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J&J PROMOTION OF RETIN-A FOR WRINKLES BEING PROBED BY JUSTICE DEPARTMENT; FDA WILL ACT AGAINST MDs WHO PROMOTE UNAPPROVED USES, KESSLER TELLS HEARING

Executive Summary

FDA is pursuing Ortho's handling of Retin-A as an object lesson in the area of stimulating consumer interest in unapproved prescription drug uses and the role of medical researchers as product promoters. The agency indicates that it has passed information on Ortho's handling of Retin-A to the Department of Justice for further investigation. The investigation was disclosed by Rep. Weiss (D-N.Y.) at a June 11 hearing on illegal promotions of drugs and medical devices before his House Government Operations/Intergovernmental Relations Subcommittee. Weiss asked FDA Commissioner Kessler what action the agency is taking against Ortho (or its parent Johnson & Johnson) regarding promotions of Retin-A as an anti-aging product. Kessler repeatedly said he could not comment on the subject of an ongoing investigation. Weiss insisted that he was inquiring into FDA action, not Justice Department action, but the commissioner persisted in his refusal to describe actions being taken against the firm. Kessler averred that promotion of Retin-A for the unapproved anti-wrinkling indication is illegal and that FDA is concerned that the drug, "if used chronically, could potentially increase the risk of skin cancer." Without identifying the action against Retin-A specifically, Kessler declared that FDA intends "to identify promotional activities that are disguised as education or public relations and hold these activities to the same standards as traditional promotional techniques." He stated the warning in the context of the recent settlement with Bristol-Myers Squibb over oncology promotions ("The Pink Sheet" June 3, p. 4). Retin-A makes an interesting test case for FDA's attempt to send a message about its renewed vigilance in policing drug promotions. A number of aspects of the situation recommend it as an attractive or expedient subject for investigation. The primary off-label use (protection from photoaging, a.k.a. anti-wrinkling) is a cosmetic improvement, which makes it easier for FDA to argue that additional risks are unjustified. Retin-A has wide visibility among the general public and on Capitol Hill where Rep. Weiss has kept the issue alive with a report issued in September 1990 and the June 11 hearing. J&J fits the recent FDA pattern of choosing an image-conscious industry leader to set an example. FDA and Justice, however, face some substantial hurdles in pressing the case. Primarily, it may be difficult to prove that Ortho had an indirect campaign to promote off-label use. One key to the investigation will be the January 1988 press conference sponsored by Ortho one day in advance of publication of an article in the Journal of the American Medical Association on an initial photoaging study of 30 patients. The government will be obliged to show that the press conference was handled primarily as a promotional vehicle. The company is said to maintain that the researchers were going to announce their results at a press conference themselves. Ortho stepped in to sponsor the press conference to have more control over the way the results were discussed. The firm partly had funded the study reported in JAMA. When the initial media response to the press conference exploded, Ortho quickly issued a follow-up press release stating that the photoaging use was investigational. The agency may have to make the press conference suffice for a pattern of violations unless it can show that the company continued to stimulate interest in the off-label use of the product. FDA reportedly debated the appropriateness of the initial reports with J&J in correspondence after the event. The company was not issued a regulatory letter about the press conference. The Weiss committee previously collected information on honoraria and consulting payments to researchers involved in the Retin-A work during the period of media attention. Those payments could also be examined as evidence of a designed promotion campaign, making the researchers in essence paid promoters (or "evangelists" in a term recently used on Capitol Hill). FDA Commissioner Kessler put the medical community on notice at the Weiss hearing that physicians involved in illegal promotions of drugs for unapproved uses will be pursued by FDA with the "full force of the law" (see box). If the agency is counting on J&J to fold in front of the threat of the Justice investigation and become a visible example of the agency's renewed strength (like Procter & Gamble in the Citrus Hill "fresh" labeling challenge), the agency may have misjudged its opponent. By referring the case to Justice, FDA may have reduced the chances that J&J can arrive at a face-saving agreement with the agency. FDA and Justice were recently successful, however, in an unapproved indication promotion case against ICN. The government got the firm to agree to a civil fine and court costs ($ 600,000) to avoid a potential criminal prosecution concerning the use of Virazole in treating AIDS ("The Pink Sheet" June 3, p. 7). The investigation does not create a favorable climate for Ortho's further development of the photoaging claim. J&J filed an NDA for Renova, a separate tretinoin formulation designed for the photoaging use, in July 1989. Although the clinical portion of the application remains under FDA review, a part of the NDA was withdrawn March 29, 1991 so that the company could develop answers to agency questions about the formulation, a J&J spokesperson said. The company expects to resubmit the withdrawn portion of the NDA "by August." Two university dermatologists testified at the Weiss hearing that studies purporting to show the efficacy of tretinoin for photoaging are not adequately controlled trials. Georgetown University Assistant Professor Robert Katz, MD, maintained that "there is not one controlled study in existence except for the British study that showed that Retin-A was no more effective for the parameters measured than an abrasive soap." Katz said that "each of these studies published, including the one last month," began as double-blind studies in that patients were given unmarked tubes of cream; however, as soon as the product was applied, the subjects and the clinicians knew whether the product was tretinoin or the control, depending on whether it caused skin irritation. Therefore, Katz said, "the investigator and patient knows what is being used." Furthermore, he added, improvement in "fine wrinkling" is a "very subjective" endpoint. University of Illinois at Chicago Dermatology Professor Lawrence Solomon, MD, maintained that normal double-blind standards "may not be totally appropriate" for studies of a topical drug like Retin-A that irritates the skin. Instead, "it is appropriate" for such studies to use "bilateral" test methodology in which the test drug and the control are applied to opposite sides of the face, he said. "Try on the same patient the drug and the placebo, side by side, and we should be able to see the results," if the drug is effective, Solomon said. The Retin-A studies "don't do that . . . because [the drug's benefit] may not be obvious." Solomon suggested that monetary penalties be imposed sufficient to eliminate any financial gain from illegal promotions. "It is necessary to make the fines equal to the profits, and then" companies that promote illegally "will stop doing it," he said. "When a company earns vast amounts of money from the promotion of a drug, and when the fine for its misuse is tiny, [the company is] going to continue to do it -- it's good business," Solomon reasoned. "You have to empower the FDA with the right to appropriate fines for inappropriate promotions." Journal of the American Medical Association Editor George Lundberg, MD, suggested that it would be better for FDA to withdraw a drug from the market entirely rather than try to force the medical profession to prescribe it only for labeled indications due to safety concerns about unapproved uses. "I think I probably would rather have FDA consider withdrawing a drug from the market for adverse effects, if those adverse effects come from any kind of use," Lundberg said. "Mostly it's a question of educating the physician so that the physician can calculate the risk-benefit ratio in a given patient at a given time, based upon the best information available." Lundberg noted that one challenge is to make sure that scientific reports and news reports on the reports do not appear as "advertorials." He praised the handling of information about the recent Glaxo study on sumatriptan. "Information was disclosed to us," Lundberg said, "that not only was the study supported by a grant from Glaxo Pharmaceuticals, and included 14 members of the Glaxo research group by name, but also that the lead author, Dr. Cady, owned Glaxo stock." FDA WARNING TO MEDICAL COMMUNITY ON PROMOTION OF UNAPPROVED USES Taken from Commissioner Kessler's June 11 testimony to Rep. Weiss "While long standing FDA policy permits an individual physician taking care of his or her patient to make a decision whether to use an approved drug for uses beyond labeling, the law is clear that the promotion of such uses is illegal. "Physicians may not, under the guise of scientific exchange, involve themselves in the manufacturer's promotion of unapproved uses. In no uncertain terms let me say to the medical community that we will subject not only the manufacturers but all those involved in the manufacturers' promotion to the full force of the law. . . . "We intend to act against instances of clearly violative behavior, whether by product producers or health care professionals, which present a public health hazard."
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