FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 331:1348-1349 November 17, 1994 Number 20 Next

Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

In 1972, topical tretinoin (Retin-A, Ortho Pharmaceutical) was approved for the treatment of acne. Today this remains the only medical indication for its use approved by the Food and Drug Administration (FDA). In 1988 a highly publicized study reported that topical tretinoin improves the appearance of "photoaged" skin¹. Since then, the manufacturer of topical tretinoin has conducted an active, controversial multimedia effort to ensure that the general public and the medical profession are aware of the "unlabeled" use of tretinoin to treat benign cutaneous changes, such as wrinkles and brown spots, that may be annoying to patients because of their association with the appearance of aging. The commissioner of the FDA, members of Congress, and others have cited these efforts as an example of inappropriate promotion of a drug for an unlabeled use^2,3,4,5. The greatly increased attention to topical tretinoin in the medical and lay press and the substantial increase in the number of prescriptions written for this agent since 1988 suggest that the company's actions in promoting the unlabeled use were successful and highly profitable.

Methods

The National Ambulatory Medical Care Survey is a national probability-sample survey conducted by the National Center for Health Statistics^6,7,8. Participating physicians complete a record of each outpatient visit that includes the patient's diagnosis and demographic characteristics, the services rendered, and the characteristics of the provider. I analyzed the data tapes available to the public to determine the number of office visits involving prescriptions for topical tretinoin dispensed by nonfederally employed office-based physicians in the United States in 1980, 1981, 1985, 1989, 1990, and 1991, the six years of the survey that include prescription data. In these six years, a total of 276,689 outpatient visits were sampled.

Using these data, I determined the number of visits during which a prescription for topical tretinoin was given, overall and for subgroups of patients with various characteristics. I calculated standard errors and statistical significance by t-test using published formulas⁸; the coefficients were provided by Iris Shimuzu of the National Center for Health Statistics.

To find the relative number of medical articles each year principally concerning topical tretinoin and the skin, I carried out a MEDLINE search of English-language journals using the PaperChase computer program⁹. Company-sponsored supplements were excluded. Using The New York Times Index and the Readers' Guide to Periodical Literature, I determined the number of indexed articles in the popular press concerning topical tretinoin and the skin^10,11.

Results

Publicity about topical tretinoin has not always been positive. In 1978 an FDA bulletin warned about a possible risk of cancer associated with the drug¹². Beginning in 1980, a number of publications, including one from a company-sponsored workshop, provided reassuring data about the risk¹³. Reports of the FDA warning accounted for most coverage in the popular press before 1986 (Figure 1). Most other medical articles about topical tretinoin before 1986 concerned its use for acne or rare dermatologic diseases. In 1988, when the highly publicized medical study suggested that topical tretinoin improved wrinkles related to photoaging of the skin,¹ 28 articles on topical tretinoin in the popular press were indexed. Nearly all discussed the treatment of photoaging. Citations in the popular press declined after the 1988 peak (Figure 1). After 1987 there were 41 times as many articles about topical tretinoin and the skin in the popular press as there had been in the preceding decade, and 3 times as many in medical publications (P<0.05 for both comparisons).

View larger version (26K): [in this window] [in a new window]   Figure 1. The Number of Articles Principally Concerning Topical Tretinoin and the Skin in Medical Publications and the Popular Press and the Number of Office Visits to Physicians Involving Prescriptions for Topical Tretinoin. The medical citations were found in a MEDLINE9 search, and articles in the popular press were found in The New York Times Index10 and the Readers' Guide to Periodical Literature11. Office visits include those to nonfederally employed physicians in office-based practices. Data on prescriptions were available only for 1980, 1981, 1985, 1989, 1990, and 1991.

 
The number of visits during which a prescription for topical tretinoin was given was significantly higher in 1981 than in 1980 (1,850,000 vs. 810,000, P<0.05). The average for 1980 and 1981 was nearly identical, however, to the number in 1985 (1,330,000 vs. 1,220,000, P>0.2) (Figure 1). The number in 1989 (2,720,000) was 123 percent higher than the number in 1985 (P<0.01). From 1989 to 1991 prescribing rates were relatively constant (Figure 1). After 1988 the greatest increase in prescriptions for topical tretinoin was for patients over 30 years of age (284 percent increase over earlier years), patients who were not seeing a dermatologist (895 percent increase), and patients who did not have acne (400 percent increase) (P<0.001 for all comparisons). In contrast, the number of prescriptions per year for patients under 30 who had acne and were visiting a dermatologist increased by only 22 percent (P>0.1).

Discussion

For over 20 years, topical tretinoin has been on the market for the treatment of acne, its only approved medical indication. In 1988 the number of medical and popular articles about topical tretinoin increased dramatically, to extraordinary levels in the popular press. Most of these articles concerned the treatment of photoaging, a medical use of topical tretinoin that has never been approved by the FDA. The 1988 Readers' Guide to Periodical Literature listed 23 articles on topical tretinoin and the skin (with 20 on photoaging), as compared with 28 on treatment of the acquired immunodeficiency syndrome (AIDS) and 15 on AIDS vaccines¹¹. In my experience and that of my colleagues, topical tretinoin became by far the therapy most often requested by patients after the highly publicized 1988 study on its use for photoaging¹. After 1988 the prescription rates for topical tretinoin more than doubled as compared with the average for earlier years. The rate of prescribing increased most for visits by women over 30, visits to nondermatologists, and visits that were not for acne.

Not all articles in the medical literature or all publicity helps drug sales. In 1978 the FDA and the popular press warned about the potential carcinogenic effects of topical tretinoin¹². The National Ambulatory Medical Care Survey first collected data on prescriptions in 1980. Unfortunately, I thus cannot assess any changes in prescribing rates that occurred immediately after this negative publicity. The substantial increase in prescribing rates in 1981 as compared with 1980 did, however, follow the publication of a number of articles, some company-sponsored, that provided reassuring information on this issue¹³.

Although since 1972 acne has been the only FDA-approved indication for topical tretinoin, the content of advertisements in dermatology journals has changed dramatically. For example, in 1985 a two-page advertisement for Retin-A in a medical journal included photographs of patients with acne and the results of clinical trials¹⁴. In 1989 an advertisement of the same size in the same journal provided no clinical-trial results or information about acne, but showed a stylized, wrinkle- and blemish-free face with porcelain-like skin¹⁵. Whether topical tretinoin has a clinically important effect on sun-induced skin damage or is cost effective for this purpose is not established. The data I report do demonstrate that medical articles and reports on them in the popular press were associated with a large increase in prescribing, especially for an unlabeled indication.

I was not able to quantify precisely the profits attributable to articles and promotional efforts suggesting that topical tretinoin helps reduce the effects of photoaging or quantify the losses attributable to articles raising questions about its safety. However, the number of prescriptions for topical tretinoin increased dramatically after 1988, and from 1987 to 1990 the average wholesale price increased by approximately 25 percent a year^16,17. At least for the manufacturer, reports of company-sponsored studies, promotional efforts (press conferences, symposiums, and advertising), and the tremendous publicity about this drug in the popular media, particularly its use for an unlabeled indication, have certainly paid, and paid well.

Source Information

From the Department of Dermatology, Beth Israel Hospital, and Harvard Medical School, Boston.

Address reprint requests to Dr. Stern at Beth Israel Hospital, 330 Brookline Ave., Boston, MA 02215.

References

1. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA 1988;259:527-532. [Erratum, JAMA 1988;259:3274, 1988;260:926.] [Abstract]
2. Randall T. FDA scrutinizes "off-label" promotions. JAMA 1991;266:11-11. [CrossRef][Medline]
3. Kessler DA. Drug promotion and scientific exchange -- the role of the clinical investigator. N Engl J Med 1991;325:201-203. [Medline]
4. Rep. Weiss seeks Retin-A NDA data from FDA in follow-up to June 11 hearing. FDC Reports "The Pink Sheet." 1991;53(Sept. 2):T&G-3.
5. J&J promotion of Retin-A for wrinkles being probed by Justice Department. FDC Reports "The Pink Sheet." 1991;53(June 17):7-9.
6. The collection and processing of drug information: National Ambulatory Care Survey United States, 1980. Hyattsville, Md.: Department of Health and Human Services, National Center for Health Statistics. Vital and health statistics. Series 2. Data evaluation and methods research. No. 90.
7. Delozier JE, Gagnon RO. National Ambulatory Medical Care Survey for Drug Mentions, 1985. (Public use data tape documentation.) Hyattsville, Md.: National Center for Health Statistics, 1987. (DHHS publication no. (PHS) 82-1364.)
8. Schappert SM. National Ambulatory Medical Care Survey: 1991 summary. Advance data from vital and health statistics. No. 230. Hyattsville, Md.: National Center for Health Statistics, 1993. (DHHS publication no. (PHS) 93-1250.)
9. Horowitz GL, Bleich HL. PaperChase: a computer program to search the medical literature. N Engl J Med 1981;305:924-930. [Abstract]
10. The New York Times index: a book of record: 1977-1991. Vols. 65-79. New York: The New York Times Company, 1978-1992.
11. Limerick Z, Marra JM, eds. Readers' guide to periodical literature: an author and subject index. Vols. 36-51. New York: H.W. Wilson, 1977-1981.
12. Retinoic acid and sun-caused skin cancer. FDA Drug Bull 1978;8:26-26.
13. Kripke ML, Glassman HN. Retinoic acid and photocarcinogenesis workshop. J Am Acad Dermatol 1980;2:439-442. [Medline]
14. To improve the surface . . . stop the inflammatory process at the source: Retin-A. Advertisement of the Ortho Pharmaceutical Corporation. J Am Acad Dermatol 1985;13:60A-62A. 
15. Ortho introduces a new dimension in Retin-A therapy. Advertisement of the Ortho Pharmaceutical Corporation. J Am Acad Dermatol 1989;20:100A-102A. 
16. Drug topics red book 1987. 91st ed. Oradell, N.J.: Medical Economics, 1987.
17. Drug topics red book 1991. 95th ed. Oradell, N.J.: Medical Economics, 1991.

Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

Related Letters:

Drug Promotion
Hoberman D., Puma J. L., Cohen S. N., Mossinghoff G. J., Stryer D. B., Bero L. A., Kalish R. S., Kessler D. A., Rose J. L., Temple R. J., Schapiro R., Griffin J. P., Stern R. S.
Extract | Full Text  
N Engl J Med 1995; 332:1031-1033, Apr 13, 1995. Correspondence

This article has been cited by other articles:

• Hoberman, D., Puma, J. L., Cohen, S. N., Mossinghoff, G. J., Stryer, D. B., Bero, L. A., Kalish, R. S., Kessler, D. A., Rose, J. L., Temple, R. J., Schapiro, R., Griffin, J. P., Stern, R. S. (1995). Drug Promotion. NEJM 332: 1031-1033 [Full Text]