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AIDS Treatment News
March 15, 1996

CONTENTS:

Indinavir (Crixivan(R)), 
Merck Protease Inhibitor, Approved

by John S. James
FDA approval of indinavir, Merck's protease inhibitor, was announced on March 14; the drug is expected to be available by March 25. For several months, indinavir will be made available under a temporary special distribution system, primarily through Stadtlanders Pharmacy. Merck's price to wholesalers will be $12 a day, or $4380 per year (retail prices are not known as this issue of AIDS Treatment News goes to press). This price is significantly less than the prices of the other two protease inhibitors now approved (from Abbott Laboratories, and Hoffmann-La Roche).

Indinavir has been studied in more than 2,000 people. It was approved under the FDA's accelerated approval regulations, based on 24-week studies which showed improvements in markers of HIV disease progression -- large viral load decreases, and CD4 count improvements -- especially when indinavir was used in combination with other antiretrovirals. Long-term studies are now ongoing to test the effect of indinavir in preventing clinical progression of HIV disease.

The package insert includes extensive prescribing information, lists of possible side effects, and key clinical trial results. "Crixivan must be taken at intervals of 8 hours. For optimal absorption, Crixivan should be administered without food but with water one hour before or two hours after a meal. Alternatively, Crixivan may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal, e.g. dry toast with jelly, juice, and coffee with skim milk and sugar; or corn flakes, skim milk and sugar.... To insure adequate hydration, it is recommended that the patient drink at least 1.5 liters (approximately 48 ounces) of liquids during the course of 24 hours." Administration with grapefruit juice decreased blood levels of Crixivan in one test. The dose of Crixivan is the same whether it is used alone, or with other antiretrovirals -- but the package insert should be checked for instructions on combination use, e.g. with ddI. A number of warnings and precautions, including interactions and incompatibilities with several other drugs, are also listed in the package insert.

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It is important to take the full dose consistently as prescribed -- without reducing the dose, skipping doses, or taking "drug holidays." But if a dose is missed, do not double the next dose. In case of nephrolithiasis (kidney stones or related symptoms, which have occurred in about 4% of patients taking indinavir), a short drug interruption may be considered.

For information on obtaining Crixivan, and on Merck's reimbursement assistance program which is called SUPPORT(TM), patients and physicians can call 800/927-8888, beginning March 18.

Note: At this time, the impression among treatment advocates is that overall, Merck's indinavir seems to be the best choice of the three protease inhibitors now approved. Still, those who can wait to start protease inhibitors may want to wait until more is known about how to use them in the best combination regimens to minimize viral resistance (which seems to be more of a problem with the Merck and Abbott drugs than it is with saquinavir, the Roche protease inhibitor). But those who do want to start indinavir within the next six to 12 months should know that there will be a limited supply of this drug over the next several months (depending on U.S. and international demand) -- and that those who seek indinavir immediately may have the best chance to obtain it. Any supply problem should end around autumn of this year, when new manufacturing facilities are scheduled to begin production. (We do not expect any shortage of the Roche or Abbott protease inhibitors.)

Since it is medically inadvisable to start indinavir and then discontinue (as that would encourage the development of resistant viruses, reducing future usefulness of this and certain other protease inhibitors), Merck is setting up a system to track prescriptions in order to make sure that refills are available for all who start using the drug. Current plans are to accept new patients into this system on a first-come-first-served basis.

If you expect to need indinavir in the near future, check with your physician now about getting it. But if you can wait, the supply and distribution problems should be over within a year -- and the drug may be more useful then than it would be now, since physicians will know more about how best to use it.


Ritonavir (NORVIR(TM)), 
Abbott Protease Inhibitor, Approved

With record speed, ritonavir (Norvir(TM)), Abbott Laboratories' protease inhibitor, was approved by the FDA on March 1, 1996 (one day after approval was recommended by the FDA's Antiviral Drugs Advisory Committee) -- and was for sale in some pharmacies within a week. For more information on the debates at the advisory meeting which recommended this approval, see "Protease Inhibitors at FDA Advisory Hearings," below.

Ritonavir is the only protease inhibitor which already has proven survival benefit (the others might work just as well, since they have comparable effects on viral load and CD4 counts, but they have not completed their clinical-endpoint trials yet, so no data on survival are available). But ritonavir has also raised more safety concerns than the others. It has strong interactions with many drugs used by persons with HIV; it should not be used concurrently with at least 22 of them, and requires dose reduction and/or monitoring with some others. Patients taking other medications must consult with their physicians before starting ritonavir. Abbott has prepared physician and patient instructions regarding potential drug interactions.

Other concerns are that ritonavir has little safety data beyond six months at this time. It strongly inhibits a specific liver enzyme, which presumably is in the body for a reason; blocking this enzyme for extended periods might cause problems. And we have heard more anecdotal reports of side effects with ritonavir than with the other protease inhibitors.

There is also the problem of resistance and cross resistance (especially cross resistance to Merck's Crixivan); this may be minimized by optimal use of the drug -- by combining it with two or more other antivirals, and by not missing doses or taking "drug holidays."

It is likely that many people who could afford to wait a few months or more before starting protease inhibitors may choose to do so. By that time, the Merck drug will also be available; and physicians will know more about which drugs to choose and how to make best use of them. Combinations may work best when a patient starts all the drugs in that combination at about the same time, without extensive prior use of any of them.

For those considering starting ritonavir now, we note some information from the package insert (the FDA-approved prescribing information for physicians). This document will be published in the PHYSICIAN'S DESK REFERENCE; meanwhile, patients may be able to get a copy from their pharmacist or physician.

Administration

Ritonavir is sold in two forms, capsules and oral solution. It should be taken with meals if possible.

"The recommended dosage of ritonavir is 600 mg twice daily by mouth. Some patients experience nausea upon initiation of 600 mg b.i.d. dosing; dose escalation may provide some relief: 300 mg b.i.d. for 1 day, 400 mg b.i.d. for 2 days, 500 mg b.i.d. for 1 day, and then 600 mg b.i.d. thereafter. In addition, patients initiating combination regimens with NORVIR and nucleosides may improve gastrointestinal tolerance by initiating NORVIR alone and subsequently adding nucleosides before completing two weeks of NORVIR monotherapy."

"Patients should be informed to take ritonavir every day as prescribed. Patients should not alter the dose or discontinue ritonavir without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patients should not double the next dose."

There is no children's dose, as there have been no studies of safety or effectiveness in children.

Drug Interactions

The package insert begins with a warning box: "Co- administration of NORVIR with certain nonsedating antihistamines, sedative hypnotics, or anti-arrhythmics may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs. See Contraindications and Precautions sections." Later text includes cautions and warnings about other kinds of drugs as well.

The warnings about drug interactions are too extensive to reproduce here. Patients and physicians should note that they appear in different sections of the package insert, including Special Populations -- drug-drug interactions; Contraindications; and Precautions -- drug interactions.

Tobacco use has been found to decrease ritonavir blood levels by 18 percent.

Adverse Events

After about three months of use of the drug in clinical trials, "the most frequently reported clinical adverse events, other than asthenia [lack of strength, fatigue], among patients receiving NORVIR were gastrointestinal and neurological disturbances including nausea, diarrhea, vomiting, anorexia [loss of appetite], abdominal pain, taste perversion, and circumoral and peripheral paresthesias [abnormal sensation]." Tables showing percentages of patients with dozens of other clinical and laboratory abnormalities which might be drug related are included in the package insert.

Because ritonavir can cause changes in some laboratory tests, certain testing should be done to establish a baseline before the drug is started. The testing should be repeated periodically during therapy, or if symptoms occur, to monitor for possible problems.

"Ritonavir pharmacokinetics have not been studied in patients with hepatic insufficiency." However, some patients with hepatitis have been included in the clinical trials of the drug.

Cost and Reimbursement

Ritonavir is the most expensive antiretroviral; Abbott's charge to wholesalers is $6500 per year. We could not get the "average wholesale price" (the price which wholesalers charge pharmacies) by press time. We found some confusion about retail prices; patients should check several pharmacies, including mail-order or other large pharmacies serving many persons with HIV, before making major purchasing decisions.

"NORVIR is indicated in combination with nucleoside analogues or as monotherapy for the treatment of HIV infection when therapy is warranted." This official language from the package insert should help in getting reimbursement from insurance companies which use FDA approval as the basis for their reimbursement decisions, as there are no CD4 or other stated limits for use of ritonavir. But many managed-care systems use their own formularies which do not include all FDA-approved drugs, so the FDA's approval language may matter less with them.

Because interrupting therapy can make one more likely to develop virus resistant to this and some other protease inhibitors, persons should avoid starting either ritonavir or indinavir unless they expect to be able to continue without interruptions.

For assistance in getting reimbursement for ritonavir, call 800/659-9050.


Protease Inhibitors 
at FDA Advisory Hearings

by John S. James
[Note: This writer was unable to attend the recent meetings of the FDA advisory committees, due to the flu. AIDS treatment writer Mark Mascolini helped with the research for our coverage of the protease inhibitor and nucleoside analog combination meetings.]

On February 28-March 1, four separate one-day meetings of FDA advisory committees took place at two different sites near Washington, D.C.

FDA advisory committees consist of outside experts (not FDA employees) who meet when requested and advise the FDA on drug approvals and related issues. While the FDA does not have to follow the recommendations of the committees, it almost always does. These meetings are important because they usually present more information and analysis about a potential new treatment than is available from any other public source. (Most FDA advisory committee meetings are open to the public, at least in large part, although sometimes closed sessions are scheduled to review confidential proprietary data.)

The Antiviral Drugs Advisory Committee, which reviews most AIDS drugs seeking marketing approval, held three of the hearings -- on recommendations for indinavir (Crixivan(R), Merck's protease inhibitor); ritonavir (NORVIR(TM), Abbott's protease inhibitor); and also on usage of AZT/ddI/ddC, in view of new data from major clinical trials. Also, the Endocrine and Metabolic Drugs Committee met separately (at the same time as the indinavir hearing) to review the request for approval for human growth hormone to treat AIDS-related wasting. This article reviews the hearings on the two protease inhibitors; the human growth hormone hearing is examined in a separate article, below, and the meeting on new recommendations for use of the older drugs will be covered in a later issue of AIDS Treatment News.

Indinavir (Crixivan) -- Merck's Protease Inhibitor

The March 1 indinavir hearing was the smoothest of the four meetings, mainly because Merck & Co. had the data and trials it needed to support the recommendation it was asking for.

Merck was seeking (and has now been granted) clearance to market indinavir under the FDA's "accelerated approval" regulations. Accelerated approval allows an HIV treatment to be approved based on CD4 count and viral load improvements in clinical trials -- provided that larger trials are in place to also prove clinical benefit to patients, such as longer survival or fewer opportunistic infections.

About 2,000 volunteers have now taken indinavir at the currently accepted dose (800 mg every 8 hours); 600 have taken this dose for at least six months, and 250 for at least a year. The main safety concerns have been an increase in bilirubin (but without evidence of liver toxicity), and kidney stones or related symptoms in less than three percent of patients. The most common (but less serious) side effects are rash, dry skin, and altered sense of taste.

Merck reported results of several trials, and they are consistent with what was known before. More information on specific trial results (some of which were never presented publicly before this meeting) is available through NATAP, the National AIDS Treatment Advocacy Project; for contact information, see "FDA Hearings: For More Information," below.

While drug interactions are much less of a problem with indinavir than with ritonavir, indinavir does have important interactions several other drugs. Dose adjustments are required in some cases; other drugs cannot be used at all with indinavir.

At the end of the day, the Committee recommended accelerated approval for indinavir -- recommending combination treatment when possible, but with an option for indinavir alone for people who cannot tolerate the nucleoside analogs.

Ritonavir (NORVIR) -- Abbott's Protease Inhibitor

The February 29 meeting on ritonavir was more difficult than the indinavir meeting. It was followed by a private late- night meeting between Abbott and the FDA, during which final agreements were negotiated. On the following day, Abbott distributed a letter announcing that it would conduct trials to provide certain additional data; and the FDA announced that ritonavir would be approved.

The reason the Committee meeting was difficult is that while Abbott came in with the best results so far for any HIV treatment -- clear evidence that the drug substantially reduced the risk of death and of opportunistic infections in a major trial -- other important information was unavailable. For example, there is little information on safety or efficacy beyond six months, which is especially worrisome for a drug with important safety concerns. There are no pediatric data. Information is inadequate on how well the drug works in people with earlier stages of HIV infection (the trial which showed clinical benefit was only open to those with CD4 counts under 100).

There were many different ideas on the Committee, and much discussion, about what proof was needed for efficacy in earlier disease. The issue is that the accelerated approval regulations require subsequent trials that show direct clinical benefit to patients, to eventually back up the early approval which is based on improvements shown in blood tests, like CD4 count and viral load. But it has always been very difficult -- and is now almost impossible -- to prove delayed disease progression in persons with high CD4 counts, because it will take many years for enough volunteers to get sick to provide statistical proof of benefit, and people are unwilling to stay on the same treatment that long while better treatments are becoming available. (The proposed "symptom reduction trials" to get around this problem -- see AIDS Treatment News #228, #229, and #231 -- have not caught on at this time, probably because while they could provide clinical proof of benefit quickly, they would not provide long-term balance of risks and benefits, especially for asymptomatic patients.)

The compromise that seemed to win wide acceptance at the FDA advisory meeting was a long-term surrogate marker (CD4 and viral load) and safety study, which would use the clinical endpoints of illness and survival primarily to assure safety, while using CD4 and viral load changes to test for durability of response to the drug. The private meeting that evening built on this idea, with Abbott agreeing to "provide long- term follow-up safety and clinical endpoint data from ongoing studies M94-247 and M94-245 to assess the comparative clinical efficacy and safety data in patients with advanced stage disease versus patients with early stage disease." Also, Abbott agreed "to provide data from a study in patients with higher CD4 cell counts (>100 cells/microliter) looking for durability of response by evaluating CD4 response, HIV RNA response and safety from a study comparing ritonavir to ritonavir+saquinavir." And Abbott agreed "to participate in a clinical study to define the safety and clinical efficacy of ritonavir in pediatric patients."

With these agreements in place, the FDA sent Abbott an approval letter "for the use of ritonavir in combination with nucleoside analogs or as monotherapy for treatment of HIV infection when therapy is warranted." The labeling (information for physicians) will describe the evidence on which the approval is based, and the limitations of this evidence for late-stage and also for early-stage HIV disease.

Ritonavir Comment

The key issue for the Committee seems to have been the balancing of risks and benefits in early disease, especially because the drug has important safety issues and no long-term safety data. The resolution which resulted left physicians and patients with maximum flexibility in the use of this drug. We believe this decision was the right one -- but that the success of this drug will depend on Abbott's ability to educate physicians, pharmacists, and patients on how to use ritonavir correctly, and on the company's continued ability to rapidly conduct the research on which this education must be based.


FDA Antiviral Hearings: 
Community Perspectives

Dave Gilden, Gay Men's Health Crisis:

[Since we did could not attend the FDA's Antiviral Drugs Advisory Committee hearings, we asked people who did attend to comment on drafts of our report. Dave Gilden, editor of TREATMENT ISSUES, sent us the following, which we found insightful and important enough to quote in full, with his permission.]

Gilden: "My sense about the FDA is that the people there have become convinced that a four drug combination will be highly effective in suppressing HIV. Researchers like David Ho are arguing that three drugs will provide long-term viral suppression but that you need four drugs to insure that there is no pre-treatment mutant HIV able to resist the entire drug combination -- or to prevent eventual emergence of such virus.

"The FDA is therefore determined to push the necessary drugs through the approval process, whether the data on each one is complete or not. The other issue affecting the FDA deliberations is the FDA reform movement in Congress, which the FDA is countering in part by showing how decisively it can act when the situation calls for rapid drug approvals.

"Therefore, I watched the spectacle of ritonavir getting the kid glove treatment from FDA reviewers, and David Kessler pushing for full approval, while I saw Serono and human growth hormone get positively torn apart the next day. We can expect easy treatment for nevirapine and delavirdine too, even though the available data on these drugs' benefits is weak indeed. These two non-nucleoside reverse transcriptase inhibitors will then be the fourth drugs in the four-drug regimens, along with one or two nucleoside analogs [e.g., AZT plus 3TC, or ddI] and one or two protease inhibitors. Viral load testing, central to optimizing and periodically adjusting the four-drug regimens in each person, now seem to be on the FDA fast track, too. (The Hoffmann-La Roche PCR test will be considered by the Blood Products Advisory Committee on March 21.)

"Speaking of using two protease inhibitors, the upcoming ritonavir/saquinavir trial assumes tremendous importance in this four-drug scenario. I would put more money on using two protease inhibitors, especially if there is little cross- resistance, than adding a non-nucleoside reverse transcriptase inhibitor. Saquinavir is extremely potent in laboratory tests, and ritonavir may rescue its disappointing performance in the body. [Caution -- these drugs will require extreme dose adjustment when combined, and must not be used together until safe doses are known. Near-fatal side effects have occurred from combining protease inhibitors inappropriately. JSJ]

"In the meantime, the most treatment-savvy PWA I know is arguing that Merck's indinavir looks better than ritonavir, from the available data, and that we should not be swayed by ritonavir's full approval for advanced disease. He is not alone in this opinion. The arguments favoring indinavir are: better safety (though neither compound has much long-term data), better patient compliance with the recommended regimen (important to avoid breakthrough drug-resistant HIV), fewer evident drug-drug interactions, better CNS (central nervous system) penetration, data indicating activity in lymph nodes, and indications of greater durability of antiviral response (at least as monotherapy). Abbott also has a much worse record of working with the community, and the chances are weak of the company now trying to fill the tremendous gaps in our knowledge of how to use protease inhibitors. In particular, we need to know how well the individual brands work over the long run, when best to start protease inhibitors (which is highly influenced by the durability of response issue), and what to follow these compounds with should they start to fail."

[TREATMENT ISSUES, "the Gay Men's Health Crisis newsletter of experimental AIDS therapies," is published monthly; annual subscriptions are available for a suggested contribution of $35 for individuals, $70 for physicians, institutions, or international subscriptions; a full set of back issues is available for $25. Make checks payable to GMHC, and mail to: GMHC, Treatment Education, 129 West 20th Street, 2nd floor, New York, NY 10011.]

Martin Delaney, Project Inform:

[The following are from a February 29 press release by Project Inform, supporting accelerated approval of ritonavir, but expressing caution about how the drug should be used.]

Delaney: "While this [improved survival] outcome is significant, it overlooks two other important facts from the study. It is our understanding that the majority of the deaths reported in this data occurred within the first six weeks of treatment, raising questions as to whether the outcome reflects the true longer-term effect of the drug. More importantly, we are very concerned that the data shows a rapid loss of antiviral activity, probably due to the development of drug resistance, within six months when used in this fashion. Since resistance to this drug confers resistance to most other protease inhibitors, there is good reason to fear that such a use of the drug may lead only to short-term benefit followed quickly by long-term multi-drug cross resistance to many of the key products in the field of protease inhibitors. There is evidence that the drug can work far better when used properly; giving too much weight to this data may promote use of the drug in this suboptimal fashion."

"We think it is critical that Abbott make clear to physicians and patients that great care should be employed in how these drugs are used. Simply adding them without thought to existing therapy is unlikely to produce a lasting benefit, while running a large risk of creating multi-drug cross resistant strains of virus."

A position paper available through the Project Inform hotline (800/822-7422, 10 a.m. to 4 p.m. Pacific time Monday through Saturday) describes these concerns in greater detail, and provides guidelines for the optimal use of protease inhibitors, based on what is known today. It will be published in the April 1996 issue of PI PERSPECTIVE.


FDA Hearings: 
For More Information

The most authoritative information about each of the three protease inhibitors now approved is the package insert for each drug. Incidentally, Merck is planning to work with the FDA to develop a patient's version of the package insert for indinavir.

Later, a full transcript and also a summary of each advisory committee hearing will be available from the FDA.

Probably the most in-depth public information at this time about the protease inhibitors is available through Jules Levin's National AIDS Treatment Advocacy Project; it includes a review of each clinical trial of the drugs, and the resulting data. If you have a World Wide Web browser, you can receive it immediately at http://www.aidsnyc.org/natap. Jules can also be reached by email at JuLev@aol.com, or day or evening by phone at 718/624-8541 or by fax at 718/624-8399. His mailing address is NATAP, 72 Orange Street, Brooklyn, NY 11201.

In addition to information from these recent hearings, NATAP also has a 45-page booklet on the five protease inhibitors likely to be the first available -- saquinavir (Roche), ritonavir (Abbott), indinavir (Merck), nelfinavir (Agouron), and VX478 (Vertex / Glaxo Wellcome). Also available is a 4- hour videotape of NATAP's community forum on protease inhibitors, January 6, 1996, in New York.

Note: As this issue went to press, NATAP announced a free community forum on protease inhibitors in Los Angeles, April 13, 1996, from 1:00 p.m. to 4:40 p.m. in the Paramount Theater, 5555 Melrose Ave. (enter at Bronson St. gate). This event is also sponsored by Kraus Medical Partners, and Being Alive -- and co-sponsored by 17 other AIDS organizations. For reservations, call 800/238-7828, ext. 8145. For more information, contact NATAP at the above computer addresses, fax number, or phone number.


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

by John S. James
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.


Consensus Statement 
on the Further Development 
of Protease Inhibitors 
And Human Growth Hormone

[The following consensus statement is an excellent summary of what is needed today in AIDS treatment research. It also reflects new common ground, after the long-running, so-called "East Coast/West Coast" disputes among AIDS treatment activists (over whether to emphasize better "answers" through more rigorous clinical trials, or faster "access" to new treatments by patients and physicians). David Barr of Gay Men's Health Crisis and Martin Delaney of Project Inform organized and led the meeting that developed this statement. JSJ]

We, the undersigned individuals and organizations, represent hundreds of thousands of people with HIV infection in the United States. We are excited and hopeful that the therapies being reviewed for approval this week (two protease inhibitors and human growth hormone) can provide a substantial benefit for people with HIV. However, approval of these products is not the end of the process of drug development. In order to provide real access and information about how to use these drugs safely and effectively, we call on the Food and Drug Administration, the National Institutes of Health and the pharmaceutical industry and third-party payers to meet the demands outlined below. Failure to do so will seriously undermine the value that these therapies will offer to patients today and in the future.

  1. Approve both indinavir and ritonavir for people with HIV infection for whom anti-viral treatment is indicated based on immunologic, clinical and biological markers. Approve human growth hormone for the treatment of wasting syndrome.
  2. Whatever regulatory mechanism is used for approval, industry and government must agree to engage in post- marketing research to answer key unanswered questions about safety and efficacy. In order for this research to be effective, it will require a collaborative effort between industry, government, academia and community heretofore unseen in AIDS research. The commitment to engage in this effort quickly should be of paramount importance. We insist that a strategic plan be presented for achieving these goals by the time of the 11th International Conference on AIDS, to be held in Vancouver in June, 1996.
  3. The following is a list of questions that we agree must be answered as soon as possible. The list is not meant to be exhaustive, but rather to highlight those issues we believe are of highest priority:
    • When in the course of HIV disease should anti-viral treatment generally be initiated?
    • Which treatment regimens should be used as initial therapy?
    • What are the best strategies for using combinations of anti-viral drugs, including protease inhibitors, for nucleoside-experienced patients?
    • When should people switch or stop anti-viral treatment regimens
    • What is the pharmacokinetic and long- term safety profile on protease inhibitors?
    • To what level must viral load be reduced and sustained to successfully halt disease progression?
    • How will pediatric formulations of protease inhibitors be developed and studied?
    • What is the effect of protease inhibitors on perinatal transmission?
    • What is the optimal dose of human growth hormone, alone or in combinations?
  4. Approve viral load test kits for clinical management now, not in six months. This is essential if we are going to be able to use these treatments effectively.
  5. Provide protease drugs and growth hormone, at no cost, to all former and current clinical trial and expanded access program participants and collect long-term safety data from this group. This would provide the easiest and fastest way to get such information.
  6. Promotional and educational materials must be developed and made available to doctors, patients, pharmacists and health educators immediately to inform them about safe and effective use of these products particularly around issues of compliance with treatment regimens and drug interaction problems. Community and consumer input into the development and distribution of such materials is essential.
  7. Reimbursement decisions should be driven by clinical and/or surrogate data from controlled clinical studies.
  8. Prices for these drugs must be fair, reasonable and sensitive to the current crisis in health care funding. Each company must guarantee treatments to those who have no other means of access or less than full coverage through patient assistance programs.
  9. At minimum, pharmaceutical companies must agree to provide AIDS Drug Assistance Programs with similar rebates that are given to Medicaid programs.

[Over 30 organizations have already signed this statement, including AIDS Action Council, AIDS Research Alliance, AIDS Treatment News, American Foundation for AIDS Research, Center for AIDS Prevention Studies, Critical Path AIDS Project, Gay Men's Health Crisis, Healing Alternatives Foundation, National Association of People with AIDS, Pediatric AIDS Foundation, Project Inform, PWA Health Group, San Francisco AIDS Foundation, and Treatment Action Group.

Organizations can sign by contacting Ben Cheng or Brenda Lein at Project Inform, 415/558-8669 ext. 221 or 214, or David Barr at GMHC, 212/337-1904.]


AIDS and Alternative Medicine, 
Seattle, April 28

Bastyr University and the Bastyr University AIDS Research Center will present AIDS and Alternative Medicine: Current State of the Science, a continuing education program for medical practitioners and researchers. This one-day program will be held in Seattle on April 28 at the Washington State Convention and Trade Center, 800 Convention Place, Seattle, WA 98101.

Speakers include Lark Lands, Ph.D., John S. James, Candace Pert, Ph.D., Leanna Standish, N.D., Ph.D., and others.

Registration is $125 for practitioners, $75 for students; there is a $10 discount if paid by April 12. For more information about registration, including continuing education credit, call Bastyr University's Department of Continuing Education, 206/517-3577.




  
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This article was provided by AIDS Treatment News. It is a part of the publication AIDS Treatment News.
 

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