This is the third in a series looking back at the first two decades of TAG's work to speed up AIDS research. In Part I: TAG's early campaigns to reform the National Institutes of Health (NIH) AIDS research, boost the federal budget, and revitalize HIV basic science research. In Part II: TAG's response to bad drugs, badly designed clinical trials, and inadequate surrogate markers. Here we look at the rise of highly active antiretroviral therapy (HAART) and the push for evidence-based HIV treatment.
The approval of therapies based on inadequate, ambiguous, uninterpretable or incomplete data offers severe and potentially insurmountable difficulties in the future evaluation of new treatments. This is the deck with which the current therapeutic house of cards was built.
-- Spencer Cox, Testimony before the FDA Antiviral Drugs Advisory Committee regarding accelerated approval of stavudine (d4T), May 20, 1994
As we pointed out in the previous article in this series about TAG's accomplishments in its first two decades, the early years of antiretroviral therapy (ART) development recalled Matthew Arnold's "Dover Beach": "And we are here as on a darkling plain / Swept with confused alarms of struggle and flight, where ignorant armies clash by night." The disappointments of the early monotherapy and dual-therapy years between 1987, which saw U.S. Food and Drug Administration (FDA) approval of AZT (Retrovir), and 1995, which saw that of the first protease inhibitor, saquinavir, were succeeded by a difficult-to-believe series of breakthroughs in viral-load monitoring, clinical trials design, and rapid development of new molecules, which came together in 1996 to form the breakthrough known as highly active antiretroviral therapy, or HAART.
The development of HAART, which first came to fruition after fifteen years of basic and ten years of clinical research on HIV treatment, was not rapid, preordained, linear -- nor was it always logical. From the contemporary vantage point, with over 32 new chemical entities (NCEs) and fixed-dose combination (FDC) therapies approved by the FDA, it is not always clear what combination of activism, industry, regulation, and research was required to lead to this discovery, which has now resulted in over 8 million people around the world receiving relatively safe, unusually effective combination therapy for a lifelong infectious and almost incurable disease, HIV infection.
Clinical drug development for HIV before HAART can be roughly divided into three periods:
Soon after AZT's approval by the FDA in March 1987, it became clear that its benefits were transient and limited by severe anemia and other toxicities, and that treatment failure was associated with the emergence of HIV resistant to the drug. Thus, even in 1989, it seemed obvious to Burroughs Wellcome's leading virologist, David Barry, who led the AZT development team, that "you're going to have four or five drugs for the OIs and two, three and maybe four drugs for antivirals."
Dr. Barry's prediction was right, and a number of companies began fortifying their pipelines. Manufacturers either bought potential HIV agents, as did Bristol-Myers with ddI and Hoffmann-La Roche with ddC; licensed them, as Bristol did with d4T; or set out to modify existing renin inhibitors (a class of blood pressure medications industry was attempting to develop from the 1970s on) to develop aspartic protease inhibitors (PIs), that could bind and inhibit the protease enzyme of HIV-1. Researchers from a number of companies including Abbott, Merck, and Roche began efforts to crystallize the HIV-1 protease enzyme and to screen compounds that blocked its activity, as did the National Cancer Institute (NCI).
Early in 1990, I remember gazing in wonder at a giant model of the crystallized protease enzyme published by the NCI in 1989, with little sense of whether its therapeutic promise as a target was likelier to become science or science fiction. The first PI wouldn't be approved until late 1995. We'll never know whether a sensible, directed research approach -- if that isn't itself an oxymoron -- could have accelerated this discovery.
By summer 1994, TAG and allies such as David Barr and Derek Link at GMHC and activist Carlton Hogan from the University of Minnesota clinical trials coordinating center had come to believe that a new approach to AIDS clinical trials was necessary, one that allowed flexibility in the control arm (participants could take whatever approved or parallel-track HIV drug they wanted) but that restored rigor to the process by randomizing participants to receive a new PI or a placebo at a 2:1 ratio -- and that used clinical endpoints, notably time to an AIDS-defining event or death -- rather than relying on the discredited surrogate marker of CD4 cell-count changes due to therapy.
We then released our report, Rescuing Accelerated Approval: Moving Beyond the Status Quo, which was distributed at a contentious FDA advisory committee hearing in September 1994 (reviewed in "On a Darkling Plain" in the October 2012 TAGline).
TAG and our allies worked assiduously to watchdog the phase II/III clinical trials of every company that was making an HIV PI, including Abbott's ritonavir, Agouron's nelfinavir, Merck's indinavir, and Roche's saquinavir. TAG's recommendations to regulators and companies were published in the February 1995 report Problems with Protease Inhibitor Development Plans.
In summer 1995, Spencer Cox published his scathing, still-compelling report FDA Regulation of Anti-HIV Drugs: A Historical Perspective -- a cautionary retrospective on the first, mostly unsuccessful, ten years of HIV drug development and regulation.
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