AIDS TREATMENT NEWS No. 116 - December 7, 1990
John S. James

Before working full time in AIDS, Mr. Delaney taught negotiation and other business skills to corporate teams. Recently he has communicated extensively with the researchers studying ddI and ddC, and with other experts from the sponsoring pharmaceutical companies, the FDA, the National Institutes of Health, and activist organizations.

JJ: You are optimistic on early approval. What are the reasons for optimism?

MD: I have had extensive meetings with the parties -- the FDA, the researchers, the companies, and other activists. There are some uncertainties about how the data will be evaluated, but there is a clear commitment on the FDA's part in making this process happen. The discussions are about how they can make it happen, not whether. The question is, how can we evaluate the data in this circumstance, and make a scientific case that what we are seeing is predictive of the usefulness of the drug?

The issues are not unique to ddI or ddC. These are broader issues for all AIDS drugs in the near future. We will not have placebo studies, so we must find ways to make comparisons to existing AZT data, and to a better picture of the recent natural history of AIDS since the beginning of pneumocystis prophylaxis. If these issues did not come up now for these drugs, they would come up for whatever drugs are next. There are scientific hurdles, but there is also a strong commitment to clear these hurdles, to find a scientifically valid way to do it.

There are no simple answers here. The simple answers have already been rejected by FDA. For example, they do not feel that T-helper increases -- even for a longer period than produced by AZT -- is, by itself, adequate proof of the drug, unless it is corroborated by other data. But others hotly dispute this view, arguing that T-helper increases alone should be enough.

The FDA does not want to be the obstacle; it recognizes the critical urgency of making the two drugs available. So they are saying that they want a joint decision, a collective decision- making process to explore all these issues, with scientists in other research and development agencies -- for example, the National Cancer Institute, and the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases, as well as activist experts -- on how the NDA (New Drug Application, with the detailed data on the drug) should be submitted. The FDA has agreed that it is safer politically to seek expert consensus in this way; if it made the decision alone without consultation, it would be highly vulnerable if something went wrong. In the FDA's view, this decision is a watershed event. We do not want them to make it alone.

JJ: The biggest questions seem to revolve around what constitutes proof of efficacy.

MD: Absolutely. The debate will hinge partly around the meaning of drug-induced T-helper increases. Statisticians are finding that T-helper counts definitely associate with survival outcome -- especially that the risk is greater when the count falls below 50.

The tougher question is, if the T-helper counts are so predictive, does increasing the counts by use of a drug predict increased survival, as a higher count does in the natural history (without treatment)? Most researchers instinctively believe it does [that an antiviral which increases T-helper count probably does improve survival]. But the FDA argues that no one has yet proven this point.

Recent statistical analysis suggested that the benefits of AZT are greater than what would be predicted simply by the T-helper increase. Why that is so is unclear. The T-helper count may not tell us all we need to know about the immune system; the benefit of AZT may be greater than this count alone would suggest. None the less, others argue that increased T-helper counts are one useful predictor of a drug's efficacy.

The National Cancer Institute, for example, says that in all its studies, any antiviral drug which has kept the T-helper count above 50 seems to keep people alive. In the NCI studies, only one patient who remained above 50 has died in the last four years. Samuel Broder, M. D., director of the NCI, strongly believes that this data alone validates the usefulness of drug-induced T-helper increases [as an indicator of clinical or survival benefit from the drug].

The long-term clinical picture, as measured by the number of opportunistic infections or by survival, is harder to evaluate than people would like, because the easiest point of comparison is the old AZT studies. And most of those were done without pneumocystis prophylaxis. So the FDA is reluctant to use them for comparison, arguing that more recent data includes other variables besides the drug. So now Bristol-Myers is collecting data from several major clinical centers in the country -- not just ddI data, but also case-history data from patients not given ddI, to get a better picture of the natural history of AIDS with pneumocystis prophylaxis. Perhaps this data can be used as a valid comparison; but of course much work is required.

Another outcome which FDA will consider will be overall clinical improvement, such as weight gain, or Karnofsky scores (a rating of overall health). If you put each of these pieces together, and if they are coherent, I think there is no question that FDA will grant the approval. But they do not want to approve the drugs on T-helper counts alone, without this other data.

There should also be some input from virology markers. Plasma viremia data (measuring the amount of virus in the blood) should be available by January.

If you keep your eye on all of these pieces of the picture, you don't get nervous with every new rumor that sweeps part of the country.

JJ: What else is at stake here, beyond the short-term availability of ddI and ddC?

MD: A great deal is at stake. If the FDA cannot find a way to accept this kind of data as proof of drug effectiveness, it will have no choice but to demand the re-use of survival as the sole endpoint in future studies. In other words, we test the drug until some of the patients die. And this would require a return to the routine use of placebo controls. We cannot allow this to happen.

JJ: If a drug is known to be an antiviral, known to be effective against HIV at concentrations reached in the body -- and if there is no reason to suspect that the drug raises T-helper counts directly -- then if T-helper counts consistently go up when the drug is given to persons with HIV, it seems hard to explain that effect other than by an antiviral action of the drug. Average T-helper cell counts do not rise spontaneously, without treatment, in any known group of persons with AIDS or HIV. It is hard for us to understand waiting months or years for conclusive proof of benefit, after it is already clear that a drug does show a substantial antiviral efficacy in patients.

Usually the FDA's Antiviral Advisory Committee meets for only a day or two, with little or no staff support. How can it possibly give the ddI and ddC decisions the attention they deserve, in view of the extensive data about these drugs, and the major issues regarding interpretation of the data?

MD: The committee probably could not do this by itself. Therefore, it will be assisted by other leading researchers brought in as consultants, who have expertise on these particular drugs. A special meeting of the nation's top experts, probably in early February, will seek a consensus on whether these drugs should be approved. In practice, this process must go through the existing structure of the FDA advisory committees.

JJ: There has been concern that neither company (Bristol-Myers for ddI, or Hoffmann-La Roche for ddC) has yet submitted its NDA (New Drug Approval application) to the FDA.

MD: The companies do seem to be on schedule for submission of that data. It would be a mistake to submit it too early, before they knew what the FDA wanted of them.

I have reassurances that Bristol-Myers will be submitting its NDA shortly after the advisory committee meeting, probably in February. Hoffmann-La Roche has not yet looked as closely at its data, but they have said that they intend to submit their NDA early in 1991.

JJ: What timetable do you see for a decision on approval of these drugs?

MD: The advisory meeting date has not yet been set, but should be in early February. I see at least one of the NDA applications coming in about a week after that time. Then it would take at least 30 days for the FDA to analyze the data; they may have to ask more questions of the company. All things considered, I think it's a do-able target to get both drugs out by March of 1991. Anything much beyond that, and we should raise the temperature politically.

The consensus building is most important, because it will set a standard of how we look at these urgent approvals in the future. We do not ask the FDA to decide all by itself in an ivory tower. Instead, we want a collective decision with input from all the people who are working in this field.

Note: On December 19, a multi-city press conference will explain the movement for early ddI and ddC evaluation. Project Inform and other organizations involved in this issue will take part.

As of this week, 35 organizations have signed a consensus statement circulated by Project Inform (with much help from ACT UP/Golden Gate and Mobilization Against AIDS), calling for urgent review of ddI and ddC. Also, the Community Consortium, a medical group representing almost all of the physicians who have an HIV practices in San Francisco, issued a separate statement urging expedited review of the data on these drugs, with a decision on licensing as soon as possible. In addition, at least 25 members of Congress have signed a letter to the FDA by Congresswoman Barbara Boxer (D-Greenbrae, CA) urging immediate review of ddI and ddC.

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