AIDS Treatment News
FDA Explores New Antiretroviral Trial Designs: Interview with David Feigal, M.D.by John S. James
On July 14 and 15, at a public meeting of the FDA Antiviral Drugs Advisory Committee, experts from government, industry, academia, and the community will explore new approaches to designing antiretroviral drug trials, based on current knowledge of HIV disease (see announcement in AIDS TREATMENT NEWS #272, June 6, 1997). On June 12 we interviewed David Feigal, M.D., M.P.H., Director of the Division of Antiviral Drug Products of the U.S. Food and Drug Administration, about current problems in clinical trials, what is needed now, and the FDA's plans for the July meeting.
A new anti-HIV drug can get "accelerated approval" by showing statistical proof of benefit in viral load and other indicators of HIV disease progression. But then the drug must undergo much larger "confirmatory trials," to show statistical proof that it reduces death or major opportunistic infections. These large trials are sometimes called "clinical endpoint" studies, because a participant is recorded as having reached an endpoint in the trial when a major disease event occurs. Because clinical endpoints are relatively rare, and depend on many factors besides the drugs used, these trials usually need to be very large -- usually with more than a thousand volunteers -- to get statistical proof that one of the drug regimens being tested is better than another. These large confirmatory trials have become increasingly problematic as knowledge of HIV disease has advanced, and volunteers do not want to continue using treatments which are not working for them.
The ideas which the FDA is now exploring, which it explained to treatment activists in a community meeting on May 16, would leave accelerated approval as it is today. But companies could choose whether to run the current kind of clinical-endpoint trial, or a new kind of confirmatory trial, which in many cases could record effective viral suppression over a period of time instead of recording clinical endpoints. In these trials, each volunteer would quickly stop any treatment which was not suppressing the virus, be counted then as having reached a treatment failure, and switch to whatever treatment they and their physician decided. This would be very different from the current system, where participants are encouraged to stay on their assigned study regimen until the trial is over, or until they become seriously ill -- which allows viral resistance to develop when participants stay on regimens which do not suppress the virus completely.
By using modern understanding of HIV to individualize the process of dropping ineffective regimens, the new approach should result in more ethical trials, which will be easier to recruit because they are more attractive. Also, these trials should avoid the bias which now occurs when volunteers recognize treatment failure which is not handled in the protocol, and drop out on their own.
Interview with Dr. Feigal
AIDS Treatment News: The FDA is considering changes in the requirements for confirmatory trials of antiretrovirals, to not require clinical endpoints in some cases. What is the main problem these changes are intended to solve?
Dr. David Feigal: I believe that the central problem with current clinical trials is not clinical endpoints, but the concern about having suboptimal study arms. For example, a study may compare two treatment regimens: an old one that we know something about, and a new one, to see if the new one is better. People do not want to put the volunteers at risk for losing drugs that could personally benefit them, by administering the drugs in such a way that the study participants are likely to become resistant, or to become intolerant in some other way.
And because many of the drugs are related to each other, there really are not that many of them. Even though eleven antiretrovirals have been approved and there are several others with more limited availability, many have overlapping resistance, or similar toxicities for patients, that limit what you can do with them.
So we have looked at what are the ways that a treatment regimen can be suboptimal. And much has been learned over the last several years, from studies of drugs' effects on viral load. We have become quite convinced that viral load measures are sensitive enough to detect when a drug regimen is effective, and they are also sensitive enough to detect when a regimen has lost its effectiveness, which can happen from a variety of reasons.
Back when there were not many drugs, there were not many choices, other than take one for as long as you could; there was only one drug, or only two that were available. But now that we are individualizing therapy, there is much more in the art of assessing whether a given combination of drugs is producing an adequate response, and trying to get an adequate duration of response. So whether or not the person is someone who is at risk for developing infections or clinical endpoints, we need to make sure that people take the drugs in such a way that they will respond to them as well as possible, for as long as possible, and with the least interference with the use of whatever other drugs are left for that person to take.
ATN: Then the basic idea seems to be to design the protocol so that people stay on the therapy as long as it is working for them, in terms of keeping viral load completely suppressed?
DF: That's right. If you had a drug combination that had a good response in a group, the old approach would be that you take those drugs until you had a clinical event, or until the study ended, or until CD4 counts fell in half, or something else like that. The new approach would say that once someone starts on a study regimen, the first thing we will do is test whether or not that person got an adequate [viral load] response. If not, that is a failure already, and there is no reason for that person to continue to take that particular regimen. And for the participants who get a good response, then of course we want to see how long that response will last.
This is a different approach than we had in the past. It is not the fault of some of the old trials, which did not even have real-time virology [viral load tests which get accurate results without having to be batched and run later] available to them at the time those studies were done. But in the past, many of those participants would not have had a satisfactory response in the first place, and some of them would have lost the response; then they just were followed, while their viruses were developing resistance to the drugs that they were replicating in the face of. So we think we can do the trials in a way that is not only more ethical, but also will provide the kind of information useful in clinical practice.
ATN: You will be looking at something like a 48-week period for the main part of the study?
DF: Yes, one of the major goals of HIV therapy is to be able to have an effect that lasts as long as possible. You cannot determine if something works for a long time with a four- month study. We want the study duration to be long enough to show us how long some of these drugs work. Of course we would like them to work longer than a year; if we had a well- tolerated regimen, it would be great if it worked for multiple years. But a year seems to be a reasonable compromise.
If a company has a new agent that is particularly promising, or has some information based on earlier data, it could seek accelerated approval, and then get the additional data over a longer time period.
During that time, the trial would follow people who had satisfactory responses, and then try to understand why some patients were losing their response. Were they losing it because resistance had developed? Because they had started a new medication for some other reason, and there was drug interaction? Were they losing it because the regimen was too hard to comply with, and they became careless about how faithfully they took the medication? Much of this information we never systematically collected; we had bits and pieces of it. But this is what you need to know to use these drugs in the modern era.
ATN: I understand that in the first part of these trials, you will look for the total viral load drop?
DF: Part of the reason for doing that is that there still is a need to understand how potent the different drugs are. And for that, you need to have complete data on people, at least for a short period of time.
So we hope that one feature of the study design will be an early study period, to assess how many patients get an adequate drop -- and that companies will study a wide enough range of viral load to get a good measurement of that.
One question is, what is the best way to characterize the degree of viral load drop due to a treatment? Should it be the percent of patients who become undetectable by current assays? Or should it be the size of the initial drop in virus? It is not either/or; you want to know both. If we just wanted to know the percent of patients whose viral load became undetectable, that would create an incentive to just study early patients with low viral levels; those are the easiest patients to suppress.
We think we will get a better picture, and a better estimate of the potency, if we say that we want to answer our four big questions:
ATN: Concerning the July 14-15 meeting of the Antiviral Drugs Advisory Committee, what is the format and purpose of the meeting?
DF: We have asked the companies, academic centers, and government study groups that have data -- data that can answer some of these questions that are needed to design these protocols -- to come in, not to present their whole studies, but to present parts of them. For example, some design questions would be influenced by how much variability there is in the same person when you just measure the virus from day to day. So we invited people who have done studies which generated data on variability, asked them to come in and make a presentation.
The format of the meeting will be for us to break the questions apart. If the question is, for example, determination of treatment loss of response (so-called "treatment failure," which I prefer to call loss of response), how much do people bounce when they are at a low viral load level? How often do you see someone who is at a very low level (of virus) have a little spike, but nothing else happens over time? Many of these trials were not trying to individualize therapy, so they have observed what happens over time; they will be able to help us design the studies so that one does not yank a therapy too quickly, because of background noise, and give us a better sense of how the assays perform.
If you step back and look at the big picture of what we are asking the Committee, we are asking a couple of very fundamental questions. One, is there adequate evidence that there is clinical benefit from lowered viral load per se? If reducing viral load really is a goal of therapy, then that should be the indication of the therapy. Now the drug labeling sort of says, "Indicated to treat HIV." That does not really tell you exactly what you are doing and how you are doing it.
We are asking, for antiviral drugs, have we moved to the era where we should focus in on the virus itself?
The other change, which is a little more subtle, is that in the past, when we looked at surrogate markers like the CD4 count, or viral load drop, the emphasis was on getting complete data on everyone for a fixed time period, with everyone trying to stay on drug. We wanted to see which treatment had the better group average response. Obviously one of the problems with those studies was that the patients whose markers were doing poorly left the study, and artificially affected the measure -- making the counts look better than they were, because people with unfavorable counts would drop out.
Now, instead of asking what is the average effect of taking the regimen for a period of time, we are asking what percentage of people get an adequate response, and how long does that last? It is much more of a time-to-event. You only stay on a therapy if it works; and you only keep taking it if it continues to work. We are essentially asking the Committee, is the data on viral load good enough that we can rely on it to do this?
Although the issue is phrased as whether we are leaving clinical endpoints, from our standpoint we are not. We hope that companies will continue to study new products in a spectrum of HIV conditions -- including patients with very low CD4 counts and high viral load, that are at high risk for developing infections and other complications. In those trials, they should be able to tell whether or not totally suppressing the virus with one regimen is just as good as totally suppressing it with another. Or is there some other problem that emerges?
Similarly, there should be studies of patients with early disease, to try to get at the questions you want to answer about early disease.
To us, the issue is not are we going to stop studying patients that are developing infections. The real issue is to see how well we can combine drugs, to individualize therapy, and to see how useful a product is within a combination, in different stages of the disease.
ATN: In this meeting, will there be any focus on the problems of getting the companies to work together, and be willing to have their drugs tested with competitors' drugs?
DF: I am sure that this issue will be raised in the public comment section. I know that has been an important issue for the community, and for practitioners who want to know information about certain options. It is clear that there are times when decisions about what types of studies to do are made by companies based on their interests in seeing what they can do with their own products; as you know, several of the companies have multiple products. They may well be missing opportunities to find combinations which are particularly effective, which would require testing their drug along with their competitor's product. I hope that some of the independent studies that are often done by groups such as the ACTG will level that playing field a little bit.
Given the way that the drug development structure is based often on economic incentives, a company would have to see that if they found that their product was useful with their competitor's product, that would have some economic advantage to them. Their first take may well be that this would not be as advantageous as selling two of their own products, so they will test that first.
But there is much screening that needs to be done, and many products to be tested. Hopefully, by basing clinical trials more on viral load and less on studies that look for disease progression, the studies will be small enough that we will be able to more efficiently screen promising combinations. And studies that in the past might only have been feasible with large-scale corporate or government sponsorship could then be done on a more modest scale, to identify hot leads to follow.
ATN: Is there a way for the public to submit written comments to be considered by the Committee, if one is not going to be there in person?
DF: Send them to Rhonda Stover, the executive secretary. They can be provided as background to the Committee members, either in the mailing we send them before they arrive, or in their packet at the time of the meeting.
[Mail or fax comments to: Rhonda Stover or John Schupp, Center for Drug Evaluation and Research (HFD-21), Food and Drug Administration, 5600 Fishers Lane, Rockville, Maryland 20857, phone 301/443-5455, fax 301/443-0699. Those who would like to speak during the public comment period at the meeting, July 14 from 11 a.m. to noon, should notify them by July 7. The meeting will be 8:30 a.m. to 5:00 p.m. each day, in Room 204 of the Armory Place, 925 Wayne Avenue, Silver Spring, Maryland, walking distance from the Silver Spring Metro stop.]
Protease Inhibitors: FDA Warns Doctors of Diabetes Risk
On June 11 the U.S. Food and Drug Administration warned AIDS physicians that there might be a small risk of developing diabetes due to use of protease inhibitors. Eighty three cases had been found, of which 27 required hospitalization and six were life-threatening, out of an estimated 110,000 U.S. patients now prescribed these drugs. Even allowing for major under reporting, the "attack rate" appears to be well under one percent -- and it is not known for sure that the drugs caused the illness. There is no evidence that any of the four available protease inhibitors is better or worse than any other.
The FDA did NOT recommend stopping protease inhibitors as a result of this information, but wanted health professionals to be aware of the possible problem, so that patients will be tested early for diabetes if symptoms develop.
"HIV patients on protease inhibitor therapy should know the warning signs of hyperglycemia and diabetes: increased thirst and hunger, unexplained weight loss, increased urination, fatigue and dry, itchy skin." (quoted from FDA Talk Paper, "Health Advisory for Newest Class of AIDS Drugs," June 11, 1997).
Letter to Doctors
The following letter was sent to about 13,000 physicians and other health-care professionals, who account for about 95% of all HIV prescribing in the U.S.
Subject: Reports of diabetes and hyperglycemia in patients receiving protease inhibitors for the treatment of human immunodeficiency virus (HIV)
Dear Health Care Professional:
The Food and Drug Administration would like to call to your attention recent post marketing reports of new onset diabetes mellitus, hyperglycemia or exacerbation of existing diabetes mellitus occurring in HIV-infected patients receiving protease inhibitor therapy. At the present time there exists no conclusive evidence establishing a definite causal relationship between protease inhibitor therapy and the incidence of diabetes and hyperglycemia. Based on present reporting, we believe the occurrence of this event is relatively infrequent. As such, patients for whom these products are indicated should not discontinue therapy without consulting their health care professional. However, given the potential seriousness of this complication, we believe that patients and health care professionals should be notified of this information.
Summary of Reports
* As of May 12, 1997, there have been 83 cases reported to FDA of diabetes mellitus or hyperglycemia in HIV-infected patients who were receiving anti-retroviral protease inhibitor therapy; 27 of the 83 cases were reported to require hospitalization. Fourteen patients were known to be diabetic at baseline; for these patients, there was a loss of glucose control. The average time of onset was approximately 76 days after initiating protease inhibitor therapy, but occurred as early as four days after starting therapy. Five cases of diabetic ketoacidosis occurred, including patients who were not reported to be diabetic at baseline; however, the baseline status of these patients is not well characterized.
* Some patients required either initiation or dose adjustment of insulin or oral hypoglycemic agents for the treatment of these events. On an average, fifty percent of patients discontinued their protease inhibitor therapy as a result of this acute adverse event. Hyperglycemia persisted in some patients after protease inhibitor therapy was withdrawn including patients not known to be diabetic at baseline; however a causal relationship between protease inhibitor therapy and these events has not been established.
* Many of these reports occurred in patients with confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycemia.
"FDA will continue close monitoring for additional events. We encourage all health care professionals to report any cases of diabetes or hyperglycemia, or any other serious toxicity associated with the use of protease inhibitors, to the FDA's MEDWATCH program at 1-800-FDA-1088/fax 1-800-FDA-0178; or to the respective pharmaceutical manufacturers: [phone numbers included in the letter]."
1592: Protests on Small Access Program
1592 (generic name abacavir), an important experimental HIV treatment being developed by Glaxo Wellcome, has been in development for about nine years but has so far only been given to 200-300 people (it was first tested in people in 1995). Glaxo has announced a small "compassionate use" program, scheduled to start in July, to make 1592 available to 2500 adults and children worldwide (in countries where the drug is already in clinical trials). In this program, 1592 will be distributed at only about 50 sites in the U.S.; according to Glaxo, these sites will accept patients referred to them. The company also plans to start a larger "expanded access" program, hopefully by early 1998, although no date has been set. [For more information on 1592, see AIDS TREATMENT NEWS #271 (May 16, 1997), #261 (December 20, 1996), #259 (November 15, 1996), and #253 (August 23, 1996).]
AIDS advocates are concerned that thousands of people with no other treatment option may be unable to obtain this new drug for at least the next six months, due to the small size of the initial program.
Glaxo has given two reasons for the limitations of the compassionate use program: production difficulties in scaling up the manufacturing process, and limited human experience with the drug. The company points out that it plans to increase human use of 1592 from about 250 now, to about 4500 in six months: 2000 in phase III trials, plus 2500 in open- label compassionate use. Most advocates expect that 2500 slots will be far too few for persons who have no other options; they acknowledge that there are production difficulties but suspect that capacity is largely determined by decisions on how much money and other resources are made available, especially with a drug like 1592 which does not appear to be particularly difficult to manufacture. Also, they believe that persons with no other satisfactory options should be allowed to take the risk of using a drug early in human testing, pointing out that ddI was made available before approval to almost ten times as many people as planned for 1592, based on about the same human experience as 1592 has now.
Programs for pre-approval expanded access to AIDS treatments have become far more restrictive in the last year and a half. The PWA Health Group researched this history, and noted the contrast between the large expanded access programs for ddI, ddC, d4T, and 3TC (the largest expanded access program of all, by Glaxo Wellcome), compared to far smaller programs for the protease inhibitors saquinavir, ritonavir, and indinavir -- and for the initial "compassionate use" program for 1592 (with a larger "expanded access" program announced for later, but with no specifics given).
Some of the protests are:
* The 1592 Access Coalition, a group of over 20 activists, are circulating a sign-on letter to AIDS organizations (see below). The letter will be sent to the CEO of Glaxo Wellcome.
The 1592 Access Coalition is also working with the White House, through the Office of National AIDS Policy director Sandra Thurman.
* Activists are planning a national boycott of Glaxo's over- the-counter product Zantac. For more information, contact ACT UP/Golden Gate, 415/252-9200, fax 415/252-9277, email email@example.com.
* On May 31, 300 AIDS activists from New York, Philadelphia, and Cleveland conducted a die-in at the POZ Life Expo in New York, protesting lack of access to experimental AIDS medications by persons who need them. After learning of the planned demonstration, Glaxo Wellcome withdrew from the Expo.
At this time no information has been released on exactly when the July access program will start, nor what number physicians or patients should call to register. More information may be available within a week or two.
1592 Access Coalition Consensus Letter
The following letter, addressed to Robert Ingram, Chief Executive Officer of Glaxo Wellcome, is being circulated to AIDS organizations for sign-on. Organizations can sign the letter by faxing their endorsement to Linda Grinberg at FAIR, 310/471-4565. If you have any questions or need more information about 1592 or the proposed access program, contact Ron Baker at 415/487-8065. If you want to join the Coalition or be more involved in the protests, leave a message for Jeff Getty at ACT UP/Golden Gate, 415/252-9200.
Re: Development of Abacavir (1592)
Community treatment advocacy groups and activists watch with growing concern as the major pharmaceutical companies continue to reduce the size of compassionate use and expanded access programs for promising new AIDS drugs. The limited 1592 compassionate use program proposed by Glaxo Wellcome provides the most recent example of the industry's misguided policy on early access.
The individuals and organizations listed below call on Glaxo Wellcome to take the following actions regarding 1592:
I. Compassionate Use Program.
A. Commit to significantly increase the size of the compassionate use program scheduled to begin in July 1997. (It is anticipated that more than 10,000 patients worldwide may need 1592);
B. Triage patients to ensure those in most critical need are given highest priority;
C. Provide monthly progress reports to designated community representative(s) regarding production capacity and patient enrollment;
D. Describe procedures to ensure equity of access and avoidance of preferential treatment to patients at selected sites;
E. Provide the drug to patients who cannot access the medical sites designated by Glaxo. (Traditionally, compassionate use programs reach patients through their healthcare providers.)
II. Expanded Access Program
A. Initiate an expanded access program at the earliest possible date in 1997;
B. Provide details regarding inclusion/exclusion criteria, size and scope of program, distribution plans, and other pertinent information as soon as possible.
III. Protocols and Clinical Trial Sites
Provide information on 1592 protocols and identify clinical study sites, as promised, immediately.
IV. Accelerated Approval
A. File for accelerated approval of 1592 no later than March 1998;
B. Initiate rolling data submissions to FDA as soon as possible.
Promising new therapies such as 1592 must become available as soon as possible to people without treatment options who face disease progression or death. Community advocates and activists call upon Glaxo Wellcome and all AIDS drug manufacturers to recognize that people with advanced disease have a basic right to speedy access to new experimental therapies when all other treatment options have failed.
"We look forward to receiving your response to our concerns regarding 1592."
1592 Access Coalition
Ron Baker, Bill Bahlman, Peter Cashman, Sally Cooper, Paul Davis, Martin Delaney, Jeff Getty, David Gilden, Linda Grinberg, John Iverson, Cleve Jones, Kate Krauss, James Learned, Jules Levin, Andrew Lipschitz, M.D., Joel Martinez, Eileen Mitzman, Leigh Paidolfino-Danas, Lili Rundback, Matthew Sharp, and Theo Smart
The letter has only been available for a few days before this
article went to press. The following AIDS organizations have
endorsed it so far:
Whatever happens with access to 1592, what is most important is to use all antiretrovirals well. It is widely agreed that a single drug should not be used by itself, and should not be added by itself to a regimen which is failing to control the virus. Otherwise the virus is likely to develop resistance to the new medication, and the patient will lose most or all future benefit of using that drug, or other treatments to which the virus may be cross resistant. To help prevent this, at least two new drugs should be added at the same time.
One reason for the importance of 1592 is that many people have already used up most of their antiretroviral options, as a result of the way these drugs were used in the past, when less was known about HIV treatment. 1592 may be a potential addition to the one or two treatments they have left.
Those who cannot get access to a combination which is promising for them might choose to wait to change treatments, if possible, until a better regimen is available -- rather than adding new drugs one by one when they become accessible.
None of this justifies any delay in making a new treatment available to patients and physicians (such as the idea of holding back a drug until it can be provided with other drugs). Each person is different -- and many now have one or more approved treatments which they could use, but also need something else, such as 1592, to put together a promising antiretroviral regimen for themselves.
Help Wanted, Washington D.C.: "Network Correspondent"
"National, nonprofit AIDS advocacy organization seeks individual to communicate with and grow its grassroots network of community-based member organizations nationwide. Applicant must have the ability to rapidly and effectively translate and communicate legislative activities and policy, as well as member benefits, to a national base of constituents. Candidate should have one to two years experience working in a nonprofit, government, or lobbying organization with demonstrated experience writing and communicating legislative policy issues. Experience in writing fax alerts and educational documents a plus. Women, people of color and HIV positive individuals are strongly encouraged to apply. Send cover letter and resume to: AIDS Action, 1875 Connecticut Avenue, NW, Suite 700, Washington, D.C. 20009."
For many years the AIDS Action Council has been better at inside lobbying than at grassroots organizing. Community organizers have not been given the status and authority within the organization which they would need to be effective. It is possible that the right person could do important work in this job, but applicants should be aware of the history.
San Francisco, Oakland: Treatment Access Workshop, June 27, July 11, July 18
A three-hour workshop, "Providing Access to Treatment: New Drugs, Clinical Trials, and the Internet," for AIDS professionals and volunteers will be held three times: in Oakland June 27 (at the Center for AIDS Services), and San Francisco July 11 and July 18 (UCSF Mission Center building). Topics include the new Federal guidelines for HIV treatment (not yet released as this issue goes to press), linking clients with clinical trials, and HIV information on the Internet.
This workshop is intended for: registered nurses (who can receive 2.5 hours CME credit), other nurses, social workers, case managers, counselors/peer counselors, benefits counselors, patient advocates, treatment advocates, patient/client educators, hotline workers and volunteers, and other AIDS service providers.
There is no charge for this workshop, which runs from noon to 3 p.m. But space is limited, and advanced registration is requested. To register, or for more information, contact the Community Consortium, fax 415/476-4734, or phone 415/502- 0657.