   |
|
| |
 | |
| |
     |
|
| |
| |
| |
   |
|
| |
|
Posted - April, 1999 Editor's Note: This article was developed from materials presented at BIO'98 as part of the session entitled "Controlling Potential Liability Through Proper Management of Product Labeling and Promotion"
Conforming to FDA Regulation
by Introduction The development of new products based on the miracles of biotechnology has increased exponentially in recent years. However, it is a fact of life for many biotechnology companies and their investors that their one breakthrough product currently under development must become revenue-producing as soon as possible. A company with a new product in the works naturally wants to disseminate as much information as possible about that product, to gain an edge on the competition and maximize market share as soon as FDA approval is obtained. A month, a week or even a day of lost sales can have an impact on a company's bottom line. In today's competitive environment, getting the message out about a new drug as early as possible can mean when the drug is in Phase III or even sooner.1 Unfortunately, companies that want to optimize their post-approval marketing position by putting out information in advance of product approval can find themselves at odds with the FDA. Medical marketers need to be aware of the FDA regulations on pre-approval promotion.
Section 312.7(a) in 21 CFR applies to pre-approval promotion. It states: "A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purpose for which it is under investigation or otherwise promote the drug."
The FDA is particularly strict about the pre-approval promotion of investigational products, because this type of promotion takes place before the safety and efficacy of the product has been fully studied and become known.2 A manufacturer may anticipate that a compound under investigation will be useful for more indications, and have fewer side effects, than are later allowed when the clinical trials are done and the labeling is finalized. The FDA believes that if information about an investigational product is inappropriately disseminated and ultimately proves to be untrue, practitioners will have already developed some misconceptions about the product that could have safety implications for patients, not to mention increased exposure for the sponsoring company.
FDA concern about pre-approval promotion is nothing new. In 1982, 1985 and 1986 the Division of Drug Advertising and Labeling at the Center for Drug Evaluation and Research (CDER), now known as the Division of Drug Marketing, Advertising and Communications (DDMAC), reissued and updated its policy guidance statements on the promotion of investigational products. In April of 1994 DDMAC revised these previous policy statements and reissued them as the Pre-Approval Promotion Guidance. This guidance, the current FDA policy on this subject, describes two forms of acceptable limited pre-approval promotion:
Once a sponsor uses either an institutional or a "Coming Soon" ad, the sponsor is committed to using only that type of ad until the drug is approved. During this pre-approval period, a sponsor may not use both kinds of ads simultaneously or switch from one to the other. To do this would establish a link between the name of the product and the disease state for which it is under investigation. Furthermore, these ads may not make any suggestions about the product that are related to or suggest safety or efficacy. "Coming Soon" ads, really a form of "reminder" ad about the product, are never allowed for drugs that will have a boxed warning in the labeling. This is usually known fairly early in the labeling development process, before the time a decision would be made to potentially run a "coming soon" ad for the product. The reason "coming soon" ads are not allowed for products that will carry a black box warning is that these drugs will not be appropriate subjects for reminder ads even after approval. Regarding institutional ads, the FDA feels that such ads can serve a very useful purpose, and provide valuable education to the public.3 However, a company that chooses to use this vehicle as a way to develop awareness about a specific disease state must be careful. The information presented in the promotion should not "point" to or highlight the drug under investigation by the use of wording, graphics or other devices that could allude to the drug. The regulation on pre-approval promotion applies to biologics as well as drugs. The Advertising and Promotional Labeling Staff (APLS) at the Center for Biologic Evaluation and Research (CBER) wants to see proposed drafts of "coming soon" ads for biological products before the ads are released, and specifically mentions this in a procedural guidance document issued in 1994.4 DDMAC wants to see "coming soon " ads at the time of dissemination.5 The same rules apply equally to pre-approval promotion of generic drugs6 and new indications for previously marketed drugs.7 The FDA takes the regulation on pre-approval promotion very seriously, and its position on this issue has remained virtually unchanged for a long time. Although the FDA has not issued any new guidance documents on pre-approval promotion since 1994, the existing rules prohibiting inappropriate pre-approval promotion continue to be enforced.
The FDA has issued regulatory letters to a number of different companies over the years, for engaging in what the FDA considers to be inappropriate pre-approval promotion. Companies can learn from reviewing these documents what kinds of pre-approval promotional activities will trigger FDA's concern In a December 1994 Warning Letter, a company was taken to task for fielding a highly organized and orchestrated pre-approval campaign for a drug under investigation for the treatment of seizures.8 Among the promotional materials cited as being violative were certain slide lecture kits. These had been excerpted from a lecture series originally prepared for the clinical investigators, to keep them apprised of current information about the drug as well as to share study results. However, when the sponsor made the decision to expand the audience for the information beyond the clinical investigators as a way to answer questions about the management of epilepsy, the FDA determined that the sponsor was engaging in inappropriate pre-approval promotion. FDA required the sponsor to do extensive remediation as a result of this, including issuing a corrective "Dear Health Care Professional " letter at the time of product launch. The FDA even required the launch materials to state that the product had not been shown to be safe for the uses promoted before approval that did not appear in the final labeling. In an early 1998 Notice of Violation letter, DDMAC criticized a sponsor for an ad that appeared on the back cover of a medical journal touting an investigational bladder treatment.9 The ad described symptoms, mentioned an indication, and contained such statements as "our answer is coming soon" and "working on the best reason yet to treat..." The FDA said these statements, coupled with the product name, violated FDA pre-approval promotion prohibitions by implying that an unapproved drug was effective, and suggesting that it was also superior to currently available therapies. In March of 1998 another sponsor received a lengthy Warning Letter for mounting a highly orchestrated campaign to promote an investigational ultrasound contrast agent.10 The campaign consisted of single-sponsor publications, articles about the drug, advertisements, a slide kit, and information on the internet. DDMAC found this information to be false and misleading, and inconsistent with respect to the uses for which the drug might ultimately be approved. Although this company was not asked to write any letters to health professionals about the campaign, it was requested by FDA to stop dissemination of the material, and to send a copy of the warning letter to all of its marketing managers including managers working for their co-promotion partners. The FDA also stated that it might ask for other corrective actions based on discussions with the sponsor, noting that other remedial measures might be necessary to correct the false impressions resulting from the sponsor's conduct. A "coming soon" ad for an investigational ophthalmic product disseminated by another sponsor also resulted in a regulatory letter from the FDA.11 The advertising division noted that the ad, besides presenting the generic and trade name of the drug and depicting an image of an eye, contained the statement "built on a legacy of proven therapies." Since the sponsor also makes other ophthalmic products that are the basis for the new combination product, the FDA determined that the "coming soon" ad actually made inappropriate representations about the drug name and its intended use. These letters are publicly available through FOI and on the FDA web site, so product sponsors can be faced with negative publicity if they engage in pre-approval promotional activities that trigger FDA scrutiny.
What about press releases announcing the results of clinical trials issued prior to product approval? These would appear to contradict the FDA's regulations on pre-approval promotion, in that both the name of the drug and the disease for which it is being studied are mentioned. However, the regulation discussed above, 21 CFR section 312.7(a), goes on to say, "This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution".
Over the years, the FDA has issued a number of regulatory letters to companies on the subject of press releases. As far back as 1984 the FDA sent a regulatory letter to one company for issuing a press release that featured news of a product's cost-effectiveness while announcing the receipt of an approvable letter for the drug.12 The sponsor's rationale for disseminating the information was that there was interest from the press and the financial community. The FDA considered this improper and unwarranted pre-approval promotion, even though the information in the press release was accurate. The FDA stated that since the Agency does not publicize unapproved NDAs, information from them would have most likely come from the drug company or the drug company's investigators. The FDA stated that the sponsor could not use, as an excuse to issue pre-approval promotion, interest that the company itself had generated. In another case, a sponsor received a regulatory letter that commented upon a press release announcing results of certain investigational studies for an unapproved drug.13 The FDA noted in the letter that the press release exaggerated the efficacy of the product through selective data reporting and minimization of adverse information about the drug. Another drug company received a Warning Letter from the FDA about a press conference and press materials provided by a physician at a university medical center, concerning his research into use of the sponsor's approved product for the treatment of an additional unapproved use.14 The FDA noted that the conference and materials constituted an extensive public relations effort. The violation, according to the FDA, was not the fact that the physician chose to publicize his study results, but that the drug company sponsored the publicity. Two regulatory letters were issued in May of 1998 by DDMAC targeting the same kinds of issues. In one letter, the agency cited a sponsor for issuing a press release announcing the approvability of its drug, that also contained promotional statements of comparison to other therapies and efficacy statements such as "the first of a new class."15 The second letter, reporting on the results of an Advisory Committee meeting, admonished a sponsor for such statements as "encouraging preliminary results," "increased clinical benefit," and for overstating the efficacy data for the investigational drug.16
One could argue that the reason some companies publicize results of their clinical studies is not to promote scientific exchange, but to do that very thing frowned upon by the FDA, to commercialize their products before approval. In the examples discussed above, the situations triggering comment from the FDA were those in which an attempt was made to mix presentations of scientific data with promotional messages. Sometimes, a company will issue a press release that announces new research results for a marketed drug, but also mentions other indications for which a product is being investigated. Promotion of additional indications or new dosing schedules for which a previously approved drug is being studied must follow the same rules that apply to other pre-approval promotional activities. All that a company can say about these investigations is that the drug is being studied for other uses. In summary, the regulations do not preclude the dissemination of scientific information about a drug under development, but merely emphasize that such information must remain separate from and not become part of a promotional campaign. As emphasized above, the intent of the provision at 312.7(a) is to "preclude commercialization of the drug before it is approved for commercial distribution."
There are some things a company can do to help maintain an appropriate separation of science and promotion in press releases announcing clinical trial results. Companies should present clinical trial data in an objective way, without including additional information that goes beyond the specific conclusions of the study. This would include not make any claims for safety or efficacy of the investigational product. All the findings of the study should be presented, including the important side effects observed during the study. The investigational nature of the study results should be emphasized, and the information disseminated to the appropriate audience. Also, the clinical or scientific group within a company, rather than the marketing department, should disseminate this information.
To summarize, pre-approval promotional activity can take one of two forms. Sponsors can disseminate either "coming soon" or institutional promotional ads, but not both. Regarding scientific information in pre-approval press releases, this must be presented without additional promotional statements, or it will be considered inappropriate pre-approval promotion. In general, the FDA is very uncomfortable with the press materials that companies have been disseminating about their investigational products in recent years. Recent activity in the press regarding potential new cancer therapies has demonstrated that media announcements, rather than peer-reviewed scientific information, can create false hope and be confusing both for patients and for health care professionals. This is a perfect example of the kind of outcome that is not desirable for a company researching an investigational compound, and that is problematic for the FDA. The Agency is currently drafting an intra-center guidance document on press releases to be issued in the near future. This should be helpful for companies that are unsure of how to manage press releases in the most appropriate way.
The information contained herein is not intended to serve as legal advice. The sources used to develop this information are believed to be reliable, but CNA accepts no responsibility or legal liability for the correctness or completeness of this material or for its application to specific factual situations. Specific legal concerns or questions should be directed to individual competent counsel. As appropriate, you may also wish to contact the Food and Drug Administration for more specific or complete information. CNA is a registered service mark and trade name of CNA Financial Corporation.
Links to other internet sites that are not maintained by CNA may be accessed through this web site. Such external internet addresses contain information created, published, maintained or otherwise posted by organizations and entities independent of CNA. CNA is not responsible for the content of those sites nor does it approve, endorse or certify information available at any external site or linked addresses contained herein.
No part of this site may be reproduced without written permission from CNA. Material may be reprinted upon proper attribution to CNA and inclusion thereon of the words ©2000 by the CNA Financial Corporation.
|