AIDS TREATMENT NEWS #219, March 24, 1995

David Feigal, M.D., is Director of the Division of Antiviral Drug Products of the U.S. Food and Drug Administration. After the February 23-24 meeting of the National Task Force on AIDS Drug Development, a meeting focused on protease inhibitors, we asked Dr. Feigal for his perspective on issues related to the current development of these experimental drugs.

Access and Supply Problems ATN: There is wide agreement that the protease inhibitors, despite their known limitations, are the most promising single approach to HIV treatment today. Yet it will be some time before many patients have access to these drugs. What should we as a country do in this situation? Feigal: At the National Task Force meeting, the companies developing protease inhibitors were fairly frank about their manufacturing problems; one of the companies even had an activist group send in a consulting chemist to verify the problems. That shows how generally open they have been. These compounds are difficult to produce -- and to make matters worse they are not very bioavailable [meaning that a large oral dose must be used, so a larger supply must be produced]. A company which is manufacturing only a few hundred kilograms, which is typical in early drug development, may only be able to supply the drug for three or four hundred patients, if a year's supply per patient is needed. Many of the candidate protease inhibitors require multi-step synthesis processes with low yields, and for some of them the synthesis takes a long time, and there are other problems with scale-up to large quantities. These problems will be solved; but it has meant that companies had to make decisions to go ahead with a much larger scale of production than is usual early in drug development.

This supply problem will pass with time; if these products meet their potential, they will be manufactured on a large scale, and then this period of poor availability will go away. The question is what to do in the meantime -- and how get the clinical answers at the same time as we provide the product to people who cannot participate, or choose not to participate, in clinical trials.

Several suggestions have been proposed, some from the companies. One is a tiered approach, to make drug available to patients with the greatest need. Very few companies have much supply, and even that would be used up very quickly.

This is an area where we could use input from the community. What do those affected by HIV think would be the fairest way to deal with these problems? In a different area, when Betaseron was approved for multiple sclerosis, there was a serious supply problem, and a lottery was used to distribute it. This was very unpopular; there was much unhappiness about using a lottery.

The companies are much aware of the difficulties this limited supply creates; and there could be a partnership between the community and the companies, to figure out how to distribute a drug in very short supply. What about a product that could meet less than half the need? The largest supply possibility we heard about at the National Task Force was enough product for several thousand people; that is not as large as the d4T expanded access, or the currently ongoing 3TC expanded access.

There must be some way of cooperatively dividing up these scarce drugs; there needs to be a partnership between the community that needs the access and the companies. To the extent that the companies feel they are being asked [by the community] to do things that the FDA would not approve, we are happy to get involved. But many of the issues revolve around such matters as logistics, and protecting trials. These issues are between the company and the community affected by the disease more than they involve the FDA. If the companies are saying the FDA will not allow wider use of the drug at a certain stage of development, then we should get involved; it usually will not be true. We have said with the proteases for a long time that we would welcome an expanded access proposal. Manufacturing remains the real problem.

Other Treatment Options Aside from waiting for the protease inhibitors: I agree with your statement that these are the single most promising agents to come along. But also, if you look closely at some of the combination data now developing [using other drugs which are more available], some of these are obtaining preliminary results in the same general magnitude as the protease inhibitors. Most of them, like the proteases, are most effective for patients who have not been pre-treated with many other drugs. But some of them were capable of getting fairly dramatic drops in viral load and rises in CD4 count, even in patients who have been on prolonged zidovudine [AZT]. So I believe it would be a mistake to focus only on the protease inhibitors, particularly since we know that resistance to these drugs does develop over time; that is an early signal that the protease inhibitors, too, are probably going to be most useful in a combination.

ATN: So people should not rule out other options that might be available now? Feigal: I would agree that there are other options now. Most of these results I referred to have been presented publicly, at the Human Retroviruses and Related Infections conference in Washington [January 29 - February 2, 1995]; the 3TC data and the nevirapine data were very interesting. Each of these has different pluses and minuses, and a different story in terms of availability; but these and some others are showing fairly similar types of preliminary evidence.

Individual Variation It is difficult to evaluate these preliminary studies, however, because some of them are based on small samples. Researchers often find that the most compelling way to present their data is to show individual patients' results. But there can be much selectivity in picking the best responders. There have always been single patients in almost any trial who have had dramatic responses at the start of the trial.

What is more important is that the average responses are better. We do not know yet how good they are in broader populations and how long the effects will last, and we still do not know how to translate changes in viral load to long- term clinical outcome. We have had these tests for a short period of time.

ATN: I remember that when the AZT trials started, there were miracle stories then.

Feigal: There was a patient in the original BW 002 [AZT] study who had CD4 count under 50, who went up to a thousand, in the first 16 weeks of the study. We attributed this to problems with the T-cell test at that time. But even though the average difference between the placebo and AZT was only 40 T-cells in that original trial, there were individuals who had very dramatic responses. The same was true for patients who started ddC after having been on AZT for periods of time.

There always have been individuals who may have responded unusually well to a drug. And just as we have learned about the pathogenesis of the disease by studying long-term survivors, we would probably learn something about drug therapies by taking a look at some of these dramatic responders, and seeing what is different about their virus, or their drug absorption, their intracellular triphosphate levels, etc. Some of the variation might be due to chance, but still I think there is potential to learn much about therapy from these individuals.

T-Cell Responses What is different about the protease inhibitors (compared to the gloom we felt a couple years ago, as we looked at developing a family of me-too nucleoside analogs) is that we have seen people who we thought could not mount much of an immune recovery, take their T-cells from under 50 into the several hundreds, and sometimes almost back to near-normal levels. The caution, of course, is that we do not have enough followup to know how much of your immunity is really restored by having your counts rise. There have been cases of patients who have developed pneumocystis with high CD4 counts (although there have always been such cases, even in the original pneumocystis trial). Despite such concerns, I still think we are on the verge of making some real progress with the protease inhibitors, and with drug combinations [with or without protease inhibitors included].

Business Incentive Issues ATN: There is also concern in the community that the rules for drug development have made it too difficult for companies to justify their financial investment.

Feigal: The businessmen would be better at addressing that issue than I. But one clear message that has been sent -- and we certainly said it again at the National Task Force meeting -- is that we would welcome a good accelerated approval package for drugs in new classes. [The FDA's "accelerated approval" regulations not only provide drugs sooner to patients with serious or life-threatening diseases; they also help companies by reducing the investment required before a drug begins to generate revenue.] When accelerated approval was first proposed, there were discussions about whether it would be used primarily just to approve new drugs in the same class. With a new class of drugs, would you have to prove clinical benefit [without using accelerated approval] for the first drug, and use accelerated approval only for later drugs in the same class? But today, so long as the clinical confirmation studies are in place, we do think that accelerated approval is a viable option [even for the first drug in a new class]. It knocks a couple years off of the development time, compared to traditional drug development. That allows the companies to begin financially recouping their development costs for the product at an earlier stage; if they still have patent life on the product, they have exclusivity for more years. They can continue to do the clinical studies funded in part on revenue from the product, rather than having to put more money into a product that is not yet generating income. And there is also the issue of the cost of money; when companies talk about the $250 million that it costs to develop a product, about half of that is the cost of money [which is reduced by having a faster development track].

Accelerated Approval and New Indications ATN: One of the criticisms I heard at the National Task Force hearings is that accelerated approval would work for initial approval of a drug, but was not available for additional indications [because the need is not as urgent].

Feigal: That is not true; in fact, there are examples where we have already used accelerated approval for an additional indication. For example, clarithromycin was on the market for non-AIDS indications, and we gave it accelerated approval for MAC.

Part of the issue here is that the cycle of developing new indications is relatively long, compared to the patent life of the product. If you look at the time frame, of usually taking about a year to design and launch the trial (not just FDA time, but the whole time of the community and the researchers in setting up a trial), and then enrolling the trial for about a year and a half, and then having another year of followup, and another half year to write up the results if it is a big study, and then another four to six months for us to review the results and get the indication changed, you are looking at a cycle that can easily run two to five years for an additional indication. So one of the issues that has been raised in AIDS and in cancer is whether that is a standard which results in the drug label not keeping up with medical practice.

Viral Load and Early Approval The other time that discussion comes up [of whether we will always need to have clinical-endpoint studies eventually] is the issue of what does it mean to have a validated surrogate marker? We, at the FDA, already accept the fact that the virus is relevant; and that changes in viral load mean that you have an active drug; and that that, along with favorable immunologic changes, form a reasonable basis for accelerated approval. What we do not know is whether or not you can individualize someone's therapy and get a better result by changing their therapy as their viral load changes. We do not know if early changes in viral load will predict a sustained response some years later -- consider the Concorde disappointment with the early changes in CD4 count [which failed to predict better outcome later]. So we still need clinical endpoints to be confirmed.

But in the future, we might reach the stage where the viral load, or some other measure, or some combination measure, is so highly predictable that it is a reasonable basis to change clinical practice. Then we would be in a situation where we are with cholesterol-lowering agents, and anti-hypertensive agents; they are not labeled to prevent heart disease or stroke, they are labeled to lower cholesterol or to lower blood pressure. Right now we would not quite know what a label would mean if it said that this drug was indicated to lower HIV RNA in the serum. We are still not quite there yet, although we are all excited by how promising these measures look.

Another consideration is that many of the nasty surprises from basing treatment on surrogate markers [such as a notorious study of heart drugs, in which two drugs which successfully suppressed abnormal heart rhythms also increased the chance of death] did not come from the fact that the markers were necessarily poor, but from the fact that the drug had some other slow, damaging effect that was only detectable by doing a clinical study and seeing what the actual results were. So I think, for drugs in new classes, we eventually need to know how good they are clinically. The incentive for the companies is that accelerated approval gets them marketing use of their product, at a time when they are still pursuing the clinical question.

Here again we need a partnership with the community; the community needs to remain convinced that it is important to find out clinically how good these things are, and has to be willing to participate in trials. We have passed the era of placebo-controlled trials, but we can still learn a lot from active-controlled trials, or dose-response trials, and we need to have the commitment to do that.

Some companies are discouraged by how difficult it is to clinical trials in HIV in the U.S., with the rapidly changing therapy, with people discontinuing early in trials because of the availability of a new trial or a new expanded access. There needs to be that commitment together to find answers. I think that commitment is still there; it just gets frayed around the edges at times.

FDA Clinical-Trials Workshop ATN: Kessler mentioned plans to set up a workshop on AIDS clinical trials. What issues will this meeting address? Feigal: The quickest way to organize this meeting may be to use the existing advisory-committee mechanism; we can turn the meeting into more of a workshop than a hearing. We will probably try to do this in late spring or early summer.

A number of questions need to be aired, and relatively quickly. For example, what are the most relevant comparison arms? That depends on whether you do a traditional standard therapy vs. new therapy, or whether you extend that design into combinations (which we at the FDA already believe should be done more vigorously), or whether you modify it even further by taking a treatment-strategy approach, and leaving some parts of protocols very wide open, in terms of use of concomitant therapies.

Another important area is the role of larger trials, vs. smaller, intensive, high-tech trials. This is not an either- or, but how you best integrate those approaches.

Then there is the question of non-survival clinical endpoints. Is it still relevant to use the old CDC infectious-disease endpoints? Or are there more efficient measures, such as counting them in a weighted fashion, or evaluating more than just the first endpoint and also counting subsequent ones? On viral load, there is still much to be learned about which viral load markers predict which clinical events, and how far into the future do they predict. We know that CD4 counts have predicted only for about a year. But we need to take a look and see what we can learn, and design further end-point research into the trials that are ongoing right now.

There are a number of interesting confirmatory trials underway from the past accelerated approvals. The d4T trials, the ddC trials, and many of the ACTG studies, will potentially give us much data fairly quickly about CD4 counts, viral load, and clinical events.

We also need continued focus on special populations: the design of pediatric trials, the issue of vertical transmission, and design for the use of drugs in pregnancy, including treating women with advanced disease who are pregnant. Some of the newer compounds do not have the genotoxic effects that many of the nucleosides have; they may be safer for use in pregnancy, even aside from the issue of vertical transmission.

I would see this as a two-day workshop to have people present designs, and have panels; and probably use the advisory committee mechanism at the end to figure out what the immediate take-away messages are, and where the Antiviral Drug Products Advisory Committee would like to comment -- messages that commercial sponsors might pay attention to as they are designing trials.

There has been some misunderstandings that the reason that large trials are not used, for example, is because the sample-size calculations are not done correctly. That may happen in some cases, but more often there is disagreement among the designers of those trials over whether they are ready yet to look for small or moderate effects, or whether they are still screening drugs for larger effects. This workshop will be a chance to put some of these issues on the table and talk about some strategies.

We will not come up with a cookbook. There are many different ways to develop drugs; we need to continue to use all the ways we can, as we continue to find surprises when we modify our designs, or try a different population. For example, we are getting a new appreciation that we too rapidly concluded that it was hard to benefit patients with very low CD4 counts.

I think this is an exciting time, as there is a renewed interest not only in the proteases, but other combinations of non-nucleosides, and the AZT plus 3TC combination, that give us some reason to expect that we could make important treatment advances if we try some of these new approaches in trials.

The Empty Pipeline? ATN: Many people are saying that after the protease inhibitors, the "pipeline" for future development of AIDS drugs is empty. How do you see this? Feigal: It is hard to judge the pipeline. We thought the pipeline was fairly empty after many of the non-nucleoside RT inhibitors were abandoned three or four years ago; but interestingly, the non-nucleoside RT inhibitors are still around, and may, at the end of the day, in the right combinations, have an important role. The proteases bloomed rather rapidly at a time when people though the pipeline was largely empty. If it seems empty at times, history shows that it is cyclical.

Many advances that have been made in other fields, in chronic infections and malignancies, have been through careful construction of rational combination therapies. Even without new drugs there is still plenty of work to be done on combinations for HIV. For example, 3TC did not look attractive before the combination result with AZT; it is fortunate that the combination trial got done.

I do not see the pipeline as being terribly empty.

And there is always the left-field factor. Although we now focus a lot on drugs that have a direct antiviral effect, it is possible that some of the immunomodulatory therapies, or therapies that try to target programmed cell death, or other mechanisms of disease pathogenesis, might make a major difference, particularly in some combinations. If you look more broadly than just the direct antivirals, there is lots of work to be done.

ATN: People are concerned that small companies are excluded from drug development, because the rules make the process so expensive.

Feigal: The possibility of a drug coming out of left field does raise the issue of the small-company problem. The biggest need of little companies has always been to have big- company partners, just to keep the business going. A lot of how well the little companies do will depend on the big companies' interest in investing [which has clearly diminished recently, in all of biotech, not just AIDS].

In terms of the FDA's response to small companies, there is only one set of laws and regulations, and they apply equally to all companies. However, we are given the flexibility to interpret and to modify the requirements. We look for opportunities to do problem solving with small companies. Typically that has involved allowing them to try and get some initial evidence of efficacy as efficiently as they can, because that is usually the make-or-break for a new product. If they say that their compound is an "antiviral," but when they give it to someone, it does not affect any parameter that they can measure, then probably the substance is not worth pursuing as an antiviral. On the other hand, if it is dramatically antiviral, the company will probably be able to find partners to develop it.

One way we can help speed the development process is to allow companies to keep the animal toxicology studies just ahead of the human trials, so they do not have to do the whole toxicology profile evaluation before they even start in humans. The big companies sometimes use that strategy, too; although often when they are fairly committed to a product, they will do the whole animal workup before they even bring it in [to the FDA]. It is case-by-case problem solving; it depends on how much is known about the product, and the class of products, and how worrisome the potential toxicity. We are committed to try to find ways to solve problems with these companies, and give them answers quickly. Problem solving and rapid review is how we see our role.

ATN: What else was significant at the recent protease- inhibitor meeting of the National Task Force on AIDS Drug Development? Feigal: Just the ability to get the companies to come and talk about drug development, and to talk about their NDA (drug approval) filing times in public, was an unusual event; some people may not have appreciated that companies do not usually like to do that, they sometimes even keep NDA filings completely confidential. Kessler [FDA Commissioner David Kessler, M.D.] was asked by the community to take a hard look at the protease inhibitors and see what could be done. Whether the meeting was an overall success or not, there were things taken away, including a commitment by Merck to try and find expanded access in their drug development, and to do pediatric trials.

The companies are asking us what is the minimum safety database [required for approval]. An unfortunate result of the supply problem is that we do not have much safety experience with some of the protease inhibitors; often there are not even three dozen patients who have received the product more than three or four months. This issue was addressed at the meeting; if we cannot have expanded access with ten thousand patients to look at safety [before drug approval], what will we settle for? What came out was a recommendation for several hundred patients with at least half a year or so of exposure and followup. I think that can happen relatively quickly, with the studies and the use of these compounds already in the pipeline. A good outcome from the meeting was preliminary discussion of what the requirements should be, what are the parameters. This helps the companies in their planning.

Kessler took the commitment to that meeting very seriously, including personally lobbying the companies to get them to come forth and talk about these issues fairly frankly. It was interesting to me, knowing what they have told the FDA in confidence, how willing the companies were willing to be frank and open. If they seem to be excited about these products, I think it is because of a sincere belief by the companies that these could be potentially breakthrough products for this disease.