translation agency

Gay Men's Health Crisis
EDITORIAL: After Concorde

May 1, 1993
GMHC Treatment Issues 1993 May 1; 7(4): 3

The release of the Concorde data was a significant and rare event. It has caused thousands of HIV-infected people to reconsider their own treatment decisions. Additionally, the study and the controversy that surrounds it are already influencing many of the current debates in AIDS research. The news media understood that Concorde was important; however, they did not fully explain the many nuances in the discussion. For instance, the media coverage contained few scientists or patients. Lead stories on the networks and headlines in The New York Times and The Washington Post questioned the efficacy of AZT and reported on the falling stock price of the company that manufacturers the drug. However, for the most part, the stories did not explain the impact Concorde is having on people with HIV, prescribing physicians, and AIDS researchers.

Due to the importance and complexity of the study, Treatment Issues offers coverage of it in a slightly different way. Rather than publish one comprehensive article, we asked leading AIDS researchers and physicians in the U.S. to comment on the significance of the Concorde data. All responses appear in their complete form. Brief excerpts from the public statements of the Food and Drug Administration (FDA), the National Institutes of Health (NIH), Burroughs Wellcome, and Project Inform are included for a sense of the initial institutional response. Additionally, this editorial is presented to help provide a preliminary context for the discussion. Treatment Issues encourages written responses to any of the issues discussed.

Although skeptical scientists have yet to scrutinize Concorde, flaws have already become apparent. As more data are released and analyzed, different conclusions may well be made. However, to say Concorde contains flaws is not enough at this point to dismiss outright its conclusions. Every scientist realizes that clinical research never runs with textbook efficiency. Nor are there ever any perfectly designed or implemented clinical trials. In fact, many have argued that the American studies which suggest a benefit to early AZT use, such as ACTG 019, contain their own methodological errors. The limitations of Concorde, therefore, must be balanced against its statistical power, relative size, and length. Concorde is, by far, the largest, most powerful, and longest-running AZT study ever.

Many in the media suggest that Concorde disproves other AZT studies. This is not entirely true. Concorde addresses a different question than previous AZT studies. It examined the long-term effect of AZT on the survival of asymptomatic patients. ACTG 019 examined only the effect of AZT on disease progression (i.e., the occurrence of opportunistic infections) in this population up to one year. It was too small and too short to examine the ultimate survival of the study participants.

To knowledgeable AIDS researchers, Concorde was no big surprise. Many have recognized for some time that the effect of early AZT on survival is unresolved. In fact, in the September 1992 Treatment Issues, we noted that Sam Broder, M.D., the highly respected Director of the National Cancer Institute, had urged researchers at the International AIDS Conference in Amsterdam last summer to design studies to answer this fundamental question: Does early AZT therapy truly prolong the lives of asymptomatic people? So why all the fuss? Concorde underscores the uncertainty many AIDS researchers and clinicians feel. A few years ago, many physicians believed that the nucleoside analogs (the class of compounds which include AZT, ddI and ddC) would transform AIDS into a so-called "chronic manageable" condition. There is now a deep and growing sense among many that some of the basic assumptions underlying AIDS drug development need to be reexamined. From the criteria used to approve new drugs rapidly to fundamental ideas of how HIV causes immune collapse, researchers have lost consensus on the central questions in AIDS research.

An open discussion on the approval criteria for early intervention drugs is clearly needed. While no one disputes the necessity of rapid approval for AIDS treatments, Concorde raises the question about the applicability of the same expedited approval criteria to treatments for asymptomatics. Many now ask if it is wise to approve treatments for asymptomatics based on small CD4 cell increases which growing data suggest do not indicate ultimate clinical benefit in this population. As more and more companies take advantage of early approval regulations to develop new therapeutic vaccines, new antiretrovirals, and immunomodulators for asymptomatics, the problem has become more acute.

The benefit of early intervention with nucleoside analogs is not clear anymore. While hardly anyone believes that AZT should be pulled from the market, the official government recommendation that all healthy, asymptomatic people with less than 500 CD4 cells take AZT must be reexamined. Ongoing trials of combination nucleosides for early intervention are now much more critical. However, like other U.S. AIDS studies, the combination studies have been criticized for a heavy reliance on surrogate marker data, in particular CD4 cell changes.

Although the CD4 data from Concorde surprises no one-other studies, including ACTG 116b/117, the Alpha study, the VA study, and the CPCRA ddI/ddC study, all suggest that small CD4 changes are independent of clinical outcome--clinical researchers are unsure what to do next. There are no obvious, well-defined surrogate markers available to replace CD4. Already some in the media suggest that Concorde's ultimate effect will be to lengthen the drug approval process by forcing a return to traditional trial designs using clinical endpoints.

On a broader level, Concorde raises disturbing questions regarding the U.S. AIDS research effort. More studies of the nucleosides are likely to provide some additional information to doctors and their patients. Yet, how do we design future clinical trials of these drugs to give us the answers we need? Moreover, have we reached the point of diminishing returns with the nucleosides? Are we better off using the limited AIDS- research dollars to develop and test new, more promising classes of compounds? Is there anyone who is presently developing an overall strategy and program for developing anti-HIV therapies? Are the President and the Secretary of Health and Human Services really using the powers of their respective offices to get the best and the brightest to lead our AIDS research effort? The blizzard of press releases responding to Concord reveals the extent of the personal and professional investment many U.S. researchers have in AZT's efficacy. While one should expect a profit-driven corporation like Burroughs Wellcome to interpret the data favorably, U.S. government agencies should be held to a different standard. Sadly, many researchers and government bodies appear to have participated in "spin control" of Concorde. We believe that Concorde researchers have a responsibility to release complete data from the study without delay, and that U.S. government officials, researchers, and doctors must let the science and the study speak for itself.

No one really understands the effect of the multiple drug combinations many people with HIV and AIDS take. Many patients, particularly those with advanced AIDS, are often treated with a dozen drugs a day. The risks, and also the costs, of multiple drug treatment seem remote when the stakes are so high. However, there are real risks. One recent example is the discovery of azole-resistant fungi in those treated with fluconazole primary prophylaxis. If azole-resistant fungi become common, it could have immense negative effects on all people with AIDS. Additionally, the possibility of adverse drug interactions cannot be eliminated and, therefore, must also be acknowledged. Finally, physicians must ensure patients clearly understand that many of the treatments they receive offer no documented chance of ultimate clinical success.

Prescribing physicians have had to ask themselves very difficult questions about their personal relationship to their patients. Unquestionably, doctors prefer to cure disease rather than comfort the dying. Accordingly, a knowledgeable and compassionate AIDS doctor told Treatment Issues privately that he would continue to prescribe AZT for his asymptomatic patients even if it did not work. He said there was nothing else for him to do. This doctor's candor highlights the real context within which physicians and patients alike make treatment decisions--the relentless progression of disease and death. The role hope and fear play in designing and interpreting clinical research must be discussed openly.

Copyright (c) 1993 - Gay Men's Health Crisis, New York City, NY Noncommercial reproduction encouraged. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. http://www.aegis.com

www.aegis.org