East Coast, West Coast
From the perspective of TAG activists, the evidence from trials like ACTG and Concorde was clear enough: neither AZT monotherapy in asymptomatic patients nor combination therapy in patients at any stage of illness had been proven efficacious. And the predictive power of the CD4 surrogate marker, in their estimation, was in grave doubt. In the summer of 1994, as the FDA granted accelerated approval to yet another nucleoside analogue, d4T, and announced an upcoming meeting to review accelerated approval, TAG activists began making noise. In August, the finance magazine Barron's ran a cover story called "Rushing to Judgment," which quoted TAG members about the risks of accelerated approval.[92] Similarly, Time magazine described the evolution of AIDS activists who in the past "threw
smoke bombs at the National Institutes of Health" but now were "changing their minds" about the fast-track drug approval policies they once had promoted.[93] Alarmed, Project Inform circulated a "consensus statement" on the need for accelerated approval and gained the endorsement of AIDS activist organizations around the country.[94]
At the Antiviral Advisory Committee meeting held in September 1994 more than forty activist groups presented their positions, including activists from the Midwest and the South who insisted that neither the East Coast nor the West Coast activists spoke for them on questions of access to drugs.[95] Kessler assured the audience that accelerated approval would continue to be FDA policy, and he promised to issue clearer guidelines for companies to follow in preparing applications for such approval.[96] TAG activists did not call for an end to accelerated approval, but they issued a hard-hitting evaluation of the program to date. Accelerated approval, these activists suggested, might well be creating structural incentives for drug companies to crank out mediocre drugs that resemble the mediocre AZT rather than invest in the development of novel treatments with other mechanisms of action.[97] (Others responded that accelerated approval created greater incentives for small companies to move into AIDS research: the alternative, long-term Phase II studies, was too expensive and too much of a risk.) Furthermore, argued TAG members, some of the companies were ducking their responsibility to perform postmarketing studies. "We pay huge amounts of money and we suffer through major toxicities, and we have to take the drug company's word for it that the drugs work. That's supposed to be empowerment?" complained TAG member Spencer Cox in comments to the New York Times .[98]
Preserving the policy of accelerated approval, as most players preferred to do, presumed finding a better surrogate marker or markers. By fall 1994, attention had focused on new, high-tech measures of viral load, such as assays that used PCR technology to quantify viral RNA. From the standpoint of Anthony Fauci (the most prominent backer of the use of CD4 counts as a surrogate marker in the early 1990s), viral load was "fundamentally … better as a marker. I don't think there's any question about it."[99] Fauci explained: "There's a lot of virus floating around, and when you treat somebody, you can see dramatic decreases in that virus." Here Fauci was referring to an important, recent finding about the pathogenesis of HIV infection: rather than a slow, subdued "latency," it now appeared that HIV disease was characterized by "rapid turnover" of both virus particles and T
cells[100] —what the New York Times described as "a pitched battle from the very start of infection," with hundreds of millions of virus particles and hundreds of millions of infected cells dying every single day.[101] This new conception of the dynamics of HIV infection implied that viral load was a crucial indicator of disease progression.
Biostatistician Stephen Lagakos, while optimistic about the possible uses of these markers, also pointed to "overstatements" on the part of some of their advocates, and he described stories he had heard reporting "that some of the producers of these [marker tests are] trying to get clinicians to buy gobs of these kits and use them on everybody at $500 a crack."[102] More emphatically, in an article subtitled "When Viral Load Is Crowned King," the Treatment Action Group railed in its newsletter against "frustrated scientists [who] have a new toy and biotechnology companies [who] have a new assay to sell."[103] TAG was calling instead for large-scale trials—so-called "large simple trials" with as many as five thousand subjects—particularly for the upcoming protease inhibitors. The virtue of such trials, these activists argued, was that they could simultaneously tell us "if these new drugs prevent sickness and death" and "if the new viral load assays are useful predictors." Hoffman-LaRoche, manufacturer of a protease inhibitor called saquinavir, was in TAG's view "racing" to the FDA with "lukewarm" data, seeking accelerated approval on the basis of a single, twenty-four-week study.[104] TAG proposed instead an expanded access program for saquinavir to accompany the larger, long-term studies.[105]
By this point, the long-simmering dispute in tactics between East Coast groups such as TAG and the San Francisco activists had "become particularly intense and often bitter," as John James explained in AIDS Treatment News .[106] In general terms, everyone avowed respect and support for his or her activist compatriots. But from the standpoint of the San Francisco activists, the TAG members had become scientific conservatives seeking to be more rigorous than thou. Said G'dali Braverman of ACT UP/Golden Gate: "There's an interesting evolution in terms of one's personal treatment activism. You reach that point where you start losing your sight of [the idea] 'We really are dealing with patients who need an option now,' and you start trying to think like a scientist." Such a tendency was "a difficult thing to temper," added Braverman.[107] "You know why I really think there's a split?" reflected Brenda Lein of Project Inform. "Because the East Coast folks don't have a constituency of people living with HIV that
they work with on a day-to-day basis. I mean, I answer hotline calls from people who want access. They talk to each other."[108]
Needless to say, TAG activists, many of whom were themselves living with AIDS and HIV infection, disputed these characterizations. They insisted they were not necessarily opposed to accelerated approval and certainly not to expanded access: Their motto was "access and answers." Nor did they oppose the right of the individual to have access to therapies. But they wanted to counterbalance that right against some conception of the greater good. And they criticized their San Francisco comrades for continuing to promote hype about up-and-coming drugs; they saw themselves as hard-nosed realists who had been burned too many times to ever contribute to the "hype cycle" again.[109] This explained the venom behind TAG's attack on Margaret Fischl in Berlin—the sense on the part of activists that they were led to believe in combination therapy and manipulated into hopping onto a roller-coaster ride of exhilaration followed by despair. Mark Harrington made this point emphatically in his written critique of ACTG 155: "ACTG 155 was riddled with investigator bias and sponsor-disseminated hype from the very beginning. … Indeed, as early as August 1990, at a meeting with ACT UP, Roche's Dr. Whaijen Soo told us: 'I'd like to confide a remark of Margaret's. … The difference she sees among people on the ddC/AZT combination [in ACTG 106] is a big difference—like the difference between people on AZT versus placebo in the original trial. She can almost tell them apart by looking at their behavior.' Say that around the country for three years and you can create a huge demand for an unproved drug."[110] TAG members were now vigilant against becoming the pawns of the pharmaceutical companies and resistant even to well-intentioned optimism. David Barr commented in 1994: "I've been pulled aside several times in the last couple of months [by people whispering], 'I'm really excited about the protease inhibitors.' … I have to say, 'Please, I understand you're saying that to me because you want to help me, but it doesn't help me .'"[111]