ICC’s Brainchild Designed to Show Every Drug and Every Combination a Success. Who Could Complain About That?
“It’s ddC Monotherapy All Over Again”
A hastily organized meeting of the newly formed Inter-Company Collaborative (ICC) was convened April 26 at the Loews New York Hotel to discuss the ICC’s master protocol for triple drug combination therapy. According to its chief proponent, David Barry of Burroughs Wellcome, the master protocol is designed to find a “homerun” triple drug combination that restores CD4+ T cell levels back to an immunologically normal state and reduces viral levels to zero for 52 weeks. Responses to the industry initiative ran the gamut from zealous enthusiasm to outrage, even among members of TAG. Michael Ravitch was particularly disheartened by the plan’s apparent lack of scientific rigor. He prepared this report.
Tired of only bad news about AIDS research? Fear no more. The Inter-Company Collaboration (ICC) has a new protocol designed only to produce good news. The cynical brainstorm calls for a one-arm unrandomized master protocol to study, in a rapid fashion, various three-drug combinations. Each cohort of 100 patients will take a different regimen. Immediately after the first cohort is enrolled, the second cohort will be enrolled, and so on, in a sequential fashion. The ICC is going to hire (and underwrite) a clinical research organization to organize a series of clinical trial centers.
The primary endpoints of the study are virological (PCR-RNA), immunological (CD4) and safety. The results will be graded on a scale ranging from “A” to “D.” The patients will be required to have between 200-500 T4 cell counts and be anti-retrovirally naive. The study will last 1 year, and regimens will initially include 2 approved drugs plus 1 unapproved, but that could change later on, once the system gets going. The first six regimens are as follows (Don’t get too excited.): According to Dr. David Barry of BW, the maestro. This series of “pilot studies” will quickly determine if any particular three-drug regimen has a dramatic effect within a year. Barry explains that if there is a “good” result, that will “merit further controlled trials.” If there is a “homerun” effect, then clearly the drugs in that combination will be quickly licensed. (“Homerun” defined as no virus, return to normal CD4 counts.)
There are theoretical reasons (e.g., the example of TB, a mycobacterium — not a virus — which is exceedingly slow-growing and involves a completely different mechanism for the development of drug resistance) why three drugs might be significantly better than two. In this “ideal” drug-naive population, we will be able to see clearly which avenues are the most promising to follow.
Such an approach could conceivably be a way to cut through bureaucracy and give us quick information about promising combinations. Not, however, with this protocol, which seems to have been designed by the marketing division rather than the scientists. The main problem is the lack of a control.
The study has been designed to give the best possible answer, for good and bad reasons. The ICC wizards say they are comparing these regimens to a two-drug “benchmark therapy.” Were one to point out that there has only been one — unpublished — study with combination therapy in this patient population (i.e., asymptomatic, drug naive) in which a wholly different measure of viral load was used, they will ignore you. This is a study relying on historical controls for which there are no historical controls.
Imagine this scenario: a combination that raises the patients’ T cells an average 120 over a year. The community will, of course, be incredibly hopeful; everyone will start taking this three-drug regimen, and the third drug will be quickly approved. Eventually, people who are drug-experienced might notice that the regimen is not working quite so well for them. But will we ever get even the rudiments of an answer on how those people could or should use this combination to the maximal benefit? I doubt it.
Industry will say to us, “Why should we put more money into studying a regimen that we know is bound to be mediocre? Let’s study new drugs.” They will also complain that it is difficult to launch controlled trials, considering the excitement. And they’ll have very little incentive to do those trials, since the results are bound to decrease the appeal of the drugs, which, at that point, will be widely — and ignorantly — used.
When asked if the industry would pursue longer trials in drug-experienced patients, Dr. Barry basically said that they would not. He said, in essence, that he doesn’t expect any of the currently possible combinations to work well in patients who have already tried therapy. When asked if, therefore, industry was going to abandon that ever-shrinking market, he said no, heavily pre-treated persons would benefit from future three-drug combinations of entirely new drugs.
The dangers of studying only the “ideal” population are compounded by the lack of a control arm. The ICC folks complain that a control arm (e.g., placebo, AZT, AZT+ddC) would make the study more difficult to do, but this looks like a red herring. When Merck wished to get quick information on the anti-viral effect of its protease, the first trial they did was a six-month study of protease vs. AZT. If the ICC only wanted to do a quick uncontrolled “pilot study,” they could use a much smaller number. My fear: 100 patients in an uncontrolled study of this population is enough to whip up popular enthusiasm, but not enough to answer any significant scientific — let alone clinical — questions.