ddC/ddI Approval Update

Much AIDS news today concerns the campaign for a rapid FDA evaluation of the experimental AIDS antivirals ddC and ddI -- the issue we listed as the most important treatment development to watch in 1991 (AIDS TREATMENT NEWS #117, December 21, 1990). The decisions now being made will affect not only these drugs, but all critically important AIDS antivirals in the future; they will determine whether any future AIDS treatment, no matter how well it may work, could possibly travel the development and regulatory pipeline without many months or years of medically unnecessary delay. We are now seeing the beginnings of major changes; but at the same time there is widespread confusion, and sometimes chaotic miscommunication.

The meaning of the current controversies cannot be understood without background on the situation which now exists, and how it developed.

Background: The Problem

Neither ddC or ddI are new; both could have been developed and approved at about the same time as AZT. ddC was delayed because of early toxicity; it was not known until later that the right dose was about 200 times less than the dose of AZT or ddI. As for ddI, it was well into human trials two years ago -- and the subject of a loud and sometimes bitter public dispute between Ellen Cooper, M. D., chief of the FDA's Division of Antiviral Drug Products, and Samuel Broder, M. D., director of the U. S. National Cancer Institute; the occasion was the first hearing of the Lasagna Committee, which issued its report on approval of new drugs for cancer and AIDS on August 15, 1990 (for background on this report, see AIDS TREATMENT NEWS #110, September 7, 1990). The dispute, an advance echo of what is happening today, concerned the FDA's refusal to approve the NCI's plan to begin testing ddI as a treatment for children with AIDS under two years old; the U. S. National Cancer Institute was ready to start this ddI trial two years ago, but apparently the FDA wanted tests on
adults to be finished before the tests with children began. (For detailed newspaper coverage of the ddI dispute of two years ago, see "Cancer Institute: AIDS Drugs Unduly Delayed," by Michael L. Millenson, Chicago Tribune, January 5, 1989, and "The Battle over FDA Drug Policy; The Pressure Is On to Speed New AIDS and Cancer Drugs through the Agency's Slow Approval Process," by Laurie Garrett, News- day, February 14, 1989.)

Two years later, one activists spoke of the spreading "ripple of terror that the trials [running now for ddI and ddC] are not what should have been designed." It seems that nobody thought through how the information to be generated by these trials -- scheduled to run for about 18 months more -- would be used to support drug approval. One effect of this lack of planning is that AZT, the first AIDS antiviral to reach FDA approval, shut the door behind it, keeping all rivals out. This happened despite the clear need for new therapies -- shown most compellingly by epidemiological data suggesting that AZT has extended average survival after AIDS diagnosis by no more than several months. (This survival data includes patients not receiving AZT because of drug intolerance or other reasons; the benefit of AZT for those who do use it might be greater.)

Much of the reason for the current complexity, confusion, and miscommunication stirred up by the push for early evaluation of ddC and ddI is the need to retrofit to cover for mistakes of the past. These mistakes occurred because of lack of higher- level oversight and planning in the AIDS research process. Key positions have long been vacant, or filled with people unwilling to deal effectively with AIDS.

One of the problems in the current development of ddC and ddI is the lack of definition of what the trials are trying to prove. Normally, the goal would be to prove efficacy (i.e., that the drug works better than no treatment) for some group of patients. It should not be necessary to prove that the new drug is better than standard therapy -- or even equal to it, because many patients cannot use the standard therapy, and because combination treatment using both the new and standard treatment is highly promising.

But since it would be unethical to run a placebo trial, ddC and ddI are being compared to AZT instead. Statistical efforts were made to use the old AZT-vs. -placebo trial of four years ago to allow ddC and ddI to be mathematically compared with a placebo, even though no real placebo is being used in the current trial. This desperate attempt to forge a case for approval out of ill-designed trials seems to have led to some of the recent controversy.

If the new drugs must be compared to AZT, then the next question is whether they must be proved superior, or only equivalent, to merit FDA approval. Equivalence, of course, would be the standard preferred. But there are statistical complications in proving equivalence. For example, in a trial to test whether one drug is better than another, the incentives are for researchers to run a tight, clean study, so that if there is a difference, it will be found. But in a test for equivalence, the incentives are for researchers to run a sloppy trial, because failure to find a difference means success. For this and other reasons, there is confusion now over whether proof of equivalence will be enough for approval of ddC or ddI, or whether proof of superiority will be required.

There are other problems with the current ddC and ddI trials, and with the regulatory process. One concern is that companies do not usually submit their data to the FDA until their NDA (New Drug Application) is finished; the FDA prefers to get the data all together, in order to save staff time. But an NDA is a large document, typically consisting of many volumes of paperwork. Anyone familiar with the influence of corporate and organizational cultures would expect that any time one organization generates such a document and passes it to another for evaluation, many points of disagreement or friction will almost certainly be found. Without inside knowledge of the operations at the FDA, we cannot know whether this potential problem does or does not in fact cause serious, avoidable delays. (If it does, procedures could be changed to encourage earlier collaboration for NDA review of critically important drugs.)

Two years ago, NCI's Dr. Samuel Broder saw that no new AIDS antivirals would be approved unless procedures were changed. "If we have to compare every drug to AZT, with death as the endpoint of a trial, we're going to be in a situation where it will be very difficult to get any other antiretroviral approved for AIDS. It took us two years to get AZT out -- how long do you think the next one will take? Five years, ten years? That's unacceptable!" (Quoted in Newsday article cited above; the comments were addressed to Dr. Ellen Cooper of the FDA. The context of the discussion was ddI. Dr. Cooper replied with the question, "Why don't you want to see a year's research in clinical trials on an antiretroviral before approval? ")

Two years later, the trials of ddC and ddI still have months or years to run -- and as we pointed out above, they are not well focused on the important questions. This is the context of the growing movement to ask the FDA to call in the existing data now, look at all that is known about these drugs, and approve them if there is "substantial evidence" that they work.


San Francisco Physicians Seek Early ddI, ddC Review

On December 26, 1990, two San Francisco physicians' organizations, representing almost all physicians with large AIDS/HIV practices in the San Francisco area, filed a formal petition with the FDA urging that Agency to use its existing statutory authority to expedite submission of existing data on ddI and ddC, and then make a decision on marketing approval by March 1, 1991. The petitioning organizations are:

(1) The Community Consortium, which consists of over 180 physicians, nurses, physician's assistants, and other licensed health care providers. The Community Consortium has been conducting community-based trials of AIDS treatments since 1986; one of its trials made major contributions to FDA approval of aerosol pentamidine for pneumocystis prophylaxis.

(2) The Bay Area Physicians for Human Rights, an organization with over 200 members dedicated to quality health care for lesbians and gay men. BAPHR has long been involved in AIDS policy issues; for example, it was the first organization to issue safer sex guidelines.

This petition is especially important for several reasons:

* It shows that the call for rapid evaluation of ddI and ddC (and of other drugs which may be equally promising in the future) has the clear support of the leading AIDS physicians in the San Francisco area, who are among the most experienced in the world. As far as we know, there was no opposition to the petition within either medical organization.

* It cites specific sections in the Code of Federal Regulations which show that the FDA has the clear legal authority and also the mandate to expedite the approval of critically important drugs for life-threatening illnesses.

* It also calls on the FDA to use its authority to establish and publish criteria by which antiretroviral drugs will be judged for approval, which would provide guidance for pharmaceutical companies and reduce the confusion which now prevails.

* The 11-page petition document itself (including 55 technical references) is the best single statement of the case for early approval of these drugs.

* The petition will become part of the Congressional Record, available for easy reference by members of Congress.

The initiative and the legwork for this petition were provided by San Francisco activists Jim Driscoll and Barry Freehill, with medical guidance and leadership by Donald Abrams, M. D., Chairman of the Community Consortium. The idea of using a petition was suggested by Sidney Wolfe, director of the Public Citizen Health Research Group.

The petition is open for endorsements by other organizations. Persons interested in receiving a copy should send a large self- addressed stamped envelope to: Jim Driscoll or Barry Freehill, c/o Community Consortium, 3180 - 18th Street, Suite 201, San Francisco, CA 94110.


Congressional Letters Support Expedited ddI and ddC Review

On November 27 Congresswoman Barbara Boxer (Democrat, California) released a letter from 25 members of Congress to the new Commissioner of the FDA, David A. Kessler, M. D., asking for early review and possibly early release of ddI and ddC. Congresswoman Boxer stated, "It is imperative that incoming FDA Commissioner Kessler make this a top priority. His background, as an AIDS pediatric physician from a Bronx public hospital, well qualifies him to take a fresh look at medical evidence supporting these drugs."

Congressman Jerry Lewis (Republican, California), Chairman of the House Republican Conference, wrote a separate letter supporting early review of these drugs.

Congressional involvement is important because in the past, the FDA has often faced criticism from Congress for approving a drug too soon, but almost never for delaying approval. These letters provide cover for the FDA, and greatly reduce the concern that fear of Congress might prevent it from moving as rapidly as it otherwise could.

Mobilization Against AIDS first asked Congresswoman Boxer to draft the letter and circulate it in Congress; she immediately agreed to do so. To obtain a copy of that letter, write or call Mobilization Against AIDS, 1540 Market St., #160, San Francisco, CA 94102, 415/863-4676.

Paul Boneberg of Mobilization Against AIDS pointed out that obtaining such assistance from members of Congress is not difficult, if local organizations choose to develop an appropriate relationship with their representatives.


Project Inform Consensus Statement on ddI, ddC Approval

The first consensus statement in support of early licensing of ddI and ddC has been circulated by Project Inform. Over 25 organizations and a number of physicians have signed.

On August 16 Martin Delaney of Project Inform first wrote to Doctors Ellen Cooper and Paul Beninger of the Division of Antiviral Drug Products of the FDA, warning them that early approval of ddI and ddC was about to become a major public issue, and exploring possibilities for expediting evaluation and approval of these drugs.

The first draft of the Project Inform statement called for early approval of the drugs, not just early review. Some physicians objected to this draft, saying that they had not seen the data, and therefore could not know whether or not the drugs were ready for approval. Later drafts of the Project Inform statement -- as well as the physicians' petition, and the Congressional letter, both described above -- took these reservations into account, and called on the FDA to rapidly review the existing data, and approve the drugs if justified.


Ellen Cooper Resigns As Antiviral Chief

Late last month Dr. Ellen Cooper asked to be reassigned within the FDA and leave her job as chief of the Division of Antiviral Drug Products. Most activists who worked with Dr. Cooper consider this development bad news, since no one else at the FDA has her experience with AIDS drugs. It is widely agreed that her job generated intolerable pressures.

In an interview published in The Wall Street Journal, December 24, 1990, Dr. Cooper cited the conflict between four groups -- people with AIDS, pharmaceutical companies, scientists running trials, and regulators (at the FDA). (It is notable that this list did not include a fifth group -- the frontline physicians with large AIDS/HIV practices.) She commented that "Politics has become paramount, but science should have a role." She said that she was open to using T-helper counts (or other measurements short of death or disease progression) to prove drug efficacy, "but there's got to be an analysis of the data by statisticians, researchers, and clinicians. That's just starting now."

One incident which must have contributed to job pressure concerns recent letters from Dr. Cooper to Bristol-Myers and to Hoffmann-La Roche concerning standards for approval for ddI and ddC. We have not seen these letters nor talked to anyone who has. Apparently they address the problems with using the old AZT-vs. -placebo trial as a basis for interpreting the data from the current ddI-vs. -AZT and ddC-vs. -AZT trials.

These letters have barely been mentioned in the press, but behind the scenes they generated a storm of controversy, because they were widely interpreted as taking back decisions already made and requiring data that everybody knew would not be available -- in effect, therefore, saying that the FDA will not approve either drug at this time. There may have been a misunderstanding, however, because others believe that the purpose of these letters was not to rule out approval, but rather to ask the companies to put forward their best case for the drugs. Without seeing the letters, we cannot know what message was intended, and whether a different message may have been received.


Comment

We are too far from Washington to cover what is happening inside the Government in AIDS treatment research and development, or in other AIDS policy; we wish there were a Washington-based newsletter to do so. We do have impressions on why Dr. Cooper's job has been such a difficult one, and on how that position could be made more workable in the future.

Over a year ago this writer was at the FDA for a class which the Agency had very commendably organized for community-based research groups; we were there as a member of San Francisco's Community Research Alliance (now the Project Inform Community Research Alliance). One lecture concerning a highly technical aspect of clinical trials was given by Dr. Cooper. We commented to an FDA staff member present that we were surprised that the head of the division would be prepared to speak on such a specialized area. He answered, with obvious respect for Dr. Cooper, that she could speak equally well on any aspect of clinical trials and the FDA's role in regulating them.

We see Dr. Cooper as a top expert on clinical trials, but one who in fact had two jobs -- not only the scientific job she wanted and could do well, but also a political job in addition. Due to lack of national leadership on AIDS from higher levels of government, Dr. Cooper had become not only the leader of the antiviral division at FDA, but also, in effect, the sole umpire to judge the standards of approval for all AIDS antiviral drugs -- and in consequence, the designer of national policy on how to respond to the epidemic, in so far as development of antiviral drugs is concerned -- development on which the life of everyone with HIV depends. There is no way that such a role could not be political.

The best outcome now might be for the FDA to separate the two jobs. Then Dr. Cooper could return to being head of the antiviral division, without also having to singlehandedly set national policy on AIDS drug development and take up the slack created by leadership default from the President on down. The head of the antiviral division is three levels below the Commissioner of the FDA; the political decisions (such as whether to insist on new technical standards now if the practical consequence is that nothing will be approved) are ultimately the responsibility of higher levels. There now is a Commissioner of the FDA -- David A. Kessler, M. D., who was installed on December 3, after the office had long been vacant -- so this best outcome might now be possible.