Human Growth Hormone Not Recommended for Approval on Narrow Advisory Panel Vote

On March 1, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee, meeting with outside experts including some members of the Antiviral Drugs Advisory Committee, voted not to recommend approval for AIDS-related wasting for Serostim(TM), the recombinant human growth hormone produced by Serono Laboratories, Inc. The vote was eight opposed and seven in favor.

According to Bill Thorne from ACT UP/Golden Gate, who was the non-voting community representative on the panel and had gone to the hearing hoping the drug would be approved, some of those who voted no believe that growth hormone does work for the requested indication, but were very disappointed with the data presented by the company. He said the Committee clearly wanted to vote for accelerated approval -- which would have approved the drug for marketing, but required the company to do additional research -- but that the FDA asked the Committee not to vote on accelerated approval, since the company had not filed for it. Many physicians are dissatisfied with the outcome; they know growth hormone works for some patients, and want to be able to use it. (The drug is currently available through a pre-approval "treatment IND" expanded access program, but the paperwork for this program is difficult.)

What were some of the concerns about the data?

* Committee members feared that the dose requested might be too high. An FDA analyst said that the dose being sought was twice as high as that used in treating any other condition, and that this dose was not justified by data. Committee members were concerned, since human growth hormone can cause irreversible side effects. (Serono told us that all the other dosage information was in children, who often use growth hormone for many years -- and that no irreversible side effects occurred in Serono's trials.)

We have been told that Serono tried to present data showing that lower doses were inadequate, but the Committee did not allow it to do so. According to Bill Thorne, Serono did not seem to understand the procedure of the hearing. In the morning, Serono presented its data (which had also been given to members in a binder before the meeting). Then an FDA analyst critiqued Serono's presentation. In the afternoon, the Committee deliberated and then voted. Serono tried to interject at that time, but was told that during the Committee deliberations it could only respond to questions. It was not allowed to pull out bits and pieces when that suited its interests, after the FDA's critique. (Serono told us that it had 60 minutes to present 40,000 pages of their NDA -- new-drug application for marketing approval -- and that in other hearings, advisory committees often allow companies to address questions that arise, but this one did not. According to Serono, they brought thousands of slides and
could easily have cleared
up many of the questions.)

[Although not part of the hearing, other dosage issues were raised in the December 1995 issue of MEDIBOLICS, a newsletter on anabolic steroids and related medical treatments published by Michael Mooney in West Hollywood, California. One article indicated that Serostim appears to be deliberately formulated to prevent people from using lower doses without throwing some of the product away -- that Serostim, packaged in 6 mg vials, is "designed to be used within 24 hours after mixing, when every other growth hormone product in the world, including (Serono's) own product sold in Italy, called Saizen, is made to last 14 days." The difference is that Serostim left out an inexpensive preservative, meta-cresol, and therefore could have dangerous bacterial growth if kept over 24 hours after mixing. The article quoted an AIDS patient in San Francisco who had "constant excruciating joint pain and random outbreaks of oil-filled cysts on my face and upper body" using 6 mg either every day or every
other day, until learning
about the dosage controversy and reducing the dose, which required him to throw part of each vial away.

Another article speculated that the oral anabolic steroid oxandrolone (Oxandrin(R)) might work as well or better than growth hormone at considerably less cost -- even though it also is overpriced. Trials of oxandrolone should be finished later this year. The article also mentions injectable anabolics which might be very low cost alternatives for some patients -- testosterone cypionate for $8 per month, or nandrolone decanoate for $32 per month. (A third article in the same issue criticizes physicians who charge $45 to $60 for each injection, when patients who are paying out of pocket could inject themselves at home.)

MEDIBOLICS is published four times a year for $15 U.S., $22 Canada and elsewhere, P.O. Box 333, 836 N. La Cienega Boulevard, West Hollywood, CA 90069, fax 310/659-1597, email mmooney@a.crl.com.]

* Serono has provided Serostim to close to 900 people in its pre-approval treatment IND program (which charges for cost recovery, as allowed under the treatment IND regulations, although as many as 30% of the patients have received drug without charge through the company's indigent patient assistance). Usually such expanded-access programs provide important data on safety, toxicity, and the frequency of dose reductions due to side effects. Yet Serono never mentioned this experience in its presentation to the Committee -- even when directly asked by Sandra Hernandez, M.D., head of the San Francisco Department of Public Health, who served on the Committee. (Serono told us that they did not present this treatment IND data because it was not part of their NDA application, due to the timing of when the NDA was filed.)

* There is little information on long-term safety and toxicity, beyond 12 weeks -- although patients clearly need to use growth hormone for longer than that. (Serono told us that, of 259 volunteers enrolled in its long-term study, more than 40% were on the drug for more than six months, and about 5% were on drug for two years or more.)

* In one of the major trials presented to the Committee, there were actually more deaths in the treatment than in the placebo group. Apparently this difference was not statistically significant (meaning that it might have resulted from chance); still it is disconcerting, and emphasizes the need for long-term data. (Serono told us that there were similar numbers of deaths for people while on study -- that most of the deaths the Committee was discussing occurred off study. In almost all cases, these people had been off growth hormone treatment for at least three months. Serono will continue long-term followup.)

* The Committee wondered if there is a target population that can be identified that is likely to respond well to human growth hormone. Or is this a treatment to use in the hope that it will work in some percentage of the cases?

* Is the once-daily scheduling best? Or could the drug be taken less often?

Cost

Growth hormone at the Serono dose is expected to cost between $50,000 and $100,000 per year (Serono has not announced a price yet); its "cost recovery" for the treatment IND program charged $25 per milligram, slightly more than $50,000 per year for the 6 mg per day the company recommends, and the price of the approved drug will be higher than that. Serono has said that its recombinant human growth hormone, made from mammalian cells, is much more expensive to produce that other recombinant human growth hormone, made from E. coli. We have no way to evaluate this claim. We do not know how much difference the mammalian cell derivation makes, since the E. coli version does promote human growth over long periods of time.

The price of human growth hormone (at least the E. coli version) appears to be almost all profit, since a quite similar product to increase milk production in cows costs about two thousand times less. AIDS TREATMENT NEWS is trying to learn why the international price has stayed so high for so long, since recombinant human growth hormone is produced by independent companies, and competition would normally have led to price reductions. Incidentally, we have heard warnings about "underground" human growth hormone from Eastern Europe, which is not recombinant but prepared from cadavers, and could carry a fatal brain infection.

Negotiations

Bill Thorne, who has been involved in three-way negotiations between Serono, the FDA, and community activists, sees Serono as "attempting to contain whatever commitment they have in the future [by holding out for traditional approval]. And now the FDA is coming to doubt Serono as a source of data on its own product, and becoming reluctant to give even accelerated approval. The FDA does have the legal authority to grant accelerated approval even without being asked by the sponsor, although it is very reluctant to do so.

"We need to push the FDA to take charge of this situation and do what is right for patients -- meaning to grant accelerated approval, whether Serono requests it or not. Activists agree that the drug does work, and has been used in other patients for years without any side effect so frightening we cannot manage it, in comparison with the dangers of wasting syndrome, which is causing many preventable deaths."

Jeff Getty, also of ACT UP/Golden Gate, is trying to negotiate a $25,000 cap per year per patient. He has told Serono that without the cap, activists will oppose Serono's efforts to get traditional (vs. accelerated) approval, and also its effort to get orphan drug status which would lock in its monopoly for seven years.

Gina Cella of Serono told AIDS TREATMENT NEWS, "Everyone agrees that Serostim should not be denied approval; we are all working toward that end. We are in active discussion with the FDA; we are pleased to have the opportunity to continue discussions with them, to respond to their questions and present additional data as requested. We are committed to obtaining approval for Serostim in some form, full or accelerated approval. We are also committed to continuing research in AIDS wasting and the use of Serostim, and will continue additional study."

For more information on the negotiations around human growth hormone approval, contact ACT Up/Golden Gate, 415/252-9200, fax 415/252-9277.

Comment

To understand what happened it is necessary to look at it from several different points of view:

* One expert physician may have summarized the views of many by commenting that human growth hormone does something important which no other drug does -- and that used to be enough for approval (implying that it should still be enough for approval in this case). He sees Serono as very good in certain other areas, but inexperienced regarding its presentation to this Committee.

* Most of the Committee may have agreed with that view of the drug, in their hearts -- but their job was to decide if that case was proven by the data placed before them, and a slim majority could not agree that it had been proven.

* The company believes that it has the data needed to clear up some of the Committee's concerns -- but could not include everything in its one hour presentation, and later was not allowed to address other concerns after they came up.

* The FDA insists that accelerated approval must not become a safety net for drugs which fail to achieve traditional approval. (Otherwise the usefulness of accelerated approval could be destroyed, as payers would consider it second rate and refuse to reimburse.)

Hopefully the company will be able to resolve enough of the remaining issues to show the FDA's staff that Serostim can qualify for some form of approval.