AIDS TREATMENT NEWS Issue #207, September 16, 1994
John S. James

The September 12-13 meeting, near Washington D.C., of the Antiviral Advisory Committee (a group of outside experts set up by the U.S. Food and Drug Administration to advise the agency on matters related to the approval of HIV treatments and other antiviral drugs), focused on the system of "accelerated approval" -- which allows drugs for serious or life-threatening conditions to be approved early, based on favorable results of certain blood tests, with the much longer trials required to prove clinical efficacy being completed later. (For background on this meeting, see AIDS Treatment News #205, August 19, 1994.)

Anyone could sign up to address the panel, and over 30 did so -- including physicians, people with HIV and their friends and family members, activists on AIDS, cancer, and healthcare, and others. Most spoke for five to ten minutes. Most addressed the access and answers controversy at some point in their talk.

Readers should note that the meeting made no decision -- it was intended to hear views and suggestions on how the accelerated approval process is working, and how it might be improved. The FDA leadership remains firmly committed to accelerated approval; no formal changes in the regulations, nor major changes in emphasis, are expected at this time. And the interested public (as shown by the comments below) also remains strongly supportive of early access to treatment, through accelerated approval and through other mechanisms -- although almost everybody also agrees that the drug- development system must be improved, to produce better drugs and also to give patients and physicians the information they need to use available drugs effectively.

While the bitterness of the dispute now seems to be receding, the controversy remains critically important because of its potential to influence (and to damage) both research and patient care. If, as some are coming to suspect, the whole controversy is in some ways centrally misguided -- if the research strategies we should be pursuing do not require tradeoff between individual patient care and scientific advance -- then it may turn out that sacrifices made to "balance" access with answers will have actually have been made for nothing.

The Public Testimony

Public testimony was scheduled in three sessions of the two- day meeting. Other sessions were reserved for discussion among the Advisory Committee members themselves, or for testimony by invited experts. All sessions at this meeting were open to the public, and about 150 people attended.

The Antiviral Advisory Committee currently consists of ten members, mostly from academic and government medical centers. This session was also joined by five members of the National Task Force on AIDS Drug Development, four past members of the Antiviral Advisory Committee, and three other guests, two representing community groups and one from the U.S. National Cancer Institute.

AIDS Treatment News has chosen to present the public testimony by quoting indirectly some of the main points made by the speakers. Each bulleted paragraph or section below represents a different speaker. Almost all the speakers are included; a handful are omitted because we did not take adequate notes. Because we worked from our notes, summarizing speakers' statements in our own words, and could not check with over 30 speakers to make sure we quoted them correctly, we did not quote anyone by name.

Our report below only includes the public comment -- not the discussion among the panelists. The panelists did well, and their discussion was among the most interesting of the meeting. But it needs to be presented in a different format, perhaps in the context of an article focusing on research strategy. The panelists share much background information and leave much unstated when they speak with each other; presenting highlights, as we did with the public testimony, would not be effective.

We tried to keep our own opinions out of the selection and summarizing of the public testimony; some of the statements below are ones we strongly disagree with. But it would be impossible to summarize two days of talks in an eight-page newsletter and eliminate the influence of one's own viewpoint. Those who want more information can obtain the full transcript from the FDA; see below for instructions on how to do this.

We left speakers quoted below in chronological order, as trying to categorize them would be misleading. Brackets indicate material we added for clarification -- or statements by panelists in response to the speaker.

* * *

* Three hundred thousand have died, and we worry about data. I can't give my patients protease, antisense, gene therapy; they're being protected until they're dead. So they go abroad for "cures."

You can open the journals and easily find 50 compounds that inhibit the virus -- but are not being tested.

How many people have died from agents that have made it through phase I [early dosage and toxicity testing]? We have FIAU [a hepatitis treatment which did pass phase I, but then killed several people in later trials]. But there are errors of omission, too, when needed drugs are not available; [these are not balanced because] the blood is not on your hands, the people just died.

* There are natural antivirals with less down side than synthetic drugs. You won't find people in emergency rooms from aloe, turmeric, bitter melon. Many people are surviving, but are not counted, as they are not in bureaucratic structures; they don't want the abuse they would take if they came forward. * When people with AIDS get drugs under the parallel track or "treatment IND" systems, the drugs are usually free, but the associated expenses [such as doctor visits, required labs] are usually not reimbursed by Medicare/Medicaid or most private insurance, but paid out of the patient's pocket; this creates economic barriers to those programs. It is different in cancer, however; with "Group C" cancer drugs, these barriers do not apply. This is because of a 1980 interagency agreement between NIH [the U.S. National Institutes of Health] and HCFA [the Health Care Financing Administration], which recognized the need to fund research in new cancer drugs. With this unique HCFA reimbursement policy, patients are reimbursed for the cost of Group C drugs, and expenses related to their use in trials.

Group C drugs are distributed by the National Cancer Institute, only to physicians registered with NCI who agree to use specific protocols.

This system should be rationally applicable to AIDS.

[Note: One member of the panel commented that he had been at the National Cancer Institute at the beginning of Group C. The NCI had a series of drugs with no industry sponsor, but with established safety and efficacy for particular indications. These drugs would have been ready for marketing, if they had an industry sponsor.]

* One woman told about the death of her oldest son, of cryptosporidiosis. She had heard that bovine colostrum might help, but was unable to obtain it. Now she is sure that accelerated approval has kept her other son, and a close friend, alive. But neither is qualified for a protease inhibitor trial. Without accelerated approval, there will likely be a two to five year trial before protease inhibitors are available.

Her surviving son had severe dementia; it was treated with AZT, and he had a miraculous response. But how long will it last with one drug alone? He may need a protease inhibitor.

* Another speaker said that accelerated approval had saved his life. We cannot go back to the "days of panic when your drug stopped working."

* The idea that some are against accelerated approval is ridiculous; the question is, what is the evidentiary standard? We need different methodologies, not just one. You can collect long-term safety and efficacy data and still remain flexible.

There is a tendency to believe that a drug is better than no drug, and that a new drug is better than an old drug. In many cases that's not true.

* The issue is access to drugs vs. access to proven drugs -- process based on belief, vs. process based on reason. If you compare astronomy students with readers of astrology columns, the latter is by far the largest and most vocal. It is disappointing to see the same trend away from reason and toward belief in the HIV community.

Trials have failed to provide the answers, leading to a cult of individuality, access to any drug with evidence of efficacy. But should we hold future trials hostage to individualistic needs? Instead, defer rights of access for long-term benefit; altruism means the individual giving up some benefit for the group. Otherwise most people will be left out; the majority of people with HIV worldwide will never have access, accelerated or otherwise, to any of the treatments discussed here. And a trend toward scientific illiteracy is leading to chaotic drug testing.

Saving lives and acquiring data are not mutually exclusive. I want to live, but I want my death to be meaningful to future generations. It is time to work together for answers for the future, for people who will never have the opportunities that we have today.

* Nothing is more important than access to treatment. After phase I, drugs with potential should be made available through accelerated approval, while the FDA commits to large- scale efficacy trials.

[One of the guest panelists then challenged the speaker, asking how do you make treatment decisions? When do you switch drugs? What combinations do you use? We don't have the data to make decisions, that's the bottom line. People with AIDS need a rational game plan; stop this nonsense about some people being against access vs. some being for access.]

* There is a tension between patients wanting access, vs. difficulty in initiating and completing studies of new agents. FDA approval is a key step; but after approval, incentives to sponsor controlled trials change substantially. Despite only two years for approval of AZT, activists insisted on parallel track for its cousins. One undesirable result is that little information is generated to guide physicians. This becomes worse as more drugs become available. * The next speaker, an economist, said that accelerated approval increased the ROI (return on investment) for companies developing AIDS drugs. This impacted on the development of cancer drugs, since there is only so much capital to go around. The FDA could have anticipated this if it had a management advisory committee with business experience. Also, the FDA needs a bigger budget. And we must have one set of standards for all life-threatening conditions.

* Drug approval is not the problem; the problem is the infrastructure of clinical research in this country. We strongly support accelerated approval as written, but it has not been fully implemented. The FDA has not insisted on adequate and well-controlled trials. We don't need to change the regulations, but we do need to improve the process. When accelerated approval is given, the sponsor must already have under way studies likely to demonstrate whether or not the drug prolongs life. Unless clinical efficacy studies are underway, we will never validate surrogate markers. And efficacy trials are most likely to succeed if we start now.

I am not proposing to delay approval; just have a good trial going first.

Before accelerated approval, expanded access (such as the parallel track program) is almost a moral requirement to show real-world safety. What if accelerated approval is given, and then there is a ghastly side effect? Expanded access is insurance that this won't happen.

[Note: This speaker suggested a "large simple trial" design for the expanded access program. In this kind of trial, many thousands of patients are assigned at random to the drug being tested, or to placebo or other treatments. Very little data is collected -- often no more than whether the volunteers are still alive -- which makes this very large trial possible. One advantage of the large simple trial is that it can enroll a great diversity of patients, obtaining real-world experience.

[But panelists and others pointed out, here and at other times during the two-day meeting, that the successful experience with large simple trials, for example with heart- attack treatments, has almost always been on drugs which are already approved, so that side effects and other information are known. (Some of the existing expanded-access programs for AIDS drugs have in effect been large simple trials, well before the drug was approved; but these programs randomized patients to different doses of the same drug, not to drug vs. placebo. These trials have provided useful safety information, but little if any reliable information about the drug's efficacy.)]

* Early access through accelerated approval, and the right to have information, are not mutually exclusive. The key issue is to avoid delay, develop drugs as rapidly as possible, and improve the process.

Many master protocols have been proposed; people get excited, but so far the plans have never gone anywhere. The FDA should look at these proposals and say if they are useful or not. Usually the impetus must come from the FDA and the NIH, not from drug companies, as many different drug companies will be involved (and they usually don't work well with each other). [Note: A master protocol is a standardized way of testing many different drugs -- including new drugs which may be unknown when the trial is designed and started. This kind of trial can save time, because when a new drug is ready to test, it can be plugged in to the existing system, without waiting for some of the paperwork, approvals, recruiting, etc., of designing a new trial from scratch. An industry group, the Inter-Company Collaboration on AIDS Drug Development, has designed a master protocol to test combination antiviral therapies, and plans to start enrolling patients later this year.]

* What will the FDA do if the accelerated approval of d4T or other drugs is not confirmed in larger clinical trials? Given political reality, it would be virtually impossible to withdraw the drug; also, it would be exceedingly cruel.

The problem is that the current system is not giving us the answers we need. Would it be better to begin with a combination treatment? Is any drug better than nothing for early treatment? The benefit of the nucleoside analogs (such as AZT) vs the risks has never been confirmed.

The FDA is not using its policing powers effectively. Companies do not want to spend money on trials of monotherapy, and patients don't want to enroll in these trials; as a result we will never get the missing answers. The current system won't work unless there is a home-run drug. We have a lose-lose situation precipitated by the current regulations. We don't need to develop drugs slower, just better.

* Accelerated approval should remain intact. When a drug is known to be safe, people with life-threatening illness should have the option of trying it.

Of course we want to know how these drugs work in women's bodies; but today's trials won't tell us. Research which excludes women must be redesigned.

* My patients in East Harlem will never be involved on a large scale in a trial with a placebo. There is a history of distrust.

And I will not sell them on an ineffective trial. These patients are already burdened. It is time to stop the choke- hold on money for treatment. We need changes in the system, and in the faces of so-called activism. It is genocide in the name of activism to stop early access to drugs, giving some people the power of life and death over others.

The system must include previously neglected communities. There are 1.2 million inmates in the U.S. today. There must be an agenda, epidemiologically oriented, for counseling, prevention, and treatment. Prisoners far exceed the general population in the U.S. in the incidence of AIDS.

* I see no hope in this conversation. It is just pushing statistics.

* We see no compelling reason to change the rules for accelerated approval, just because there is a new class of drugs. Almost everyone agrees that the FDA will eventually approve saquinavir [the Hoffmann-La Roche protease inhibitor]. But when? There should be accelerated approval when the drug is safe, and shows some promise of effectiveness. This may be as soon as data becomes available from an interim analysis of phase III studies. * We are mistaking the discussion of how to get better data from clinical trials, with accelerated approval. That's why we're at each other's throats. We must get better data, but in no way at the expense of accelerated approval. We all want better data. But we must ask, what price are we willing to pay for it? If we want to know about a small difference in drug efficacy, then how small a difference, and how much do we pay to get it? There is a widespread perception that we already spend too much time studying marginal drugs.

We could approve accelerated approval by doing a better job in phase II pivotal trials. They should be larger, more clearly defined, with more power in them.

But no number of trials will ever predict what a drug will do in one person. Trials will increase the confidence level; but still each individual case is unique. So the try-and-see element will loom large.

It is unrealistic to think that we can conduct followup studies with survival or other clinical endpoints on every drug coming down. Look at the numbers. Where are the bodies going to come from? Almost every trial today already has recruitment problems, both from dislike of the drugs that volunteers may be randomized to, and because of the large number of trials and options for people.

Remember that we still have ongoing studies of aspirin. We will never have all the answers about how to use a drug.

Will plasma RNA testing show quickly which drugs are working? Six studies now have produced some significant evidence that it does work; but none of them were prospective studies designed to answer that question. We need to design trials to test whether this viral measure has value. Do trials with this marker, then analyze those trials.

We are moving from testing individual agents, to testing treatment strategies. The National Task Force for AIDS Drug Development must take the initiative, as companies do not have a motive. The ACTG (the AIDS Clinical Trials Group, of the U.S. National Institute of Allergy and Infectious Diseases) has not done it. The CPCRA (Community Programs for Clinical Research on AIDS) is trying, but has had no support.

Placebos are generally unethical in long-term studies without a safety net, such as the "switch points" which have been described. But there are times when you can use placebos in this disease -- for example, to study viral markers. And there are large numbers of patients who refuse to take AZT; they should be permitted to make decisions about placebos.

* My T-helper count is higher today than it was at diagnosis five years ago. There is a polar split now in AIDS treatment activism, between optimism and pessimism.

A large simple trial which counts dead bodies after three or four years is largely irrelevant to making better treatment available. It is wrong to force people to comply with trials for several years, or give up new-drug access altogether.

Clinical trials is my only access to new drugs -- starting with ddI, as I was lucky enough to be randomized to it. Taking away our choices in order to force us into a controlled trial is immoral.

* The rationale for accelerated approval remains sound. Hundreds of patients at our clinic in Birmingham have received treatment under accelerated approval that they would not have received otherwise. They have obtained therapy, and hope. I am puzzled by the current debate about accelerated approval, and the reason for this debate to happen now.

Three protease inhibitors tested at our center have produced responses in viral burden which are unprecedented.

* Atlanta is seventh in the nation in the number of cases, and there is no adult ACTG center; the only access is through the CPCRA [which mostly tests treatments for opportunistic infections]. Birmingham is 150 miles away. And most Veterans Administration or county health-department patients do not have access to drugs not FDA approved; we fight that every day, but it is the reality. Accelerated approval is a better option; access to trials is not adequate.

We need more studies that are women-specific. Women are harder to reach. But they have incredible interest and need. It is important to find a way to research alternative and natural therapies.

* We should not abandon reason. I do not want to see the FDA reduce its standards for safety and efficacy. Accelerated approval to bad drugs is not a good thing.

Experiments must compare groups that are equal in all ways except one, the drug. Only randomized, blinded trials are valid.

* I fear that decisions [in Washington, etc.] will limit peoples' ability to make personal decisions about their treatments. Recent faxes, phone calls, and articles have contributed to that fear -- that some organization, agency, or individual, who feels that they are looking out for us, may make decisions for us.

In the South, there is limited access; many people depend on accelerated approval for treatment options.

* Many are concerned with access; I am not sure why. The consensus is that people should be allowed to take risks -- treatment guessing. But this is an act of desperation, not reason.

What's at stake is the right of a small group of people to impose these choices on all. Accelerated access requires clinical confirmation, and we're not getting it.

[In response to questions from panel]

With AIDS, a moderate effect may be measurable in a clinical trial in a year. We will be getting a flood of drugs -- four nucleoside analogs already, another one coming along [3TC], and perhaps 12 protease inhibitors being developed -- and we don't know how to use them.

Individualizing therapy is an argument for surrogate markers. This may work for the individual. But we need to know whether, on average, it is better to take a drug or not to take it.

We do not necessarily need a new large simple trial for every protease inhibitor. If we develop a reliable index therapy, then there are other options. If we reliably know what it does in a patient population, we can compare new protease inhibitors to the established product. The worst thing we can do is to do nothing.

* How accessible is accelerated approval to the underserved? If they can't get primary care, they can't get accelerated approval. In the ddI parallel track program, only five percent were women, eight percent African American. With d4T, it was 5 percent women, 8 percent African American. With 3TC so far, it is 4 percent women, 15 percent African American, and 4 percent Latino. Only the 3TC program includes pediatric, ages 3 and up.

In other words, the parallel track programs serve mostly white men. We need to be creative and flexible about getting underserved populations into trials, and into expanded access.

Restrictions apply to public clinics. I have done the paperwork for the d4T parallel track; it's not complicated, but it is time-consuming. Our office had to hire an extra person. How is this paid for -- bill the patient or insurance, or require an extra visit? In San Francisco, you can get into parallel track through the public clinics; but every year we must fight budget cuts, so we don't know if this will continue.

Women have social constraints that single men often do not. They may be the caregiver for their spouse or children; they may be head of the household. And there is still the stigma: a woman with HIV may be considered either an IV drug user, or a whore. Many are not "out" to their families and friends; how can they rationalize the extra visits which parallel track may require?

* I get calls daily [from people with hemophilia and HIV]. They have two concerns: access to new therapies, and data on safety of new therapies. Rarely do they ask about better ways to learn about approved antiretrovirals. But they know there are safety problems even with the standard approval process.

Many hemophiliacs are excluded from clinical trials [because of various medical complications]. They need expanded access [parallel track] that works for them -- and they need accelerated approval. They don't have time to wait for detailed efficacy information before having the option to use an emerging therapy.

* We support the right to make decisions. We also support regulations, and understand that they will sometimes compromise autonomy. The responsibility for achieving this balance lies with the FDA. We need maximum access and answers.

A message from the Yokohama conference is that AIDS will endure for many years. While we seek shortcuts for people with AIDS today, we should not circumvent building knowledge for tomorrow. There is now a crisis in the design of trials to get the necessary answers. A drug with unknown efficacy is also a drug of unknown harm.

There should be premarketing studies, with much broader access and much harder data than now. And postmarketing studies with much larger trials; whether "simple" or not is a matter for statisticians and economists to decide.

As our knowledge about surrogate markers changes, the FDA must clarify in a public forum what data will be enough for approval.

* People are being told there is no hope if they cannot tolerate standard therapy. They should be able to request a list of treatment options to treat the HIV virus.

New herbal products should be tested -- in part to put to rest the hype. The National Institutes of Health, and private organizations, should begin well-designed trials of non- pharmaceutical-company treatments now.

* The current system of drug development has failed to deliver any antiviral drug which we believe will extend life. Natural antivirals, including amino acids and their analogs, need to be studied.

* It seems that new treatment regimens are being held to a higher standard than old ones. For example, two weeks ago today, the FDA rejected an extension protocol for the Salk HIV treatment vaccine. This treatment has been in human use since 1987 with a perfect safety record. Now people are being denied booster shots and additional clinical trials. We have a waiting list of 900 in the Philadelphia area alone.

* A growing problem is that companies are refusing to provide parallel track programs because of the expense. Perhaps some drugs could be given a carefully regulated accelerated approval in place of parallel track. This would allow companies to charge for the drug, using the income stream to help offset expenses. The key would be enforcing the reporting of major adverse events -- which does happen effectively with parallel track, but not always with approved drugs. This system would not create a new subminimum for industry, since each drug would either build a safety database (making it equivalent to the accelerated approval we have already), or be withdrawn.

[One guest panelist commented that large companies would be unlikely to charge for a drug at the parallel-track stage, because they are not ready to make pricing decisions until development is complete.]

* With nucleoside analogs [AZT, etc.], there was no plan to guide their development. Now we need a Protease Inhibitor Task Force to plan for the orderly and effective development of this class of drugs.

* We need to move toward individualized therapy -- and perhaps toward individualized clinical trials. We should build on existing expanded access programs, not go to old style trials with death or illness as the endpoint. Early access can be more flexible and innovative, with simpler followup.

* The context for this entire debate is the impact on the affected communities, during the last couple years, of disappointing data and limitations of drugs. The only possibility for real hope is an effective standard of care that works for patients. When accelerated approval drugs come out with no efficacy data, and apparently no hope for efficacy data, that's a false promise that can hurt people, and slow the search for a cure.

Transcript Available

Either a complete transcript of the two-day meeting, or summary minutes, will be available. The following ordering information was distributed at the meeting:

"Mail written request specifying data [September 12 and 13, 1994], name of committee [Antiviral Drugs Advisory Committee], and a description of the documents requested [either complete transcript, or summary minutes] to: Food and Drug Administration, Freedom of Information Staff, HFI-35, Room 12A-16, 5600 Fishers Lane, Rockville, MD 20857.

"Invoices are sent monthly by the Freedom of Information (FOI) staff. If requested, FOI will inform you of fees in advance.

"Transcripts ... will be available from FOI fifteen working days after the meeting. You may also purchase transcripts directly from the transcribing company. Summary minutes will be available approximately 90 days after the meeting. Please wait until this time period has elapsed before you place your order... or phone 301/443-5455 for status of minutes."

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