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David A. Kessler, M.D. - University of Pennsylvania

NOTE: THIS TEXT IS THE BASIS OF COMMISSIONER KESSLER'S ORAL REMARKS. IT SHOULD BE USED WITH THE UNDERSTANDING THAT SOME MATERIAL MAY BE ADDED OR OMITTED DURING THE PRESENTATION.

Remarks by
David A. Kessler, M.D.

Commissioner of Food and Drugs
Charles C. Leighton Memorial Lecture

University of Pennsylvania
October 10, 1994

Good afternoon.

It is an honor to inaugurate the Charles C. Leighton Memorial Lecture. This is a special privilege for me because I knew Dr. Leighton and had enormous respect for him. He was widely respected as a man who brought a new level of professionalism to the relationship between FDA and regulated industry.

In fact, when we began thinking about setting up a joint task force on AIDS Program Development several years ago, I came to West Point to meet with Dr. Leighton, Dr. Scolnick and Dr. Vogelos to talk about on how to go about it.

Dr. Leighton cared about improving peoples' lives, and his way of doing that was to try to make sure that new therapies moved from the bench to the bedside as thoughtfully, as meticulously, and as expeditiously as possible.

Thus, it seems fitting to talk to you today about FDA's policies to get promising therapies for serious and life- threatening diseases to patients as quickly as possible.

I want to begin by telling you about another extraordinary meeting that took place a couple of months ago.

I sat in a conference room on the 3rd floor of the Parklawn Building and I listened to a group of AIDS activists caution me about approving HIV drugs too quickly. It was a meeting most of us would not have anticipated. As I sat there, I thought back to a scene only a few years earlier when there were AIDS activists literally scaling the walls of the FDA building in Rockville, Maryland, demanding access to potential therapies that had barely moved out of the test tube.

In stark, personal terms, patients with serious and life threatening diseases have told us over the years that they do not have time to wait as we dot every "i" and cross every "t". They told us they want to make more of their own choices about the therapeutic risks they were willing to take. To many patients, experimental therapies represent a rare source of hope for conditions that seem to have outsmarted modern science. When a doctor looks a patient in the eye and says: there is no cure and not much to impede the disease's deadly course, people begin knocking on FDA's door.

And FDA has responded over the last decade by instituting new policies for drugs for serious and life-threatening diseases. In the last several years, the agency has approved four antiviral AIDS drugs, each in less than seven months: AZT, ddI, ddC and d4t. We have also expanded access to unapproved therapies.

None of this could have happened without some dramatic changes in the way we do business. What I would like to do first is to review what we have done to facilitate early access to new treatments. Then I will come back to some of the difficult policy issues that we talked about in that meeting several months ago between some activists and the FDA.

The agency's policy changes fall into two categories.

First, through a variety of mechanisms, we have expanded access to promising therapies before those therapies have been approved for marketing. And second, through the accelerated approval process we can approve drugs for marketing for serious and life-threatening diseases before all necessary studies are completed.

Let me begin with expanded access to unapproved drugs.

Historically, the agency has had several ways to make promising experimental therapies available prior to their approval. A Group C designation allowed cancer patients to gain access to unapproved drugs. The Emergency IND designation and open-label safety studies were other tools available to desperately ill people.

With the emergence of AIDS, we realized that existing approaches to expanded access needed to be formalized and augmented.

This next slide shows some of the mechanisms we have developed. We now have a parallel track program so that patients who are unable to join controlled clinical trials for one reason or another can still get promising therapies. This increases access for patients who can not travel to the site of the clinical trial or who do not meet strict entry criteria, for example. Industry is not permitted to charge for these experimental drugs, which are usually supplied by private doctors or clinics.

Although research was not the primary intent of the parallel track, we realized it was possible to capture some extra data on patient experience through this mechanism. For that reason, we found a way for physicians to secure a lot of safety information with a minimum amount of paperwork. This proved very helpful with ddI. ddI was approved partly because Bristol Myers had secured safety data from almost 8,000 people outside formal trials. In all, 26,000 people received ddI on the parallel track.

Another important mechanism is the Treatment IND. This has served as a bridge between the time clinical studies are complete, or nearly so, and the time a drug is formally approved. Sponsors are allowed to charge for therapies that are designated as Treatment INDs. One problem we've encountered is that most insurers don't reimburse for these drugs because they are still considered experimental.

The second major mechanism to speed approval is accelerated approval, what some have called conditional approval. To understand accelerated approval, let me take a moment and first briefly summarize the traditional drug approval process.

Clinical trials of a new drug typically have three phases.

In phase I, a drug is usually tested in a small number of healthy subjects to determine appropriate dosage and sometimes to gather other preliminary data. Phase II involves actual trials and includes control groups. Here, safety and efficacy information is collected in patients who actually have the condition for which the drug is being tested. Results from Phase I and II studies guide phase III studies, which can involve several thousand patients. Sponsors usually submit a new drug application or NDA after Phase III studies demonstrate clinical benefit. I should add that Phase IV studies, conducted after a product is marketed, can also be an important source of additional information.

This slide shows how the rules change for serious and life- threatening diseases. Drugs that show promise in Phase I and II trials may be made available through parallel track and treatment INDs and may receive accelerated approval prior to the completion of phase III studies.

A drug can be approved even in the absence of direct evidence that it affects clinical endpoints like illness or death. We rely instead on "surrogate markers." A surrogate marker is a laboratory measurement intended to predict clinical outcome. They are not unique to AIDS -- surrogate markers have been used in cancer and cardiovascular studies for years. CD4 cell counts, a measure of the strength of the immune system, have been used in approval of drugs for HIV infection.

Only drugs for serious or life threatening diseases for which no effective therapy exists qualify for accelerated approval. Requirements are shown on the next slide.

Accelerated approval is used only under carefully defined circumstances:

First, the surrogate must have a "reasonable certainty" of being correlated with clinical benefit.

Second, approval is conditioned on the completion of postmarketing studies to verify the anticipated clinical benefit.

Finally, if the sponsor does not demonstrate clinical benefit in a timely manner, accelerated approval will be revoked.

Our commitment to withdraw a product approval if the product does not demonstrate clinical benefit when all the studies are in, underscores a very important point: in the end, these drugs are being held to the same standards of safety and efficacy of traditional approvals.

Although we have not revoked an approval to date, we recognize that one day that is exactly what we may have to do. Eventually, we will make a mistake. We will approve a drug through accelerated approval that turns out not have a clinical benefit. Patients will have wasted precious time taking an ineffective product and perhaps they even will be harmed.

That's a risk we are all taking. But when it comes to getting therapies to dying patients, the riskiest thing we can do is not to take risks.

Let me summarize with the next slide the arguments for various mechanisms to get drugs for patients who need them.

To illustrate how accelerated approval has worked, I want to take you through our approval of ddI.

In October 1989, ddI was made available on an expanded access basis. Eventually, 26,000 patients received ddI before it was approved.

In April, 1991, Bristol Myers asked the FDA to approve ddI based on data from the very first phase of clinical studies.

Usually, we expect to secure only safety information from an uncontrolled phase 1 trial. We generally don't learn much about efficacy. And we certainly don't expect to make an approval decision.

But patients were desperate. Thousands had stopped deriving any benefit from AZT. Within a year, we knew we would have a lot more definitive information from three ongoing, controlled trials. For many, a year would come too late.

Researchers following patients in one of the controlled studies allowed FDA to take a highly unorthodox peek at CD4 cell counts. Although we were not sure of the precise relationship between a drug's effect on CD4 cells and its effect on survival, there was some scientific support for a link. We also had the expanded access data that demonstrated ddI's safety.

Less than six months later, in October 1991, we approved ddI, primarily because it increased CD4 cell counts- Albeit a slight increase.

However, we placed important conditions on our approval. We told Bristol Myers they had not yet demonstrated any clinical effect from ddI. We insisted the company analyze and submit more data when the ongoing trials were complete. We also said ddI would have to be withdrawn from the market if the expected results did not materialize.

In seven months, Bristol Myers came back with persuasive evidence of clinical benefit. Along with confirming the earlier approval decision, their data allowed the FDA to expand the indications for ddI and to lower the dose.

That approach became the model for the accelerated approval initiative. I think it is an important success story but it also highlights the risks we take when our knowledge is incomplete.

Let me move on then to some of the complexities and risks associated with expanded access and accelerated approval that I alluded to at the beginning of my remarks.

The first point is that we must strike a balance: give patients with life-threatening and serious disease access to new and promising therapies, while insisting that in the end we have the data to determine whether the drug will be of real benefit. We are striking a balance between access and answers.

Information about an experimental drug accumulates gradually. At some point on that continuum we decide that there is enough promise in a drug to make it available, even before studies are complete. But the less time that drug is in clinical trials, the less we know about it. That is why it is so critical that studies are completed to show whether the drug has an effect on clinical endpoints.

I think we at FDA can do a better job of making sure that sponsors undertake and follow through on the kind of studies needed to establish clinical effects. And we must insist on that data within a reasonable period of time after approval.

At the same time, we can't deny that getting answers can be complicated by the availability of the drug through expanded access.

One concern is that patients who feel a new therapy is their only hope may not be willing to be randomized into a trial where they might get a placebo or standardized care. If the drug is widely available through expanded access, they do not need to be part of a trial to get it. There is a tension here between providing access to dying patients and producing answers for future patients.

The dying patient today feels he or she has nothing to lose by trying the drug, but patients who can wait until studies are completed have much to lose if we are unable to collect the solid data required to guide their choices.

Another issue is that things can change between the time the trial is designed and the results are available. New drug combinations or advances in our understanding of surrogate markers may mean that the design of the original study and the questions it intended to answer no longer give us the data we need.

For example, it is not hard to imagine a scenario like this: Supported by up-to-the-minute research, a company suggests basing an application for accelerated approval on Surrogate A. The FDA agrees. But before the drug comes in for formal review, an article is published casting doubt on the value of Surrogate A and suggesting the use of Surrogate B instead. Despite the considerable resources a company has spent on data analysis -- and despite the FDA's earlier encouragement -- we may now insist that a new analysis be undertaken using Surrogate B. Patients and physicians will not get the answers they want when they want them. Industry will have lost time and money.

As someone recently observed, "Surrogate markers are not magic markers." When ddI was approved, CD4 cell counts were the best surrogate we had. We had to base our approval decision on what we knew at the moment -- but we also had to make sure we kept learning more. We now know more about the limits of CD4 cell counts as a surrogate for disease progression and survival. Better markers are clearly needed and researchers are now focusing on a drug's impact on viral load. We may eventually find that a combination of immunologic and virologic markers provide the most valid surrogate.

If we are going to use surrogate markers to speed drug approvals, we need good data assessing their validity. This fall FDA is cosponsoring three meetings on surrogate markers in an effort to advance the science in this field.

Let me be very clear: FDA stands firmly behind expanded access and accelerated approval for promising new therapies for serious and life-threatening diseases. But that commitment also carries a responsibility to ask the tough questions along the way and to be willing to adjust the policy when the answers demand it.

That is what is happening now. And it comes as a new class of antiviral treatments for HIV disease -- called protease inhibitors -- are in line as the next candidates for accelerated approval.

The activists at the meeting I referred to earlier were especially concerned that as we begin to review new protease inhibitors we learn from our experience with accelerated approval of the four nucleoside analogues. "We are not here to drive a stake into the heart of accelerated approval," they told me. But what I heard was a passionate plea to know more, sooner, about whether an experimental medicine really works -- and for whom, when, and in what doses.

There was enormous frustration that patients and doctors simply do not know what they need to know to make the best use of antiviral products on the market. They do not want the price of early access to be less information in the long run about the value of these drugs. They argued that we may need to delay drug approvals and perhaps conduct larger studies to get more answers.

Certainly the AIDS community is not in full agreement with that position. In subsequent meetings with other activists I heard great concern expressed about any policy changes that might curtail access to new therapies.

Just last month, FDA's advisory committee on anti viral drugs held a two day meeting at which the public was invited to offer comments on expanded access and accelerated approval. More than 200 members of industry and academia as well as patients and their advocates attended. Nearly fifty took the opportunity to come up to the microphone. There was widespread support for the accelerated approval and expanded access program but also intense discussion about problems that need to be addressed.

A number of speakers put provocative proposals on the table.

One suggestion was to make any drug that is a candidate for accelerated approval available first through parallel track. The goal is to ensure an extensive safety data base. Critics argue that this costs too much. They are afraid it might oust small companies from the race for new drugs.

Another proposal requires sponsors seeking accelerated approval to submit plans for postmarketing tests to a public forum - to our advisory committee. The intention here is to subject trial designs to close scrutiny and to make sure the FDA's expectations are clearly understood.

A lot of attention was also paid to large, simple trials. A large, simple trial some have suggested takes place in the real- world environment in which most patients actually use drugs.

As the next slide shows, the entry criteria are usually not very restrictive, the system of data collection is simple, and endpoints are easy to document. It is designed so that individual community based physicians can participate.

In general, the value of a large, simple trial is that it provides a large data base on how a drug is best administered in a clinical setting. The down side is that it tends to generate a lot of noise. The patient population is heterogenous, physicians may be lax about monitoring protocol compliance and consequently results may be difficult to interpret and it may be anything but simple. Some people say large simple trials should be a requirement for accelerated approval. Others argue that the design works best for postmarketing studies. Another approach is to try to gather the kind of data one gets from large simple trials from parallel track.

An alternative comes from Dr. Ellen Cooper, a former colleague at the FDA who is now with AMFAR (the American Foundation for AIDS Research). Dr. Cooper proposes large, but not-so-simple trials that include an ongoing, industry-sponsored master study. Before an AIDS drug would be considered for accelerated approval, the sponsor would agree to provide financial support and sufficient free drug to allow the drug to be tested in combination with other available therapies. A master trial would be fluid and flexible, incorporating new pharmaceutical regimens as they become available. The intention is to involve industry in a more vigorous, systematic and cooperative effort to improve the standard of care available to people with AIDS. Dr. Cooper's proposal also creates a framework for assessing the value of surrogate markers.

We will be reviewing these and other proposals and we will develop more specific guidelines for companies considering applying for accelerated approval.

Let me re-emphazise, we are absolutely committed to accelerate approval. Before closing, let me emphasize that building an effective system to get new and promising therapies to dying patients is not a task for FDA alone.

Over the past several years we have been communicating with industry about their new therapies at the earliest stages of drug development, so that we can move promising drugs through the system as expeditiously as possible.

It is an approach close to Charles Leighton's heart and he championed it ably. Gone are the days when the FDA waited passively until a drug company knocks on our door to say its completed application was ready.

Industry plays a critical role in making this system work. We can have parallel track regulations in place, for example, but the sponsor must produce the drug in sufficient quantity to make it widely available. I was disappointed to hear Hoffman LaRoche report at the recent advisory committee meeting that there will not be a sufficient supply of its new protease inhibitor, now in clinical trials, before mid-1995.

There is another industry-related issue that concerns me -- and I know it would concern Dr. Leighton as well. It involves incentives. When we put accelerated approval in place, we thought it would lead companies to invest research funds in AIDS development because they could bring drugs to market sooner. But something else has come into play. Our regulations provide for accelerated approval for drugs to treat patients who have no effective therapies available. Once AZT was on the market, companies tested drugs on populations who were not responsive to AZT to gain accelerated approval. And with each successive drug, the populations studied have narrowed. Of course that leaves open the question of whether a drug that was effective in a narrow population in clinical trials would be useful to the many other patients who don't meet those criteria. The fear is that while we hoped to be encouraging breakthrough drugs for AIDS, instead we may have inadvertently encouraged companies to go after small improvements in existing therapies that have been shown to benefit only very small portions of the affected population.

Finally, there are problems of equity and access that concern me greatly, but which we alone cannot solve. They involve access for underserved populations -- the poor, minorities and women with AIDS.

Just a couple of weeks ago, a group of women AIDS activists from here in the Philadelphia area told us disturbing stories of how their efforts to enroll in clinical trials are stymied. Women and minorities are also poorly served by the parallel track and treatment IND mechanisms. Medicaid and many other third- party payers generally do not cover unapproved drugs. As a practical matter, tens of thousands of people with HIV disease are cut off from expanded access initiatives because they do not have private doctors or other sources of comprehensive care.

d4T, the most recent nucleoside analogue to gain accelerated approval, highlights this problem. Eighty-five percent of the people who received the drug on parallel track were white. Obviously, that figure does not reflect the demographics of the disease.

Some progress has been made in terms of representation but there is still a long way to go.

Recently, however, several AIDS activists from the rural South reminded me how accelerated approval is increasing access for some undeserved populations. They said it was a day's journey to the nearest doctor willing to prescribe experimental therapies. Unless they had the time and the resources to make that trek, they had no way to secure promising, but unapproved, drugs.

Those of us from major East Coast and West Coast cities need to remember this reality. AIDS has no geographic boundaries. Access to cutting-edge medical care still does.

I have no doubt that accelerated approval and expanded access is the right policy to pursue. But getting drugs to patients quickly is not always as simple as it seems. That was brought home to me several weeks ago when I was reading an article in Barrons. In the artricle, a Columbia University professor was quoted as saying that the person who thought of accelerated approval and saw to its acceptance should be fired. Nobody ever promised me this job would be easy.