Final Exit ?: Feet to the Fire, ACTG Investigators Scramble to Convince Industry They Can Produce

Like a slap-stick comedy sketch from a kiddy's cartoon escapade, the AIDS Clinical Trials Group is coming unraveled at both ends. Only there are no ubiquitous Acme parts purveyors here. Nor do the squashed or singed characters return resurrected in subsequent scenes. It's the federally funded AIDS clinical trials network, where public money and private lives are being sucked irretrievably down a wanton black hole. Farcical goings-on which unwittingly lend themselves so well to absurdist comedic fare would be hysterically funny were they not so gravely serious. The ACTG operates with an annual budget of $125M (adult + pediatric) and conducts clinical trials following some 7,000-10,000 patients each year. Its reputation internationally is of a top-notch research network, envied across the globe.

Down in Bethesda, Wellcome's Sandy Lehrman is PO'd about not getting to see Volberding's Q-twist paper which trashed AZT -- until after it had already come out in the New England Journal. "We were supposed to be partners," she opines. Boehringer's Maureen Myers, desperately scrambling to demonstrate a use for its now notorious Nevirapine, complains that the ACTG is not "user-friendly." While Roche's Waijen Soo laments over control of data and the arrogance of Harvard's stats center. Searle's Susan Smith explains how her company completed three phase I trials in the time it'd taken the bumbling ACTG behemoth to merely get one off the ground. Steve Carter, of Bristol-Myers Squibb (said to be secretly developing a protease inhibitor of its own), threatens to develop it -- alongside virtually all the industry's anti-protease drugs -- outside the ACTG unless he sees "substantial progress."

In the past 18 months, only 2 companies have come to the ACTG with phase I development proposals, while the likes of Merck (with its disappointing L-drug along with its protease), Bristol (the d4T phase II), Roche (its protease phase III) Abbott (its protease), Hybridon (GEM 91), ISIS (its CMV antisense) -- and even ACTG favorite Wellcome itself (something called FPC and a uracil compound) by-passed the federal trials network altogether and proceeded with early development on their own.

In all of 1993 only the flailing Upjohn (atevirdine) and a poorly capitalized start-up company called VIMRx (oral hypericin) have approached the ACTG with new products for phase I investigation. The beleaguered Upjohn, strapped for cash as its blockbusters Xanax and Halcion went generic, simply couldn't afford to turn down the resources offered by the ACTG system. And Searle too, which hasn't had a hit since NutraSweet, is being pressed into giving South Florida's Margaret Fischl a second chance -- even after ACTG loused up the development of its glycosidase inhibitor, N-butyl DNJ.

As the befuddled ACTG Primary Infection team (which continues to receive what some see as a disproportionate share of the ACTG pot -- some $16M for 1993-94 -- whether it has anything to study or not) watches one phase I after another pass it by, its research prowess at the other end of the spectrum -- phase II/III studies -- is being equally eroded. It was the OI committee that struck a blow for long-term follow-up with its unprecedented performance on ACTG #081, but the PI committee has failed miserably in its effort to hang onto patients in phase II/III antiretroviral studies such as ACTG #019 and #175. Drop-out and lost-to-follow-up rates in these two trials have grown so immense that neither is expected to reach statistical significance. With its seeming inability to successfully conduct phase I or phase II/III trials, one might query exactly what expertise the internationally revered research institution can purvey.

ACTG study #175 is only the most egregious and pathetic example of the ACTG's inability to follow study participants long enough to answer clinically relevant treatment questions. As far back as the early AZT studies, #019 and #016, one may recall that the clinical conclusions were based on the comparatively short time to development of, for example, PCP pneumonia; whereas it took the Anglos and the Gauls to actually follow the study participants to their final endpoint -- and reach a far different and statistically more powerful conclusion. For their part, British researchers have already begun savagely scrutinizing the ACTG's would-be white knight, RNA-PCR and bDNA viral measures, smugly quipping away about the "new magic" of as-yet-unvalidated virologic markers. Were these bold, new surrogates to prove reliably predictive of eventual clinical outcome, they would forever obviate the need for long-term follow-up --and the entire Primary Infection committee would breathe a collective sigh of relief.

A hotly debated study from the get-go, ACTG #175 was to reveal the optimal nucleoside regimen. But half-way through the study, some 30% of those originally enrolled have dropped out and 15% have been lost to follow-up. It is now readily accepted that this $18M-plus mega-trial will be a bust, lacking the statistical power to make any clear comparisons between the various treatment regimens.

Sometime this summer, Monsanto's drug subsidiary G.D. Searle is expected to bring its two anti-protease drugs into the ACTG system. (Actually, the company must first present its product to the AIDS Clinical Drug Development Committee (ACDDC), a needless and often humiliating formality which itself can add six months to a year of developmental delay in bringing a new drug to market.) The Primary Infection folks will be asked to turn around a quick-and-dirty phase I in record time even as they prepare for a larger phase II (ACTG #280) to begin sometime in December. It is the first phase I study the PI committee has seen in over a year, and ACTG simply can't afford to blow it.

With this mid-summer trial-by-fire, the ACTG organization will be given perhaps its final reprieve. Either it proves to industry once and for all that it can turn around a study with the speed and efficiency comparable to that of private research or it forever forgoes future opportunities for early investigation of anti-HIV agents. With the approaching "recompetition," where all ACTG committees must recompete for funding -- and which is expected to result in a Draconian down-sizing of the current ACTG structure -- the stakes could not be higher.

Most of those involved with the ACTG will readily acknowledge the fundamental conflict between the interests of science and those of profit. And in carrying out the Herculean task of clearing a common ground between the goals of public health and private industry, the ACTG has made a respectable showing. As for industry's concerns with the ACTG, emeritus Primary Infection committee member Mark Harrington is quick to point out that no one will demand proof of clinical efficacy if the "community" doesn't. "It's in everyone else's interests to approve ineffective drugs with the vaguest whiff of surrogate activity," he observes. "For industry, this means profits; for FDA, the illusion of compassion; for NIH, the illusion of progress. For people with HIV, however, it means stuffing handfuls of questionable substances down our throats and building up liver, nerve and other unknown toxicities, while paying through the nose." "As for Maureen Myers," Harrington continues, "she should know whether the ACTG is user-friendly: she helped to design it. And Ken Stanley couldn't have done more for Roche than he did with his post hoc subset trend analysis [of ACTG 155]. The drug companies want to throw out the DSMB [Data Safety Monitoring Board] and dredge the data every day looking for spurious short-term 'statistically significant' trends. What is Steve Carter's beef? Bristol got an NDA on the cheap with ddI, with the NCI [National Cancer Institute] doing phase I, the ACTG phase I and II, and no one doing phase III/IV. They'll probably get an NDA even cheaper with d4T. Probably the only thing less useful than ACTG phase I/II trials will turn out to be industry phase I/II trials, at least concerning antiretrovirals."