On a Darkling Plain -- The Years of Despair
Before the Discovery of HAART
So by mid-1993 it was apparent that our hopes that early and limited CD4 cell increases would reliably predict clinical benefit were unfounded -- since ddC had not shown the same benefits earlier seen with ddI -- and that two drugs, at least in experienced patients, were no better, and possibly worse, than one drug.
No results were available yet on whether two drugs started at the same time -- among people who had never taken anti-HIV drugs at all (combination theory postulated that two might delay resistance from emerging as quickly as it did with a only one drug) -- were better than one. ACTG 175 was one such study, comparing AZT alone to ddI alone to AZT + ddI. Its results wouldn't come in until late 1995.
In the meantime, d4T crawled forward as the next anti-HIV drug submitted for FDA approval, in mid-1994. The Alice-in-Wonderland quality of HIV drug development at that time was well captured in a New York Times story headlined, "F.D.A. Panel Recommends AIDS Drug Despite Incomplete Data":
TAG and its allies sent a delegation that was frankly split about the drug's effectiveness, but in agreement that the data as submitted were impossible to interpret. TAG's Gregg Gonsalves, who was the community representative on the FDA panel at that time, correctly predicted that the pivotal studies by d4T's sponsor, Bristol-Myers Squibb, would be too small to prove that the drug worked. TAG's Spencer Cox testified from the public, as did GMHC's Derek Link. Neither could interpret the data clearly and both pointed out the flaws in the existing paradigm.
The next drug to engage the attention of the community was the first in a new class, the protease inhibitors. This drug was saquinavir. Unfortunately, the sponsor was Roche. At that time, I was a member of the ACTG's primary infection (HIV treatment) committee. The negotiations between Roche and the ACTG were nontransparent, to say the least.
Roche had failed to find a maximum-tolerated dose of saquinavir, so we did not know whether the dose they were moving into phase II was the best possible dose in humans. The company refused to provide the committee with its preclinical or phase I data. Instead, it took the two principal investigators (PIs) into the hallway, showed them the data, and the PIs came back and told the rest of the committee that the saquinavir dosing data looked fine. They proceeded to enroll a couple hundred patients into another badly designed study, this time comparing two- and three-drug combinations in people who were already failing AZT. ACTG 229 enrolled 302 people and randomly assigned them to AZT/ddC/saquinavir versus AZT/saquinavir versus AZT/ddC (the combination that bombed in Berlin).
Later it became clear that the dose of saquinavir was far too low. Ninety-six percent of the drug was excreted unchanged in the urine, meaning that just four percent of it got into the blood and the body's cells to block HIV replication. Even at an insufficient dose, however, saquinavir could produce enough antiviral activity to lead HIV to become resistant, not only to saquinavir itself, but to all the first-generation protease inhibitors.
Despite the inadequate dose, small study, short duration, and shoddy data, Roche, undeterred, went to the FDA in midsummer 1994 to request that it consider saquinavir for accelerated approval.
When Bristol-Myers sought accelerated approval for ddI in 1991, there had already been over 35,000 people on the drug through expanded access since 1989, and thousands of people had been in ddI studies over a five-year period. By contrast, in mid-1994, saquinavir had been studied in fewer than a thousand people for less than a year. Neither the safety data nor the efficacy -- such as they were -- of saquinavir looked as good as those for ddI alone had three years earlier.
This time, TAG drew the line. We were determined that the failures to study and regulate the approval of the nucleoside analogues not be repeated with the protease inhibitors, which looked like a much more promising class of drugs, even if saquinavir itself appeared to be relatively weak.
We wrote a letter to and obtained a meeting with FDA Commissioner David Kessler -- an impassioned reformer who was the intellectual father of accelerated approval -- and the agency's HIV drug-review staff.
It wasn't a friendly meeting. TAG and our allies criticized the FDA for failing to hold Roche accountable for not fulfilling its promised postmarketing studies for ddC, and for allowing Roche and other sponsors to conduct studies that were both too small and too short to show whether the drugs worked in the majority of people with HIV.
TAG presented a plan to address these issues for the protease inhibitors as a class by combining the best of expanded access with a better clinical trial design that was both large and long enough to show whether adding a protease inhibitor -- or starting with one -- was better than adding or starting with a nucleoside. Modeled after a series of successful cancer and heart disease studies, we called this a large, simple trial (LST).
TAG had rushed into the FDA meeting and the LST proposal without sharing our ideas quickly or broadly enough with the wider community. The death rate from AIDS was still climbing and in our haste to change the direction of the ship we neglected to inform or collaborate with our fellow comrades in the crew.
This haste backfired on us later that summer when Barron's business magazine published a provocative interview with TAG's Spencer Cox criticizing the saquinavir trials with the even more provocative headline, "Do We Have Too Many Drugs for AIDS?"6
Quickly, TAG became the most unpopular organization in the AIDS activist world. During the late summer and early fall, we retrenched, putting forward our position in a report, Rescuing Accelerated Approval: Moving Beyond the Status Quo,7 which we distributed at a heated FDA advisory committee hearing in September 1994, where the debate reached impassioned levels.
As HIV gastroenterologist Donald Kotler stated in a dramatic scene from that era, documented in David France's How to Survive a Plague, ACT UP was talking about access. TAG was talking about answers. We were talking past each other -- but all of us needed both.
Luckily we found allies as well as detractors. One of the most notable new allies was the brilliant HIV-positive activist and virtually self-taught statistician Carlton Hogan, a New Yorker in exile in Minneapolis, Minnesota, where he worked in the statistical center for the NIH-funded Community Programs for Clinical Research on AIDS (CPCRA), a community-inspired and grassroots rival to the more academically slick and sometimes self-satisfied ACTG.
Inadequate Surrogate Markers
Early methods to measure HIV activity directly yielded conflicting results. One of the easier methods was to measure blood levels of the p24 protein, a component of HIV that was sometimes measurable at high levels. In many people, however, p24 was hard to measure, probably because it was bound to p24 antibodies, gumming up the test.
An even more demanding technique was quantitative co-culture -- taking blood from the cells of a person in a study and measuring how fast that blood could infect cells in culture. This was difficult, varied from lab to lab, and could not be commercially standardized.
But in the earlier phases of research there was, suddenly, promise.
This article was provided by Treatment Action Group. It is a part of the publication TAGline.
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