Correspondence
Drug Promotion
N Engl J Med 1995; 332:1031-1033April 13, 1995
- Article
To the Editor:
The article by Kessler et al. (Nov. 17 issue)1 provides a useful summary of questionable promotional activities by pharmaceutical companies. It does not discuss, however, the inappropriate promotional use of published and unpublished clinical studies. Dr. Kessler gave examples of the questionable use of data in a letter in 1992.2 As the statistician who reviewed the studies cited in promotional material from October 1991 to October 1993, including the critique of the antiulcer medication claimed to benefit smokers,1 I found that the majority of promotional claims referred to me citing clinical studies violated the advertising regulations of the Food and Drug Administration (FDA).
Promotional material has made promiscuous use of studies that analyze retrospectively identified subgroups and multiple clinical end points (practices that can increase the chance of false positive conclusions); claim therapeutic equivalency between drugs; interpret crossover trials; fail to address the issue of patients who leave trials prematurely; use open-label, single-blind, or nonrandomized trials; select data obtained at one of several time points; compare data from the package inserts of two drugs that were not in the same trial; and display graphics that suggest the superiority of one drug to another.
Accurate initial promotion is relatively easy to guarantee, because it follows immediately after a comprehensively reviewed New Drug Application. On the other hand, promotional material that uses data culled from studies conducted long after a drug is approved can be assembled in such a way that the FDA can object only after the material has had its desired effect in circulation. . . . Routine violation of the law governing the fair and responsible use of clinical data appears to be a very small price to pay for a share of the market.
2 ReferencesDavid Hoberman, Ph.D.
Food and Drug Administration, Rockville, MD 208521
Kessler DA ,Rose JL ,Temple RJ ,Schapiro R ,Griffin JP . Therapeutic-class wars -- drug promotion in a competitive marketplace. N Engl J Med 1994;331:1350-1353
Full Text | Web of Science | Medline2
Kessler DA . Addressing the problem of misleading advertising. Ann Intern Med 1992;116:950-951
Web of Science | Medline
To the Editor:
Kessler and colleagues note that seeding studies are often used to promote duplicative (“me too”) drugs. These studies pose unexplored ethical problems for participating physicians.
In 1992, we surveyed 733 community physicians and 269 consecutive general internal medicine patients about seeding studies. The response rates were 54 percent and 74 percent, respectively. Most physicians who responded (64 percent) found it acceptable to be paid for being involved in seeding studies, whereas most patients who responded (56 percent) found these fees unacceptable (P<0.005). Relatively fewer physicians (75 percent) than patients (86 percent) said that a physician paid to enroll a patient should inform the patient of the payment (P<0.005). Most physicians (67 percent) and patients (69 percent) thought some physicians might be influenced to enroll patients just for the fee.1
Until seeding studies are improved and more closely regulated, the information provided to their prospective subjects should include the amount of the remuneration the physician receives for prescribing one drug instead of another.
1 ReferencesJohn La Puma, M.D.
1945 N. Burling St., Chicago, IL 60614To the Editor:
The article by Kessler et al. describes problems to which the FDA seems unable to respond very effectively. To the aggressive marketer of pharmaceuticals, the benefits of bending the rules until they break clearly outweigh the costs of a letter from the FDA saying, “Stop it.” It takes a while for the offense to be detected and a response formulated, and the penalty is minor or nonexistent.
I realize there is no easy solution, but perhaps more vigorous use of negative publicity would be a step in the right direction. The public and the medical profession might be interested to see prominently featured in their newspapers (and perhaps in a periodic direct-to-the-physician newsletter from the FDA) that company X has been reprimanded by the FDA for claiming unproved efficacy or minimizing the side effects of drug Y. The appropriate supporting details could be included — rather like the recall notices published in Consumer Reports.
Stephen N. Cohen, M.D.
University of California, San Francisco, Medical Center, San Francisco, CA 94143-0100To the Editor:
Kessler and his associates grant that there is now “a highly competitive marketplace for prescription drugs.”1 But instead of celebrating the expanded range of therapies and the smaller price increases brought about by this competition, Dr. Kessler and his colleagues focus on overzealous marketing.
Most new medicines represent incremental improvements over existing ones. Their existence not only gives physicians an opportunity to tailor therapy to the precise needs and conditions of patients, but also creates competition. In a few isolated instances, companies may have overstepped the bounds of propriety in trying to increase their share in the marketplace. But these rare abuses should not be allowed to overshadow the benefits of the new competition, cost containment and improved quality.
For the 12 months ending in October 1994, price increases for drugs were at their lowest point in 20 years — 1.9 percent, according to the Producer Price Index.2 Competition has also resulted in lower initial prices for new drugs. For example, four new angiotensin-converting–enzyme inhibitors were launched in 1991–1992 at an average price 36 percent below that of the market leader.3
Competition improves the quality of health care by enabling physicians to choose among several drugs. Often it is helpful when drugs with different side effects are available.
Of course, competition is not always pretty. If overzealous competition has produced isolated instances of promotional campaigns disguised as clinical trials, Commissioner Kessler is justified in condemning them. In any case, the strict guidelines adopted by both the medical profession and the pharmaceutical industry are working to stop unethical marketing.
3 ReferencesGerald J. Mossinghoff
Pharmaceutical Research and Manufacturers of America, Washington, DC 200051
Kessler DA ,Rose JL ,Temple RJ ,Schapiro R ,Griffin JP . Therapeutic-class wars -- drug promotion in a competitive marketplace. N Engl J Med 1994;331:1350-1353
Full Text | Web of Science | Medline2
Bureau of Labor Statistics, PPI Division. Producer price indexes, data for October 1994. Washington, D.C.: Department of Labor, November 1994.
3
The changing environment for U.S. pharmaceuticals: the role of pharmaceutical companies in a systems approach to health care: a report. Boston: Boston Consulting Group, 1993:8.
To the Editor:
The Special Articles by Stern1 and Kessler et al.2 discuss the potentially dangerous practice by pharmaceutical companies of increasing sales by publicizing the use of certain medications for unapproved indications. To promote such uses, drug companies employ additional techniques besides those discussed by Stern and Kessler.
One such technique is to disseminate material directly to physicians that discusses unapproved uses. In a recently completed study of material distributed by pharmaceutical-company representatives to physicians, we found that a number of the promotional items discussed uses for which the drug in question had not received FDA approval. For example, one reprint distributed to numerous physicians at an academic medical center discussed the treatment of chronic pain with the antiarrhythmic drug mexiletine.
Another technique is the publication of sponsored symposiums. In an analysis of symposiums published in 11 journals,3 51 percent of those focusing on a single drug discussed products that had not received FDA approval. Furthermore, the lower the therapeutic value of the drug discussed, the more likely it was that the symposium promoted unapproved indications.3
3 ReferencesDaniel B. Stryer, M.D.
Kayenta Health Center, Kayenta, AZ 86033Lisa A. Bero, Ph.D.
Institute for Health Policy Studies, San Francisco, CA 941091
Stern RS . Drug promotion for an unlabeled indication -- the case of topical tretinoin. N Engl J Med 1994;331:1348-1349
Full Text | Web of Science | Medline2
Kessler DA ,Rose JL ,Temple RJ ,Schapiro R ,Griffin JP . Therapeutic-class wars -- drug promotion in a competitive marketplace. N Engl J Med 1994;331:1350-1353
Full Text | Web of Science | Medline3
Bero LA ,Galbraith A ,Rennie D . The publication of sponsored symposiums in medical journals. N Engl J Med 1992;327:1135-1140
Full Text | Web of Science | Medline
To the Editor:
The article by Stern1 on the use of drugs for unlabeled indications raises several questions about the importance of unlabeled indications. The labeled indications for a drug strongly reflect the marketing decisions of pharmaceutical companies. The approval process is extremely expensive, and many drugs are never approved for appropriate indications.
This is especially true of drugs not protected by patent and of indications for uncommon diseases. Dapsone was the standard treatment for dermatitis herpetiformis decades before it was approved for that indication. During that period, the use of dapsone for this unlabeled indication was extensively supported by the medical literature. Clearly, for a dermatologist to rely on the drug's approval by the FDA would have been poor medical practice.
This problem is particularly relevant to less common diseases. As a practicing physician, I need to make individual risk–benefit decisions with my patients. The bureaucracy of the FDA is incapable of making such judgments, particularly in a clinical field such as dermatology, in which it has traditionally had little expertise.
1 ReferencesRichard S. Kalish, M.D., Ph.D.
SUNY at Stony Brook, Stony Brook, NY 11794-81651
Stern RS . Drug promotion for an unlabeled indication -- the case of topical tretinoin. N Engl J Med 1994;331:1348-1349
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Problems with data presentation and analysis of the kind identified by Dr. Hoberman have resulted in many letters to companies informing them of violations. Although the FDA lacks the authority to clear promotional material before it is distributed, the agency attempts to identify violations and to stop or correct them. Because we cannot scrutinize all references in all advertisements, we encourage anyone detecting a violation to report it to the FDA and the manufacturer. As Dr. Hoberman notes, sometimes this after-the-fact approach is not disincentive enough for companies to stop engaging in misleading promotions.
Dr. Cohen suggests that the fear of negative publicity may be an effective deterrent. When the violation is repetitive or could have an important effect on the public health, the FDA does ask manufacturers to notify physicians of it in a “Dear Doctor” letter or sometimes to correct the misleading promotion in the publication where it appeared (for example, by placing a corrective advertisement in a journal). The FDA cannot ensure that violations are covered in the lay press. Obviously, our current practice is not a complete deterrent, but we believe it has some effect.
Stryer and Bero cite several instances of overt promotion of unapproved uses of drugs. Manufacturers may not promote such uses by distributing articles about them or promoting them through industry-controlled symposiums. They may, however, respond to questions from health care practitioners and support independent educational events (i.e., those in which the company has no control over content), including symposiums, where unapproved uses can be discussed.
Dr. La Puma's proposal that physicians inform prospective patients if they are receiving a fee for prescribing one drug instead of another is appealing. There is growing support in government (including the FDA) and academia for disclosure by investigators of possible conflicts of interest. The question of just what information should be given to patients is at an earlier stage of discussion, but it merits continued attention.
Finally, Mr. Mossinghoff emphasizes the expanded choices and reduced prices resulting from vigorous competition, although he acknowledges that this competition is “not always pretty.” The FDA must be concerned about those “not always pretty” effects of competition when they lead to promotions that can mislead physicians in their choice of therapies.
David A. Kessler, M.D.
Janet L. Rose, P.A.-C., M.B.A.
Robert J. Temple, M.D.
Renie Schapiro, M.P.H.
Joseph P. Griffin, J.D.
Food and Drug Administration, Rockville, MD 20857Author/Editor Response
I fully agree with Dr. Kalish that many drugs have clinical uses that have not been approved by the FDA. The U.S. Pharmacopeial Convention, the American Medical Association, and the American Society of Hospital Pharmacists publish legally recognized compendiums designed to help guide health care providers in the rational use of drugs, including prescriptions for indications not approved by the FDA.1-3 For clinicians to use drugs optimally, they require robust, objective, and scientific data on risk and benefit. When promotional efforts based on a preliminary study of the use of a drug for a new and unlabeled indication produce extraordinary publicity in the medical and general press and generate hundreds of millions of dollars in profits, it seems appropriate to consider whether these actions are in the best interest of patients, the company, or both.4 Drug promotion that distorts the perceptions of prescribers or patients about the magnitude of benefit of a drug is unlikely to help either the clinician or the patient. In the case of the use of topical tretinoin for “photoaging,” some experts viewed the initial findings as a half-full cup, whereas others argued that the cup was half empty. The company's promotional use of these findings made tretinoin appear to be a fountain of youth.
Unfortunately, we are unlikely ever to know the full story of the promotion of topical tretinoin by Johnson and Johnson. Because it destroyed the records, Johnson and Johnson recently pleaded guilty to charges of conspiracy to obstruct justice in government investigations of this promotional effort, and the company paid a $5 million fine.5
As Drs. Stryer and Bero also note, companies use many methods to promote their drugs. Our society seems to have great difficulty establishing a balance between the free and open exchange of objective information about the best use of drugs and inappropriate promotion that provides a distorted view of a drug's benefit, cost effectiveness, or optimal use or that otherwise induces prescribers to consider factors other than the patient's best interest in deciding whether to prescribe the drug. If the promotion of old drugs or the development of “me too” drugs is more profitable than investment in truly new agents, medical progress will suffer.
5 ReferencesRobert S. Stern, M.D.
Beth Israel Hospital, Boston, MA 022151
Drug information for the health care professional. 15th ed. Vol. 1. Rockville, Md.: United States Pharmacopeial Convention, 1995.
2
Bennett D, ed. Drug evaluations annual 1994. Chicago: American Medical Association, 1994:2364.
3
McEvoy GK, ed. AHFS drug information 94. Bethesda, Md.: American Society for Hospital Pharmacists, 1994.
4
Stern RS . Drug promotion for an unlabeled indication -- the case of topical tretinoin. N Engl J Med 1994;331:1348-1349
Full Text | Web of Science | Medline5
Tanouye E. Johnson and Johnson admit to shredding Retin-A papers. Wall Street Journal. January 11, 1995:B1, B6.
- Citing Articles (1)
Citing Articles
1
Sofia B. Ahmed, Sherry L. Grace, Henry Thomas Stelfox, George Tomlinson, Angela M. Cheung. (2004) Gender bias in cardiovascular advertisements. Journal of Evaluation in Clinical Practice 10:4, 531-538
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