ELSEVIER

In Memc, dam: David Byar as an AIDS Activist

Mark Harrington Treatment Action Group (TAG), New York, New York 10009

It is a great privilege to be able to address David Byar's professional colleagues and peers on behalf of his AIDS activist comrades. I fear that neither group on either side of the great divide which our work has for years striven to bridge possesses an adequate comprehension of the magnitude and generosity of David's contribution to AIDS research. His insights and energies transformed the field (in terms of a new methodologic openness) and empowered his colleagues (the statisticians and the activists alike) to create new models and seize greater control of the clinical trials process from the hitherto supreme, insular, academic clinical AIDS researchers.

I will try to briefly sketch David's unique contribution to the ongoing process of opening up tile research system and rendering it more flexible and responsive to people with AIDS by contrasting the state of the activist critique of research before and after his engagement with it and by examining the concrete changes in the way AIDS research is performed.

There were two arms to the activist response to the perceived failures of clinical research up to 1989: the activist critique of regulation (led by ACT UP) and the community-based clinicians' response to academic/NIH/pharmaceutical research, led by the Community Research Initiative (CRI) in New York and by the Commu- nity Consortium (CC) in San Francisco. Few in the establishment have realized how close tile AIDS community b.-,s come repeatedly to utter despair in any hope for rendering the research enterprise either useful or humane. Few understood the importance of the alternative structures we created such as the underground buyers' clubs, the CRIs, or Parallel Track and Expanded Access in rendering the rigors and protracted duration of randomized controlled trials more bearable.

In early 1989 confidence in the randomized controlled trial was at a low ebb. ~4~idothymidine (AZT) was still the only approved AIDS drug. Few drugs were available to treat or prevent the opportunistic infections which kill most people with AIDS. The federal research effort was still pouring most of its research dollars

Remarks delivered at the NCI Conference, "David P. Byar: An Accidental Career," November 7, 1991. At the time the speech was delivered, Mark Harrington was a member of the Treatment + Data (T + D) Committee of the AIDS Coalition to Unleash Power (ACT UP/New York).

Address reprint requests to: Mark Harrington, Treatmen~ Action Group (TAG), 611 E. I1 St., New York, New York 10009.

Received July 19, 1994; revised January 18, 1995.

Controlled Clinical Trials 16:270-275 (1995) 0197-2456/95/$9.50 © Elsevier Science Inc. 1995 SSDI 0197-2456(95)00005-2 655 Avenue of the Americas, New York, NY 10010

David Byar as an AIDS Activist 271

into AZT studies. Inclusion criteria were irrationally restrictive, life-saving pro- phylaxis forbidden, placebos all too common, trials excruciatingly slow, and re- sults few and far between. Only one randomized AIDS treatment trial existed in the peer-reviewed literature [1]. The community was very close indeed to losing its faith in research altogether and to withdrawing its investment in any of the procedures of the randomized controlled trial.

Of all the historic revolutions of 1989, the one which has received perhaps the least recognition is the regulatory revolution whose key battle was fought on February 1, 1989, at the Guest Quarters Hotel in Bethesda. An extraordinary chorus of new voices-opinionated, fractious, well informed, and not always unanimous in outlook-seized the day and demanded entre to the counsels of science.

The Lasagna Committee was wrapping up a rather polite, routine questioning of Ellen Cooper that afternoon, w h e n - in an eruption of popular rage documented in the extraordinary verbatim transcript of that hearing- the AIDS activists burst into the counsels of the experts like the chorus in a Greek tragedy.

I want you to hear these voices, for I cannot otherwise convey to you how desperate our plight was then.

LASAGNA: Aren't you working on getting your committee?

COOPrR: For our division, yes.

LASAaNA: Thank you very much.

A CHORUS or Voxcrs: What about DHPG7

VoicE: Why are people being allowed to go blind?

VoicE: We want answers.

VoicE: Is not to be sighted in one eye ethical? Why don't you answer the question?

Voxcr: We represent tens of thousands of people in the United States of America.

VoicE: Let her speak.

COOPER: Let me speak. Anticipating this question, particularly after the flyer was distributed this morning [2], I . . . put down a few notes. And what I will do first is just recite what has happened with DHPG, ganciclovir, as far as regulation or the FDA is concerned [3].

At this point Dr. Cooper narrated a long, sad saga of ganciclovir's frustrated development. During and after her narrative, the chorus of voices continues:

VoicE: They did not perform a controlled trial because they thought that it would be not campassionate to not provide the drug.

VOICE: These patients are going blind.

VoxcE: Studies don't matter [4].

Here was the crux of the matter. If people in the communities affected were saying that studies didn't matter, the whole research enterprise would collapse. In fact, it came very close to collapse during these months. If the regulatory environment did not change, and change rapidly, it would face growing irrelevance

272 M. Harrington

in a setting where underground treatment networks and buyers' clubs were spread- ing around the country, and underground clinical trials were just around the corner.

At the same time that the ganciclovir disaster seemed to demonstrate the failure of the medical-industrial complex, the concurrent development of aerosolized pentamidine (AP) in the community through two randomized dose response trials at CRI and CC seemed to prove how quickly effective research could be done in the community. (In retrospect, this assumption proved to be a liability.) That spring, the American Federation for AIDS Research (AmFAR) began to fund scores of community-based clinical trial sites around the country, and that fall, the Na- tional Institute of Allergy and Infectious Diseases (NIAID) funded sever~.l more. Not even the CRIs were willing to test Compound Q, however, and an undergound, unregulated treatment protocol sometimes described as a Phase I/II study began at four sites around the country. Finally, activist pressure to decouph access to investigational new drugs from their randomized, controlled trials, frustrated by the FDA's limited interpretation of the Treatment IND up to that point, resulted in the creation of the Parallel Track, under which people intolerant of or failing standard therapy and ineligible or inaccessible to the trial site could receive a new drug prior to its FDA approval while randomized trials took place.

By the summer of 1989, everything was improving except the randomized con- trolled trials. We were not satisfied. AP and ganciclovir were rapidly approved by the FDA, and dideoxyinosine (ddI) was about to become available on Parallel Track, but the systemic flaws of the research infrastructure remained unscathed. We condensed our critique in a 16-page National AIDS Treatment Research Agenda and distributed 4000 copies at the Fifth International Conference on AIDS in Montreal that June. Among the recommendations relevant to our discussion were the following:

• People with AIDS, HIV, and their advocates must participate in designing and executing drug trials.

• Resources must be focused on drugs which treat or prevent opportunistic infections, not just on antiretroviral drugs.

• End the exclusion of AZT-intolerant individuals from trials for infections or other antivirals.

• Protocols should be flexible enough to accommodate new knowledge about HIV infection, al!owing subjects to receive state-of-the-art care for opportu- nistic infections (Ols) as such standards evolve.

• Trials must be designed for the real world: prophylaxis permitted, placebos avoided, efficacy criteria and endpoints humane [5].

Luckily for our story, Susan Ellenberg of the NIAID Division of AIDS Biostatis- tics Branch received one of the copies and was excited and intrigued by its contents. She asked David Byar to chair a meeting of the Statistical Working Group at the American Statistical Association (ASA) meeting on August 8, 1989, two years to the day before David's untimely death.

Through our intelligence sources, ACT UP found out about the meeting and sent two fearsome representatives, Bob Huff and Rebecca Smith. This meeting became the start of an extraordinary partnership between the activists and the statisticians. It was also the start of an extraordinary personal and p~ofessional

David Byar as an AIDS Activist 273

friendship between Rebecca Pringle Smith (our community statistician par excel- lence) and David Byar (the acme of the establishment) which lasted until David's death. Rebecca provided extraordinary love, intellectual companionship, and moral support for David in his last two years, and I salute her here.

At the ASA Statistical Working Group meeting, much attention was focused on Parallel Track. At the time, many establishment figures, with the exception of NIAID director Anthony Fauci, whose endorsement was politically pivotal, feared an erosion of the randomized controlled trial gold standard. David, with his dual insights as a statistician and a member of our community, saw it differ- ently. To him Parallel Track sounded like a primitive, unevolved version of the large, simple trials which had proved so powerful in cardiovascular disease. Per- haps after a single nonrandomized Parallel Track, circumstances would allow the superimposition of randomization (between doses, perhaps) on the next Parallel Track drug.

I remember the first time I heard David's voice. It was on an AmFAR conference call discussing Parallel Track. David asked Jack Killen of NIAID to describe what form of data was to be collected on Parallel Track. In a sign of the extraordinary identity of views between the NIH and the activists at this time, Killen deferred to Jim Eigo of ACT UP, who said that the primary purpose of Parallel Track was to provide access to treatments rather than to collect efficacy data. "Parallel Track will be nothing but a giant anecdote," said David. Later I asked Rebecca Smith, "Is he gayT" "How did you know?" she asked. "He just sounded so worldly," I said.

Over the fall, Parallel Track was initiated to the great chargrin of the AIDS Clinical Trials Group (ACTG) principal investigators, who mounted a public assault through the New York Times's Gina Kolata. Parallel Track met its primary objective distribution of ddI under safety monitoring to over 23,000 people with AIDS prior to full FDA licensing but an opportunity was missed to do a giant, randomized, dose-response trial. (This deficiency was rectified in later expanded access programs negotiated by ACT UP, e.g., in the randomized dose-response expanded access program from Abbott for clarithromycin against disseminated Mycobacterium avium intracellulare.)

Our campaign to infiltrate the research infrastructure continued. Dr. Fauci vaguely invited us to the November ACTG meeting. His senior staff specifically disinvited us. We had been asked to attend tl.e Statistical Working Group, how- ever. With this precarious excuse, we descended on the Bethesda Hyatt in Novem- ber. The researchers were furious. While NIAID was paralyzed by indecisiveness, the Statistical Working Group met us with open arms. At that meeting, David Byar presented the draft which was to grow into the article "Design Consideration for AIDS Trials." Among David's conclusion, explicitly working off ACT UP's agenda, were the following:

1. Traditional phases of research can be combined: Phase I/II and II/III. 2. Of the three sacred cows randomization, double blinding, and placebo

controls, we can dispense with at least two and sometimes with all three. 3. Nonrandomization may be preferable in certain situations. 4. We can compare doses or drugs instead of using placebo or no-treatment

controls. 5. Clinical trials should be open to as many people as possible; entry criteria

should be much broader.

274 M. Harrington

6. The choice of endpoints can make trials faster and more humane. 7. Clinical trials must adapt to new data as they arise, allowing subjects access

to useful new treatments. 8. Patients can be in more than one clinical trial at the same time, e.g., in

an antiretroviral and an OI prophylaxis trial. 9. Applying these new ideas may reduce the need for a Parallel Track.

10. Applying these new ideas is a challenge for government and industry [6].

During and after this meeting, David was busy pulling together an unprecedented coalition of world-renowned statisticians to collaborate on fleshing out his ideas. We could see our efforts bearing fruit.

The night before, Rebecca introduced me to David. We went out to dinner at a Japanese restaurant in Bethesda. I ordered sushi. David asked, "I used to love sushi." "Why can't you have it'/" I asked. "Because I have AIDS," he said stoutly. I was shocked by my own naivete in assuming that an NIH biostatistician was immune to AIDS.

David presented another draft 2 weeks later at Susan Ellenberg's conference on "Methodological Issues in AIDS Clinical Trials" [7]. There a top NIAID official confessed, "We haven't paid much attention to how we actually do these trials." From then on, attention would be paid.

David's analysis ratified many of our concepts and corrected others. He disman- tled the traditional edifice of randomized controlled trials brick by brick, examin- ing each one, and rebuilt a structure specific to AIDS and flexible to its unique circumstances.

By reevaluating each element, he led us to do the same and to recognize the usefulness of the various methods when appropriately applied. By showing that even randomization could be eschewed in certain circumstances- and was perhaps unnecessary with ganciclovir, which had not been randomized in any case-he helped to convey the power and precision derived from randomization in most other circumstances, such as when there is a standard treatment or when the hoped-for treatment difference is small.

David Byar enthusiastically threw himself into community-based clinical trial research, which was in danger of foundering due to its preference for small, single- center studies, most of which lacked the power to detect a clinically important treatment effect. That legacy was the result of the all-too-easy seeming community development of AP and of the ganciclovir end-run around randomization.

David worked on the Observational Database (ODB) project to provide an epidemiologic foundation and a logistical infrastructure to conduct multicenter studies through the AmFAR Community-Based Clinical Trials Network. The ODB now is following 4000 people with HIV around the country, and its data can be pooled with additional data from the NIAID Community Programs for Clinical Research on AIDS (CPCRA) ODB.

He also spearheaded months of discussions with CR1, AmFAR, and ACT UP about a multiple opportunistic infections prophylaxis (MOPS) protocol, designed to simultaneously tackle the major infectious complications of AIDS. This project was a casualty of time, however, for David's energies were flagging.

In December 1990, I asked Anthony Fauci to have David Byar, Rebecca Smith, and me to dinner to discuss the large, simple trial concept. David gave Fauci a stirring account of its power and speed. Fauci said, "Large simple trials? Sounds

David Byar as an AIDS Activist 275

like large expensive trials to me." We eIIdeavored to indicate the reverse. Discus- sions with NIAID about using the large simple trial continue, but it is more likely that the AmFAR Community-Based Clinical Trials Network will become the first AIDS network to adopt this powerful tool.

Amidst and after this, a rich friendship between David and myself developed. I wish I had time to recount the fun we had together. Listening to him and Joseph Sonnabend play piano duets in New York or in Bethesda. Driving in his Acura blasting Vivaldi. Sitting in his house late at night talking about life while the chestnuts rustled against the roof. Having him host raucous feasts for my ACT UP friends in the middle of yet another ACTG fracas.

I have often compared our struggle to open up research and make it accountable to its ostensible subjects to the Soviet process of glasnost and perestroika. David Byar was our Andrei $akharov, like him in his tragic, premature death, leaving the revolution unfinished.

I loved David. He had a joy in life, a gift for friendship, and a unique genius enabling him to build bridges between two worlds previously separated by an abyss. I salute you, his teachers, colleagues, and friends, and call on you to carry on his brave, ebullient, activist fight.

REFERENCES 1. Fischl MA, Richman DD, Grieco MH, et al: The efficacy of azidothymidine (AZT) in

the treatment of patients with AIDS and AIDS-related complex: a double-bind, placebo- controlled trial. N Engl J Med 317:185-91, 1987

2. See "DHPG Trials: A Monument to Regulatory Hypocrisy." ACT UP/NY fact sheet, February 1, 1989

3. National Committee to Review Current Proced,re.~ for Approval of New Drugs for Cancer and AIDS [the Lasagna Committee]. Unedited :erbatim transcript, meeting of February 1, 1989

4. Ibid 5. ACT UP: A National AIDS Treatment Research Agenda. 5th International Conference

on AIDS, Montreal, June 1989, pp. 2-3, "Twelve Principles for a New AIDS Drug System" (principles 1, 3, 5-7)

6. Byar DP: Oral draft presentation of "Design Considerations for AIDS Clinical Trials" presented at the ACTG Statistical Working Group, 7th ACTG, Bethesda, November

• 8, 1989 7. See Journal of Acquired hnmune Deficiency Syndromes, Vol. 3, Suppl. 2, 1990