ACT UP & TAG: A Brief History of AIDS Treatment ACTAGanism

by Raan Medley

Most recently, I was one of the first people to congratulate Mark Harrington upon the announcement of his MacArthur "genius award" last year. The first AIDS activist to win the award and probably the first openly gay male to boot. The rumor was that friends had been nominating him for years since he left ACT UP in 1993 in what by all accounts was a bitter and public split with the rank and file AIDS community. The irony of the award and the point of the rumor was that the MacArthur people were unwilling til quite recently to give a quarter of a million dollars to someone who might not live to spend it all. My how times have changed. Now that Mark has become the subject of a much deserved media spurt, we can perhaps put all of this into perspective.

Let's begin at the beginning.

Compassionate use; Expanded access; Parallel track; Accelerated Approval ­ terms all used interchangeably and which resonate deeply with the earliest days of grassroots activism ­ were all attempts to put drugs into the bodies of desperately ill people while the drug companies jumped through the prescribed regulatory hoops. But, Harrington, the brains behind ACT UP's well-orchestrated campaign to change FDA regulations was not deterred by labels. He and a small cadre of like minded laymen that included Jim Eigo, John Bohne, Tom Cunningham, Ken Fornataro and Iris Long had devised most of the labels anyway.

As he stood behind the podium during the July 21, 1992 Plenary Session of the Eighth International Conference On AIDS in Amsterdam, Mark was already acknowledged on both sides of the stage as ACT UP's ambassador to the scientific community. A bright, pugnacious graduate of Harvard's rough and tumble queer underground, he perfected a manner of dealing with drug companies that he would later call "the two-pronged approach": charm and erudition when they seemed willing to play ball; vituperation and calculated mayhem when they didn't.

Admirers were often struck by the subtle changes in his hair color through the course of the year: from brown to reddish blonde and back again. After Amsterdam that would not be the only thing they noticed changing.

"What is the point of streamlining access and infrastructure", he would ask the assembled dignitaries, "when the result is merely to replace AZT with additional mediocre, toxic, expensive nucleoside analogues?"

Monotherapy was the Holy Grail of accepted AIDS treatment. The only problem was that the reigning gold standard of the group; the one that dozens upon dozens of experiments all used as a benchmark every year--AZT--didn't work; at least, not in most people, beyond the first six months. Ddc and ddi were in the pipeline, but as a Barron's magazine article would point out, the lion's share profit from any new class of drugs traditionally accrued to the drug approved first in time. It would be another year before researchers such as Aaron Diamond's Martin Markowitz and others would stumble upon the idea of combining drugs in a cynergistic cocktail of three or more unrelated drugs, not unlike chemotherapy among cancer patients. And , yes, for all intents and purposes, protease inhibitors looked like just one more "mediocre drug."

By the time information began to leak out about a little known experiment tucked away in one of the satellite labs belonging to drug giant, Hoffmann LaRoche, hope was beginning to fade that any form of chemotherapy would stop the spread of HIV within the body. The virus' genetic material was simply too unstable and thus quick to evade whatever regimen combined with the body's defenses to eliminate it. By the spring of 1994, when the FDA sponsored clinical trials, tests would confirm that at 1800 mgs a day, Roche's "anti-protease" drug was no better than AZT.

But, to someone at the end of their tether--resistant to AZT, blood work headed south--one more shot at even a mediocre drug sounded awfully good. Hope was the only medicine keeping some people alive. Stung by criticism that, after his speech in Amsterdam, he was only interested in advancing the very narrowest interests of people in the earliest stages of disease (an accusation he vigorously denies), Mark proceeded to form a parallel group called the Treatment Activist Group, or TAG.

With seed money from AmFar he was able to travel extensively, put out a first-rate newsletter, and for the first time not worry about coming hat in hand to an increasingly restive membership. Based on Harvard's famous men's clubs, the public at large was welcome "to observe" TAG's meetings, but voting was restricted to those who had been tapped for the honor.

At first, ACT UP and TAG worked together. For policy wonks it was a bonanza. They could now discuss the intricacies of Parrallel Track and Accelerated Approval twice as often each week. TAG even picked up the check at a post-demo breakfast following a blockade of the corporate headquarters of Hoffmann-LaRoche during which approximately 100 members of both groups handcuffed themselves to strategic entry gates. One of the demands was that they release the results of their Saquinavir studies.

Then, one summer evening in 1994 as the skeleton crew of ACT UP's Treatment and Data Committee, a virtual Harrington alma mater, gathered to discuss the buzz coming out of Yokahama (site if the 10th International Conference) someone produced a letter with a faintly familiar letterhead. But there, instead of ACT UP's trademark white letters on a black square was the word "TAG".

Substantively, the letter, addressed to FDA head, David Kessler, was a proposal to submit Roche's protease inhibitor, now called Saquinavir, to the rigors of a Large Simple Trial. It was signed by Harrington and three other former members of ACT UP. The proposal elicited initial excitement. LSTs were one of those ideas that seemed to make the rounds from time to time among the autodidactic world of treatment activists. Its main utility seemed to be its ability to incorporate disparate data along stratified lines of inquiry, thus, for example, enabling a biostatistician to credibly state whether Saquinavir was overall better than AZT or ddc or--bat's wings--if enough people enrolled.

The problem was that at 16,000 people, Harrington's proposal would have taken years to complete and with nearly a dozen other companies planning protease inhibitors of their own, there was no telling how it might effect future trials or even whether current enrollees would continue once other drugs became available. Gradually, as the proposal made the rounds from New York to Southern California, the self-styled "treatment community" was thrown into chaos.

In the face of blistering criticism from an array of mainstream advocacy groups and researchers, TAG reacted initially by digging in its heels. Only "large-scale, community based clinical trials of new AIDS drugs" would provide the answers they sought.

And the questions were growing. Morale within ACT UP was at perhaps its lowest point since the results of the Concorde trials, a European sponsored set of protocals which first revealed AZT's inadequacies. Roche's competitors were warning that protease inhibitors exhibited evidence of cross-resistance--meaning that resistance to one might confer resistance to some or all of the others after a few months. Roche itself added to the confusion by confirming that a new, improved formulation was in the works even as they were vigorously pursuing approval of the old one.

But, by far the most serious question was whether approval of Saquinavir would be delayed due to the TAG proposal. That it would be readily available to anyone who enrolled did little to dampen the outrage. Harrington has never acknowledged that if some of the sentiments expressed in the 1994 letter, co-signed by him and David Barr and other members of TAG, had been implemented--even without creating a choke point in the approval process--the possibility existed that people would still be dying who might not have had to. For example, there was the issue of dosage. It would be another year before Roche was even sure of what the optimal dose would be. A large simple trial in 1994 would have committed 16,000 people to a protocol that was less than half the dose it should have been.

By summer's end, comrades in arms were no longer listening to each other. The heat generated by the controversey was so great it would eventually reach Kessler himself. By October of 1994, he was forced to convene a panel to review the process by which companies gained Accelerated Approval of their products and after a day of bitter denunciations and counter-charges the system was reaffirmed with minor changes.

Following the FDA shootout, TAG decided to initiate what would subsequently become their *modus operandi*--dealing directly with company headquarters. Roche, which is actually a multi-national of Swiss origin, was also seeking a way to dampen months of toxic p.r. By November, both sides were engaged in secret negotiations. Roche even took the unprecedented step of sending its CEO all the way from Basel to join the talks.

By early 1995, exactly two years after TAG and ACT UP stormed its U.S. headquarters, Roche had worked out a temporary truce. In return for TAG's not actively opposing its New Drug Application, Roche agreed to a Parallel Track program for their drug. Saquinavir would be made available to over 4,000 people with AIDS. Other groups, including ACT UP/New York formed a working group and a lottery system was worked out. Entry criteria included a limit of 50 t-cells and soon that became the industry standard as other companies were pressured into setting up similar programs.

All went smoothly at first. Private physicians would serve as enrollment sites instead of the traditional institutional center. Forms were made as simple as possible to limit paperwork and there were remakably few complaints according to advocates who monitored the lottery. But built into the program was one compromise of gigantic proportions. The dosage that would be prescribed was less than half what was beginning to be known about Saquinavir's effectiveness. Scientists at a research lab at Stanford were now saying that to adequately ensure cross-resistance was kept at a minimum, Saquinavir should be taken at 3,600 mgs. a day, and more likely at 7,200 mgs. a day rather than the 1,800 originally proposed to the FDA.

Doing a super high dose study of Saquinavir during the lottery process was never an option. The problem was that at some point it had become an article of faith that Roche could not possibly manufacture more drug. To do an optimal dose study using the lottery volunteers would have meant halving or even quartering the available slots.

Although the lottery for the first 2,200 slots was held in July, actual drug did not begin arriving until late October. Another 2,200 were randomly chosen in October bringing the total to 4,400 PWAs with free access to Saquinavir. Then, just as suddenly as drug began arriving, the supply was cut off. Why? The FDA had announced Saquinavir's approval. Lottery winners were told in no uncertain terms that the study had ended along with their supply of drug. As a prerequisite for approval, Roche had to have known as early as the previous spring that enough drug to fill drug store shelves by the first of the year would be available. Yet, no one demanded that they continue the program or that another dosage arm be added.

As Larry Kramer, put it to the New York Times: "Hoffmann acquired significant pre-marketing sales information from the clinical data it demanded for entry into the lottery...insuring a market success for the drug even before its true effectiveness in the treatment of AIDS has been defined by clinicians."

The same danger existed for winners of the other activist-approved lotteries, including Merck and Abbott. Both experienced delays in supply and, wondrously, both anticipated FDA approval within months. The question again arises, where is all this drug going to come from? Was it being stockpiled? Were drug companies lying to activists when the original lotteries were designed? A lot of people eschewed other alternatives while waiting for these drugs.

Much of the blame was placed with the extremely lengthy lead time Roche and the other drug companies required to plan output. The plant specifications for Saquinavir production were set in stone over a year before the first case left the loading dock. To have changed the specs in mid-stream would have meant reassembling a team of chemical engineers, consultants, and various bean counters most of whom were engaged in other projects by the time the dosage and demand miscalculations were discovered.

One reason given for the lack of outrage in the community, was that along with Saquinavir, two other nukes were also approved by the FDA thus helping to tamp down the fires. People simply left the delayed programs in order to make use of some other regimen. But, one wonders whether at least as much culpability lies with the fact that their leaders, including Mark Harrington, were themselves handcuffed to the very programs they helped design.


written by Raan Medley

excerpts originally appearing in LGNY, March 1996


see also: Treatment Access - Activists Philosophies


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