FDC Act defines labeling, and FDA interpretations and Court decisions help to define the term. In addition to the approved product labeling and package label that are evaluated by the new drug review divisions in CDER, labeling includes written, printed, or graphic matter that supplements, explains, or describes a drug product or use of the product (“promotional labeling”). It does not need to physically accompany the product. Thus brochures, booklets, and other written, printed, or graphic materials that are disseminated by or on behalf of the manufacturer, packer, or distributor are considered labeling. The labeling category is considered broadly2 and includes giveaway items, ranging from pens, mugs, pads, hats, and shirts to videos, sound recordings, product monographs, literature reprints, and product listings in the Physicians ’ Desk Reference. The FDC Act and regulations do not specifically define advertising, except to describe it as being other than those materials considered to be labeling.’ However, the term is described by example in the regulations.3 According to the regulations, advertisements are those materials published in journals and newspapers, and broadcast through media such as radio, televi-

sion, and telephone communications systems. Under the regulations, labeling and advertising have different disclosure requirements. The promotional labeling described above must be accompanied by the complete approved product labeling, but advertising needs only a “brief summary” of the approved product labeling. In addition, the FDC Act and regulations only address the requirements for prescription drugs in the context of acts by the applicant or sponsor. They do not consider the recipients of the information. Thus promotional materials for health care providers and consumers must meet the same requirements for disclosure; that is, they may not be false, lacking in fair balance, or otherwise misleading. However, language or terminology may differ for these distinct audiences because disclosures that would be understood clearly by physicians may be misleading to consumers. The regulations also provide exemptions from the disclosure requirements for certain types of advertisements.4 For example, reminder advertisements and labeling are the most common exemptions. These types of advertisements and labeling are limited in the amount and type of information they may contain. These reminders may contain the name of the product, manufacturer’s name, dosage form, and strength to be stated in the advertisements without triggering any disclosure requirements. They are intended only to call attention to the name of the drug product. Reminder advertising and labeling regulations do not permit representations, either explicit or implicit, about the product, and this type of advertising or labeling may not contain any information about the indications or dosage recommendations for use 039

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of the product. Furthermore, reminder ads and labeling cannot be used for any drug that has a boxed warning on the label relating to a serious hazard associated with use of the drug. Another issue that is extremely important in prescription drug promotion is fair balance. Fair balance refers to the disclosure of the benefits and risks associated with use of the drug. One significant distinction between prescription drug products and most other consumer products is the requirement for risk disclosure. The FIX Act specifically requires sponsors to disclose facts that are “material with respect to consequences which may result from the use of the article to which the labeling or advertising relates under the conditions of use prescribed in the labeling or advertising.“5 The statute and regulations require reasonable comparability between the presentation of such disclosures. In the absence of such balance, the advertising and labeling materials would be considered in violation of the law. The FDC Act and regulations impose a variety of requirements on sponsors with regard to promotional materials. The basic premise for all advertising and labeling is that these promotional materials may not promote off-label uses and may not be false, lacking in fair balance, or otherwise misleading. An important difference exists between CDER’s authority and responsibilities in the first stage versus those in the later stages of a product’s life cycle. During the first stage, the burden and responsibility rest primarily with the sponsor. The sponsor must submit an application and provide the data and information necessary to support FDA approval. Unlike the FDA’s authority to approve NDAs, the FDC Act and regulations do c90

not generally provide the FDA with prior approval authority over advertising and promotional labeling. Except in extraordinary circumstances, the FDA does not have the authority to require sponsors to submit promotional materials for approval prior to use.ly6 The regulations only require that the applicant submit copies of labeling at the time of initial dissemination and copies of advertising at the time of initial publication.7 Thus DDMAC does not usually see promotional materials until they are published or otherwise disseminated, and usually operates in a reactive posture. The regulations, however, provide a mechanism by which sponsors can voluntarily submit proposed promotional materials for FDA comment before use.8 Nonetheless, except for launch campaigns-that is, promotional materials disseminated immediately after approval for the introduction of a new product to the market or approval of a new use for a marketed product+nly a small percentage of the total promotional materials disseminated annually by industry are voluntarily submitted for comment. AVAILABLE ENFORCEMENT ACTIONS The regulatory process depends on voluntary compliance by the pharmaceutical industry. In general, sponsors attempt to comply with the FDC Act and regulations. When the FDA makes a determination that a violation has occurred, sponsors usually cooperate with the agency and revise their promotional activities to comply with the regulatory requirements. Under the FDC Act, advertising and promotional labeling violations may result in a product being misbranded and

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may result in regulatory action. Allegations of misbranding may result in seizure of the violative product, injunctive proceedings, or criminal prosecutions of both firms and individuals. Although the FIX Act and regulations do not require notice, DDMAC will usually notify a sponsor by sending an untitled letter or a Warning Letter, indicating that the FDA has determined that the sponsor’s promotional activities are considered violative. A Warning Letter may be used for more egregious violations such as repetitive misconduct. These letters contain a statement that failure to respond may result in further regulatory action without notice. An untitled letter or Warning Letter, however, is not a prerequisite to the FDA taking other regulatory actions. In cases where DDMAC believes that violations are occurring, involving several firms in a crowded and competitive market, DDMAC may issue an industry guidance concerning the specific issues raised by the violative promotional materials. Such guidances notify all sponsors as to how DDMAC applies the regulations to specific issues.

materials has ceased, DDMAC focuses on the type of corrective message needed, if appropriate, and how it should be disseminated. The use of a corrective message is intended to correct any misinformation and impressions provided by the violative message. Therefore, corrective messages should attract attention, be assertive, and reach the appropriate audiences. The FDA has requested that sponsors use both direct mailings and publications in appropriate journals for corrective letters to health care providers. These methods of dissemination are intended to effectively reach the same targeted population that received the violative promotional material. These enforcement actions and remedies have been used by the agency for many years in the regulation of prescription drug advertising and labeling directed to health care providers. Although the same actions are available for materials directed to consumers, until recently, there has been little direct-to-consumer (DTC) promotion. This situation is now changing, particularly with the significant expansion of DTC broadcast advertising.

Remedies

DIRECT-TO-CONSUMER PROMOTION

In most regulatory enforcement actions, DDMAC usually seeks the immediate termination of the violative conduct. Generally, a firm should not continue to disseminate violative materials while new promotional materials are being prepared. However, sometimes when a firm receives an untitled letter concerning a technical violation, such as the size of the type used for the established name, DDMAC may permit the firm to continue to use its materials for a specific time period. After the dissemination of violative

Although the regulations state the requirements for all prescription drug advertisements, some regulations specifically address broadcast advertising. The broadcast regulation states that: “Advertisements broadcast through media such as radio, television, or telephone communications systems shall include information relating to the major side effects and contraindications of the advertised drugs in the audio or audio and visual parts of the presentation and unless adec91

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quate provision is made for the dissemination of the approved or permitted packaged labeling in connection with the broadcast presentation shall, contain a brief summary of all necessary information related to side effects and contraindications.“9 Thus if a pharmaceutical company runs an ad that states or suggests claims about the safety or effectiveness of the product on television, radio, or by telephone, the regulations require that the ad also disclose the major side effects and contraindications associated with the product. The regulations require that such disclosures appear in either the audio or audio and visual portions of the ad. It is important to note that the regulations do not require that all side effects and contraindications be disclosed, just the major ones. The regulations also require that the ad contain a brief summary of the side effects and contraindications. One way of providing such disclosures on television is to scroll this information at the end of the ad. However, this method of disclosure requires a significant amount of time, is expensive, and many of the major networks have not traditionally permitted such ads. There is also considerable doubt as to whether these scrolls actually communicate information. Historically, some cable stations have used scrolling to present the brief summary in conjunction with product advertisements on cable programs directed to consumers and physicians. However, this process does not appear to be feasible for broadcast ads for the broad range of consumer programming. The regulations also provide an alternative to the presentation of the brief summary with a broadcast product advertisement. Under the regulations, in lieu of

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the brief summary, the sponsor can make “adequate provision” for the dissemination of the full prescribing information. What would constitute “adequate provision” had not been described by the FDA until recently. For consumers, the FDA believed that to satisfy the adequate provision portion of the regulation, some consideration must be given to how information is obtained by both active and nonactive information seekers. In addition, unlike physicians who normally seek such information as part of their professional practice, consumers may be concerned about confidentiality when they seek information. Thus other means of providing the full prescribing information had to be developed. For many years, the FDA grappled with issues related to DTC broadcast ads. Up until a year ago, most of the prescription drug ads presented on television or radio were either “reminder ads” that could make no representations about the product, or “help-seeking” ads that discussed a disease or condition and recommended consultation with a health care provider for help. Neither of these kinds of ads must make “adequate provision.” The FDA recognized that reminder ads were not particularly useful for consumers and believed a mechanism was needed for providing useful information about prescription drugs that would be consistent with the FDA’s mission to protect and promote public health.

THE FDA’S DRAET

GUIDANCE

In August 1997, the FDA published a draft guidance in the Federal RegisterlO that set forth one method that the FDA believed could be used to satisfy the

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“adequate provision” requirement in the regulations for broadcast ads. This draft guidance did not change any of the regulatory requirements for prescription drug ads. The ads must truthfully communicate the product’s indication. In addition, there had to be a “major statement” about the side effects and contraindications associated with the product. The “major statement” must be in the audio or audio and visual portions of the ad. The FDA’s draft guidance set forth a multifaceted approach for “adequate provision” of the full prescribing information that included sponsors providing the information by mail, telephone, facsimile, use of an Internet address, or a product brochure that would be available in publicly accessible places. In addition, the FDA recommended inclusion of a reference to a print advertisement currently running in a widely circulated publication. With this multifaceted approach, the FDA believed that consumers would have adequate access to this important information. The comment period for this guidance closed October 14, 1997. The agency received 29 comments on this guidance, all of which are available publicly. (Comments are filed in Docket No. 97D-0302 and may be seen at the Dockets Management Branch, US Food and Drug Administration, 12420 Parklawn Drive, Rockville, MD 20857.) The FDA is carefully evaluating these comments and will consider this information before the agency issues a final guidance. In the Federal Register notice that accompanied the draft guidance,10 the FDA committed to evaluating the effects of the guidance, including the public health effects, and the agency encouraged the private sector to conduct research intended to evaluate

many of these issues. Further, the FDA indicated that 2 years after the publication of a final guidance, the agency would evaluate whether the guidance should be withdrawn, continued, or modified. The FDA has evaluated many DTC promotional labeling materials and advertisements over several months, particularly DTC broadcast ads. From these evaluations, several issues were identified as violations of the regulations, some of which follow. First, the indication must be completely and accurately communicated. If limitations have been imposed on the indication, such as the need for concomitant therapy including diet and other nonpharmaceutical therapies, they must be disclosed. Second, the major side effects and contraindications must be presented. Third, the major warnings and significant precautions and drug interactions must be presented. Fourth, a fair balance of benefit and risk information must be presented. This balance requires that the presentation of risk information be reasonably comparable to the presentation of benefits information. Finally, careful consideration must be given to the context in which the safety information is presented. Any attempts to trivialize important safety information would be misleading. The FDA does not believe that the sponsor’s decision about the length of the ad, such as 30,45, or 60 seconds, should determine how much critical information should be presented. Since the issuance of the draft guidance, the FDA has informed many companies that their ads were in violation of the FDC Act and regulations and, in most instances, has requested that the company withdraw the ad. The agency has indicated in its letters that the ads were misc93

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leading for reasons such as a lack of fair balance in the presentation of risk information, unsupported superiority claims, and inadequate provisions for dissemination of the full prescribing information. Because, as discussed above, the FDA generally does not have the authority to require prior approval of these ads, the ads frequently appear before the agency has reviewed them. Direct-to-Consumer Print Advertisements As previously discussed, the regulations do not distinguish between professional and DTC advertising. However, if an ad targets consumers, the FDA believes that it would be misleading to present information in a manner that would not be comprehensible to the average consumer. Advertisements for prescription drugs appear in many consumer-oriented magazines today. Accompanying these ads is a “brief summary” of the prescribing information.” In a public meeting in 1995, the FDA received many comments that this information was not useful because it was difficult to read and comprehend. It has been recommended that this information be presented in language more useful to consumers. The FDA agrees that making the brief summary more useful to consumers is an important issue. It is worth noting that some companies have already reformatted this information in an attempt to ensure that it is more “consumer friendly.” As with broadcast advertisements, the FDA has issued many letters to companies regarding violations with DTC print advertisements. In some instances, the FDA has requested that the company purc94

sue a revised campaign designed to correct misimpressions in the community. CONCLUSIONS The prescription drug market is more competitive than ever before. Markets for products for the treatment of allergies and asthma, angina, hypertension, hypercholesterolemia, diabetes, bacterial and viral infections, pain and arthritis, gastrointestinal ulcers, and other medical conditions have become highly competitive as new products are introduced. Sponsors are engaged in advertising and promotional labeling that use new technologies, such as the Internet, as well as novel uses of older means of communication. These materials and activities are constantly raising new challenges and questions as the FDA seeks to fulfill its mandate to protect and promote the public health. Advertising and promotional labeling materials are potentially valuable to society because they provide a means of disseminating drug information to both health care providers and the public, but the value of these materials is dependent on the content and integrity of the information being disseminated. The FDA recognizes that many parties are concerned about DTC promotion. The FDA further recognizes its responsibility to balance the public health effects against First Amendment rights. These are important considerations, and they must be evaluated carefully. The FDA plans to continue to examine these issues and must carefully consider what types of information would not mislead consumers as they acquire knowledge about their medical conditions. The agency must consider whether the current format is appropriate for providing

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this information. As a public health agency, the FDA must also be mindful of the outcome when classes of drugs, such as anti-infectives, are promoted directly to consumers. The FDA will continue to encourage organizations to engage in research projects on this topic and, after careful consideration, will pursue a course of action designed to provide the best protection for the American people.

REFERENCES 1. 21 U.S.C. Q 352(n). 2. 21 C.F.R. $ 202.1(l)(2). 3. 21 C.F.R. 8 202.1(1)(l). 4. 21 C.F.R. 0 202.1(e)(2). 5. 21 U.S.C. 8 321(n). 6. 21 C.F.R. 5 202.1(j)(l). 7. 21 C.F.R. 0 314.81(b)(3).

Address

correspondence

Baylor-Henry, sion of

to: Minnie

Rph, JD, Director, Divi-

Drug Marketing, Advertising, and Communications, US- Food and Drug Administration, 5600 Fishers Lane, Room 17B20-HID-40, Rockville, MD 20857.

8. 21 C.F.R. 0 202.1(j)(4). 9. 21 C.F.R. Q 201.1(e)(l). 10.62 FR 43171, August 12, 1997. 11. 21 C.F.R. 0 202.1(e)(l).

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