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Keystone Group Addresses Crisis in Post-Marketing Treatment Research and Access to FDA-Approved Therapies

So Many Drugs, So Little Data

The Keystone Center is a non-profit agency which brings together scientists and policy makers to develop consensus recommendations about urgent issues in biomedical and social policy. At the request of Vice President Al Gore, the Keystone Center convened a national policy dialogue on the establishment of clinical effectiveness research of HIV therapies. TAG policy director Mark Harrington was asked to participate in this dialogue, and wrote the following report for TAGline.

AIDS treatment activists cut their teeth on demanding reforms in the NIH drug testing and FDA drug approval process in the late 1980s and early 1990s. Our success has been such that there is an entirely new standard of care, and people newly-diagnosed with HIV can expect to live at least twice as long as in 1985. Indeed, by the end of 1996 we can expect at least eleven anti-HIV drugs to FDA-approved and on the market: five nucleoside analogues (AZT, ddI, ddC, d4T and 3TC), four protease inhibitors (saquinavir, ritonavir, indinavir, and Agouron’s nelfinavir), and two non-nucleoside analogues (delavirdine and nevirapine). The successes of research and activism bring with them an entirely new set of problems. No one has a clue about how best to use eleven antiretrovirals over the ten or more years of HIV infection. When to start? With what regimen? When to switch? How to use viral load, CD4 measurements and clinical status to optimize therapy? Which drugs are safe to combine?

Not only are we faced with unprecedented research and medical management questions, but the dawning era of managed care, along with cutbacks in Federally-mandated health care programs such as Medicaid and Medicare, are putting unprecedented pressure on the health care delivery systems upon which PWAs and people with HIV rely to receive treatment. Since third-party payers are not sure which HIV treatment regimens are the most effective, they may be unwilling or unable to pay for some obviously effective therapies. For example, New York State’s AIDS Drug Assistance Program (ADAP) covers all five nucleoside analogues–though only two of them, AZT and ddI, have ever demonstrated a clear survival benefit–while refusing to cover protease inhibitors, even though one of them, ritonavir, has clearly demonstrated a survival benefit in late-stage disease. Since the protease inhibitors are three times as expensive as the nucleoside analogues, ADAP figured out it could cover nucleosides for three times as many people, rather than covering possibly more effective protease inhibitors.

In the meantime, the pharmaceutical sponsors have yet to undertake significant phase IV post-marketing studies to determine how best to use these new anti-HIV agents. Thus, where the access crisis for AIDS drugs in the late 1980s focused on experimental treatments, now, in the mid-1990s, there is a new access crisis focused on already FDA-approved treatments. If insurers won’t cover them, PWAs won’t get them, and they’ll do no good.

Like the previous, FDA-centered crisis, the new one depends on designing clinical studies which can show how best to use these drugs. If their uses are more clearly defined, and benefits clearly proved, insurers will have much greater incentive to reimburse for these new treatments. Unfortunately, current clinical trials networks (see Spencer Cox’ s accompanying article) are inadequate to the task at hand. All NIH networks combined can enroll perhaps just 10,000 persons a year. Yet some of the post-marketing questions about protease inhibitors, or about opportunistic infection prophylaxis, may require larger, longer studies.

Vice President Gore asked the Keystone Center, a non-profit agency which tries to foster consensus-building about urgent science policy issues, to convene a broad national dialogue on how to address this emerging crisis. The first meeting of the Keystone process was held on April 30, and a final report is to be presented to the Vice President on August 1.

Participants include seven community advocates–Moisés Agosto of the National Minority AIDS Council (NMAC), Art Ammann, MD, of the Pediatric AIDS Foundation, Dawn Averitt-Doherty of the Women’s Information Service & Exchange (WISE), David Barr of Gay Men’s Health Crisis (GMHC), Ellen Cooper of the American Foun-dation for AIDS Research (AmFAR), Marty Delaney of Project Inform and myself–along with leaders of the ACTG and Community Programs for Clinical Research on AIDS (CPCRA), FDA officials, pharmaceutical company representatives, officials from National Institutes of Health (NIH), the Public Health Service (PHS), Health Care Financing Admin-istration (HCFA), Office of National AIDS Policy (ONAP), state health-care delivery officials, statisticians and representatives of health maintenance organizations (HMOs) and the insurance industry.

This unprecedented group of people is expected to develop a framework for conducting research to optimize medical management of HIV disease. The framework might include ways of coordinating existing clinical research networks (see Cox again), building new cooperation between the public sector (NIH) and the private sector (drug companies), as well as exploring the possibility of using managed care, HMOs, or the Veterans Affairs system to conduct long-term follow-up and randomized post-marketing studies of various HIV and opportunistic infection treatment regimens. Key issues will include who pays for this research, as well as where and how it is conducted. All the activists present agreed that it is a matter of the greatest urgency to focus research quickly on optimizing protease inhibitor use; otherwise, there is a very real danger that promiscuous or careless use of these powerful drugs will create an epidemic of protease-resistant HIV, rendering the drugs useless within five years or less.

Many activists have long viewed the pharmaceutical industry as having exploited accelerated approval to get drugs out quickly, then shirked its responsibility for carrying out appropriate post-marketing studies to more clearly define their drugs’ efficacy. Clearly, in the last year, Glaxo-Wellcome has failed to mount post-marketing efficacy studies of 3TC, and Abbott has failed to do so for ritonavir. Now that the FDA is no longer the arbiter of last resort with regard to anti-HIV drugs, the insurance industry and third-party payers (including Medicare, Medicaid and ADAPs) are becoming the arbiter, for if they refuse to subsidize the treatments, people with HIV won’t get them. It will be critical over the months leading up to August to force industry, NIH, FDA and insurers to agree on an infrastructure and a research agenda to ensure that people with HIV receive the information–and the treatments–they need to live.

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