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Growth Hormone Cut Down at the Pass




 

GMHC Treatment Issues 1996 Mar 1; 10(3): 3

The FDA was in classic form on March 1, when Serono Laboratories' version of human growth hormone (HGH) came up for review as a treatment for AIDS-related wasting (see Treatment Issues, May, 1995). The hearing took place at a joint meeting of the endocrinologic and the antiviral drugs advisory committees. By the time the session was over, Serono's case had been demolished point by point by agency reviewers.

Growth hormone is one of several candidate therapies for AIDS wasting syndrome, defined as an involuntary weight loss of at least ten percent of normal body weight. At $1,000 per week, though, it is definitely the most expensive. During the hearing, Serono's case turned out to be built around two twelve-week trials (referred to as trial 5341 and trial 7033) with about 180 participants each.

By the end of twelve weeks, total body weight in both trials' growth hormone arms was up about 1.6 kg, but weight in the placebo arms was up, too -- 0.1 kg in the 5341 study and 0.4 kg in the 7033 study. The differences in weight gain in this second study were not statistically significant, although in the first study they were. Serono was able to supplement the weight gain data in the first study with evidence from that study showing significant increases in the proportion of lean body mass and losses in body fat among those on growth hormone.

Unfortunately, no body composition analyses were done in trial 7033, so Serono could not counter the impression that growth hormone made only a marginal contribution to weight gain -- a gain that could be nearly equaled through the nutritional assessment and counseling the placebo group received along with the HGH group. The benefits of HGH seemed to lie mainly in the first week or two of therapy, according to the FDA reviewer, Saul Malozowksi, M.D., Ph.D. Moreover, his reanalysis (using an "intent-to-treat" approach that included dropouts' experience) showed only a one kilogram weight gain for HGH.

The advisory committee, seriously put off by the lack of confirmation of HGH's benefits by study 7033, was nonetheless impressed by the testimony from patients and doctors of dramatic improvements in weight, strength and energy while on growth hormone. Much time was spent trying to define a subset of people with AIDS who would be the candidate population for "best responders" to HGH.

This salvage effort, too, was nixed by Dr. Malozowksi and the FDA, who produced a slide indicating that weight changes in both the HGH and placebo arms of the trials basically represented a conventional bell curve, with the HGH curve shifted only slightly in a more positive direction than the placebo one. Tellingly, both the greatest weight gainer (+14 kg over the twelve weeks) and the greatest loser (-12 kg over the same period) were receiving growth hormone.

In the end, the advisory committee voted against Serono's application seven to eight. Most of the eight opposing approval supported a suggestion from the nonvoting community representative on the panel, Bill Thorne of ACT UP/Golden Gate in San Francisco: that some kind of accelerated or conditional approval be granted while Serono conducts a third, confirmatory trial of growth hormone.

After the hearing, Mr. Thorne expressed his impatience with the company: "Serono seems completely inept. The data on responders were obscured by Serono's poor trial design and poor analytical technique. It would be dangerous to grant full approval as it is." In contrast, Donald Kotler, M.D., of Columbia University, who is a world authority on AIDS wasting and who appeared before the advisory committee as a Serono consultant, blamed the FDA: "I was real disappointed. The approval process was based on inaccuracies. Weight gain as the endpoint is wrong because the result is the product of two contradictory factors [loss of fat and gain in lean tissue]. The FDA said it had to be weight, but that's wrong� How can they have trashed HGH, when it is obviously an anabolic agent?" But it is Serono's own fault that it failed do body composition analysis in its second study. "Until 5341 was unblinded, which was after 7033 started, there wasn't as much appreciation of lean body mass," said Robert Kauffman, M.D., who is medical director of metabolic and immune therapy at Serono. "Lean body mass is the best way to look at HGH," he now concludes, with the benefit of hindsight.

Lean body mass results were not the only missing piece of information. Questions were raised during the hearing as to whether the proper dosage and length of administration had been adequately determined. Negotiations are now proceeding between Serono and the FDA over the conditions under which growth hormone might yet be approved. Certainly, some further data will be required to resolve all the uncertainties swirling around the therapy.



 


Copyright © 1996 -Gay Men's Health Crisis, Publisher. All rights reserved to Gay Men's Health Crisis (GMHC) Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, INC. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 Email GMHC. Visit GMHC

Information in this article was accurate in March 1, 1996. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.