statistical issues arising in aids clinical trials: comment

Statistical Issues Arising in AIDS Clinical Trials: CommentAuthor(s): Mark HarringtonSource: Journal of the American Statistical Association, Vol. 87, No. 418 (Jun., 1992), pp. 573-576Published by: American Statistical AssociationStable URL: http://www.jstor.org/stable/2290294 .

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Comment MARK HARRINGTON*

"Statistical Issues Arising in AIDS Clinical Trials" is a fair, if too modest, narrative of the immense and ongoing contributions made by statisticians to the clinical research effort against acquired immune deficiency syndrome (AIDS). Indeed, from the perspective of an AIDS activist long involved in efforts to restructure the clinical research efforts of the National Institutes of Health (NIH) and the regulatory role of the Food & Drug Administration (FDA), it would not be too much to say that many if not most of the fruits of our labors-the creation of the Parallel Track mechanism for expanded access to AIDS treatments while randomized trials are ongoing, the development of more inclusive and realistic clinical trials, the abandonment of unnecessary restrictions (such as, in many cases, placebos), and the prior prohibition on concomitant medications-would not have been possible without the early, vociferous, and erudite support of leaders in the statistical community. In many ways, they were our first allies "in the system."

Before commenting on the specific issues raised by Dr. Ellenberg and her colleagues, it may be worthwhile to sketch out for the reader of the Journal of the American Statistical Association the impact of the collision between the AIDS advocacy community and the research establishment over the last five years. Let me take the reader back to 1988. Just one drug, azidothymidine (AZT), was approved to treat AIDS. There were no approved treatments or preventive therapies for the opportunistic infections (01's) that cause the majority of AIDS deaths. Many promising therapies were languishing in an inefficient, restrictive drug development pipeline, and most people with AIDS lacked access to drugs that could save their lives. Drug trials forbade participants from taking concomitant therapies, which were necessary due to the fact that AIDS is a disease involving multiple pathogens, each needing treatment and some requiring prophylaxis. Because of such restrictions, that many people with AIDS resorted to clinical trials to obtain access to experimental therapies and failed to disclose which concomitant medications they were taking. Others attempted systemati- cally to unblind their study drug, which was easy to do in the case of a drug like AZT. Still others eschewed randomization altogether, preferring to obtain their treatments un- derground through people with AIDS (PWA) buyers' clubs. The community of people with human immunodeficiency virus (HIV) was on the verge of losing whatever faith they had in the clinical research system.

Initially, the efforts of activists such as the AIDS Coalition to Unleash Power (ACT UP) focused on the role of the FDA

* Mark Harrington is a member of the AIDS Coalition to Unleash Power (ACT UP). He has worked as a consultant for the Community Research Initiative (CRI) of New York and for the American Foundation for AIDS Research (AmFAR) and currently represents people with AIDS on the NIH AIDS Clinical Trials Group (ACTG) Primary Infection Committee.

as an obstacle to drug access. By learning the jargon of research and regulation and using it to couch our demands, we developed the ability to negotiate inside with top FDA officials as well as to demonstrate outside, seeking to harness public sympathy for the plight of PWAs denied access to life-saving therapies. These efforts culminated in a demon- stration of 1,500 PWAs and activists at FDA headquarters on October 1 1, 1988. The protest drew major media coverage nationwide.

These efforts spurred the FDA to radically transform its approach to the regulation and approval of AIDS drugs. For the first time the Treatment Investigational New Drug (IND) regulations of 1987 were applied in a comprehensive and inclusive manner. Within a year four AIDS treatments were granted Treatment IND status, under which they could be distributed to patients while clinical studies proceeded. Within the first six months of 1989, FDA granted full mar- keting approval for aerosolized pentamidine to prevent Pneumocystis carinii pneumonia (PCP), the leading killer of PWAs, and ganciclovir (DHPG) to treat cytomegalovirus (CMV) retinitis, a deadly eye infection. Although adequate, randomized, prospective clinical trials for DHPG had not been carried out, the evidence for the drug's activity was compelling:

1. There was no standard therapy for CMV retinitis. 2. If untreated, CMV retinitis progresses rapidly to blind-

ness and death in virtually 100% of patients. 3. DHPG halted the progression of CMV disease in over

80% of patients treated. 4. DHPG's toxicity was acceptable given the lack of stan-

dard therapy. 5. DHPG had been distributed to thousands of patients

in the United States and abroad under an FDA-approved ''compassionate plea" program.

Also in 1989, ACT UP and others forged an alliance with NIH Director of AIDS Research Anthony S. Fauci. Spurred by the DHPG fiasco, in May 1989 Dr. Fauci endorsed an idea generated one year earlier by Jim Eigo of ACT UP, the so-called "Parallel Track," a broader form of expanded access under which certain drugs entering Phase II efficacy trials would be made available to patients who were (a) intolerant of standard therapy, and thus unable to enter randomized trials comparing the new treatment with standard; (b) failing standard therapy, and thus also unable to enter comparative trials; or (c) unable to enter clinical trials because they were protocol-ineligible or lived too far from the trial site. The Parallel Track proposal was endorsed by an FDA advisory committee in August 1989 and codified into Federal Reg-

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574 Journol of the American Statisticol Associotion, June 1992

ulations published on May 21, 1990 by a Public Health Ser- vice (PHS) Task Force that included members of ACT UP, other activists, FDA, NIH, and industry. In the meantime, the new anti-HIV drug ddl was made available under a Par- allel Track prototype from September 1989 to late 1991 and distributed to over 23,000 PWAs who had failed AZT or were intolerant to it.

The Parallel Track provided useful drug safety and tol- erance information on the real-world uses of ddl, making ultimate FDA approval of the drug in October 1991 less risky than it would have been without such a track record. The parallel track also demonstrated how the alliance of NIH, FDA, and activists could transform public policy, meeting the needs of researchers and patients alike. Although a few researchers initially feared the impact of the parallel track on their randomized trials, the comparative studies of ddl conducted by the NIH AIDS Clinical Trials Group (ACTG) enrolled on time and will be complete and ready for analysis by mid-1992.

Even in 1989, however, it was clear to us that simply im- proving access to unapproved therapies was inadequate. We wanted answers, not just access. This meant that we needed to participate in the design, conduct, and analysis of the clinical trials themselves. A long campaign to infiltrate the ACTG resulted by the end of 1990 in the creation of the ACTG Community Constituency Group (CCG), a mechanism by which PWAs and their advocates from diverse com- munities across the USA had voting membership in all the research committees of the ACTG and could participate in research prioritization and protocol development. This led to a historical paradigm shift in which for the first time researchers worked hand-in-hand with the people whose lives they were supposed to be saving.

Key to the ability of AIDS activists to participate in the counsels of the clinical research establishment was the early and enthusiastic advocacy of statisticians, who were piqued by our ideas and empowered by our example. ACT UP's A National AIDS Treatment Research Agenda, distributed in June 1989 at the Fifth International Conference on AIDS in Montreal, spurred a historic discussion among the ACTG Statistical Working Group at the American Statistical As- sociation (ASA) meeting that August. Chaired by David P. Byar of the National Cancer Institute (NCI) Biometry Branch, the meeting brought together for the first time ACT UP members and statisticians from NCI, the National In- stitute of Allergy and Infectious Diseases (NIAID), Harvard's Statistics and Data Analysis Center (SDAC), and other in- stitutions. This initiated an ongoing dialogue that has had profound effects on the work of ACTG researchers and industry-sponsored trials.

Under the guidance of David Byar and with coordination provided by Susan Ellenberg of NIAID, the statisticians pooled their response to the ACT UP critique in "Design Considerations for AIDS Trials" (Byar et al. 1990). The tragic death of Dr. Byar in August 1991 has left a very real gap among the statisticians involved in AIDS work. Dr. Byar possessed the ability to lance conventional thinking with a single well-placed cutting remark and was able, by system- atically dismantling the edifice of conventional clinical trials,

to teach AIDS activists just which elements were required to construct an appropriate clinical trial for an AIDS-asso- ciated condition. His emphasis on the ability to study multiple treatments at once and to allow co-enrollment in several clinical studies has had a salutary effect on the restrictions previously mandated by FDA and obeyed by industry. With the loss of Dr. Byar it becomes incumbent on those working in his wake to honor his legacy by speaking out fearlessly when circumstances demand it and working tirelessly to ensure that clinical trials remain responsive to the task at hand and not to past models derived from other disease settings.

With this background in place, let me briefly note my reactions to some points raised in the Ellenberg, Finkelstein, and Schoenfeld article.

1. THE NATURE OF AIDS The authors note that AIDS is epidemic, chronic, infec-

tious and usually fatal. What they do not state is that it in- volves a dizzying array of acute secondary infections that must be treated or prevented while therapy for the underlying immunodeficiency proceeds. Furthermore, although AIDS does not yet take the toll in lives that cancer or heart disease do, its cost in years of life lost is equivalent because it pre- dominantly strikes people in the prime of life.

2. NATURAL HISTORY AND TREATMENT The pathogenesis of AIDS remains unresolved. Although

it is clear that HIV induces an immunologic vicious cycle that results in depletion of CD4+ lymphocytes and subse- quent susceptibility to opportunistic infections, cancers, neuropathies, and wasting, the exact mechanism by which HIV evokes such profound immunosuppression remains unclear (Fauci et al. 1991). Therefore, the proper choice of therapeutic strategies remains controversial. Anti-HIV treatment does not restore the immune system, nor does it stop the progression of the disease-it simply slows it. Is it more worthwhile simply to prevent or treat the secondary complications or to use anti-HIV treatments such as AZT or ddl as early as possible, given that these latter treatments seem to work only for a short time in a subset of patients? More- over, there has been only one randomized clinical trial that shows a survival difference in people with AIDS treated with anti-HIV therapy (Fischl et al. 1988). Thus the ultimate efficacy of these therapies remains controversial, although they have become the standard of care for persons with impaired immune systems. Although Ellenberg and colleagues state that "median survival after the CD4 count has reached 200/ mm3 for untreated patients was shown by Volberding et al. (1990) to be approximately two years," the clinical trial she cites was conducted in people who entered with CD4 between 200 and 500/mm3 and was not designed to show survival differences and did not show them, because too few people died to assess whether AZT therapy in this study (ACTG 019) affected survival (Volberding et al. 1990).

3. EVALUATING DRUG EFFICACY IN THE PRESENCE OF "sSTANDARD THERAPY"'

Although AZT is now standard for HIV-infected persons with CD4 < 500/mm3, far from all such persons take AZT.



Harrington: Comment 575

Many do not yet know of their HIV infection; others choose to wait until their absolute CD4 count drops precipitously or falls below 200/mm3. Still others, fearful of AZT's side effects and cognizant of its brief and selective efficacy, eschew AZT treatment altogether. This leaves clinical trialists in a bind: they must provide standard of care treatment to design an ethical study, and yet many of the most useful potential participants (those not yet on AZT) are unwilling to participate in such a study. At the same time the original blanket opposition of persons with HIV to placebo-controlled studies has left the perception that placebo studies are impossible with new anti-HIV treatments. Moreover, studies using clinical progression to disease or death as an endpoint must be large and lengthy if they are to prove equivalence of a new treatment to AZT.

4. SURROGATE ENDPOINTS These considerations have led to the recent adoption by

the ACTG and FDA of the view that in evaluating new anti- HIV treatments from the same class of AZT (the "dideoxy- nucleoside analogues" ddl, ddC, d4T, and others), if the new agent shows a beneficial effect in raising CD4 levels or slowing their decline analogous to that demonstrated by AZT, then these agents may be validated by using CD4 changes as "surrogate markers" for efficacy. Incidentally, the rise in CD4 levels is rapid (occurring in 8-12 weeks), and thus many persons at earlier stages of HIV infection may be willing to enter a placebo-controlled study using CD4 changes if it is only 12-24 weeks long. Yet it is important to recognize that data from studies with clinical endpoints (the original Bur- roughs-Wellcome Phase II AZT study, ACTG 002, ACTG 016, and ACTG 019) remain unclear on just how much of AZT's clinical efficacy can be accounted for by its effect on CD4 levels and on how much a rise in CD4 can be predictive of improved survival (Schoenfeld, Finkelstein, and Richman 1991). Although the use of CD4 as a surrogate marker for efficacy remains controversial, it was the basis for the October 1991 FDA approval of ddl as an anti-HIV treatment for patients intolerant of or failing AZT therapy. The decision was based on interim data from an ongoing study designed to evaluate clinical outcomes (ACTG 1 7), which showed that ddl raised CD4 levels in patients who had taken AZT for over 48 weeks, whereas AZT did not. Final analysis of the ddl studies (ACTG 1 6 and 1 7) may help resolve these issues. In the meantime, changes in CD4 levels are used by many in the primary care community to determine the time to initiate or change antiretroviral therapies. Thus researchers and primary care physicians alike are taking a risk in using CD4 levels to determine therapy, and research is more likely to assist in answering questions relevant to the real world of clinical practice. It remains incumbent on researchers and statisticians, however, to continue efforts to validate the use of these and other surrogate markers in evaluating anti-HIV treatments.

5. FACTORIAL DESIGNS AND CO-ENROLLMENT IN MULTIPLE STUDIES

Because AIDS is a multipathogenic disease, factorial designs could usefully be applied-for example, to the joint

study of an anti-HIV drug and an immune system modulator or to the joint study of prophylaxis for two different opportunistic organisms. The promise of this approach has yet to be achieved, partly because of the difficulty in reconciling the demands of different pharmaceutical sponsors and partly because many people with HIV wish to choose most of their treatment options themselves and choose randomization only in the presence of a clear clinical controversy or in order to obtain the trial treatment. Further, the rapidly changing availability of both experimental and approved treatments makes factorial design a potentially "unrealistic simplification," as noted by Ellenberg and colleagues. Per- haps encouraging co-enrollment into several studies as they become available and facilitating this by rendering standard the schedule of clinical and laboratory evaluations and the design of dataforms would be a more realistic solution to this problem. In this regard, the "optional factorial" design suggested by Ellenberg and colleagues is a promising new concept.

6. ANALYSIS OF LONGITUDINAL ENDPOINTS

Currently, in most AIDS trials patients are studied inten- sively for a limited period, then no longer followed once the trial reaches significance and is stopped. Chances to integrate clinical trials with ongoing lifelong epidemiological surveil- lance are being missed. A precious resource is squandered when, as currently, people coming off clinical trials (either after reaching an endpoint or because the trial is terminated) are lost to follow-up. This is happening now with those participants from the AZT early intervention studies (ACTG 016 and 019) who are either ineligible or choose not to enroll in the new study for asymptomatic persons (ACTG 175). This cohort includes many of the putative AZT "respond- ers"-people with CD4 counts under 500/mm3 when they entered ACTG 019, but now above 500/mm3. With no long- term follow-up, we also lose the opportunity to assess whatever effects (if any) AZT has on propensity to neoplasms, for example, or on survival. As is well known, there is no survival data on any antiretroviral therapies except that from the BW-02 AZT study in 1986, which hardly can reflect current realities. Indeed, given rapidly changing treatment patterns, survival effects are unlikely to be seen in any one clinical trial, whereas they will be apparent in observational data bases such as the one proposed here.

In certain cancer studies similar mistakes have been rec- tified at great cost by initiating follow-up after an interruption of several years (P. Meier, personal communication, De- cember 2, 1991). Rather than succumb to this danger, it would be useful to consider a policy under which any HIV- positive person leaving a NIH-sponsored AIDS clinical trial would be followed at six-month intervals in an observational/ epidemiological cohort study for life. Such a study need not be expensive, because only about 15,000 PWAs have ever enrolled in an ACTG study and because the data collected would be minimal, but vital. This proposal would foster greater collaboration between the many important clinical cohorts run by NIH, allow for greater interaction between studies of natural history and treatment research, and main-



576 Journal of the American Statistical Association, June 1992

tain a continuous data base of persons who might be eligible for upcoming studies.

7. STATISTICAL DESIGNS AND PATIENT ADVOCACY

Finally, I address an area to which statisticians and methodologists working in all areas of clinical research should turn their attention. The collaboration between AIDS activists and methodologists has been of immense benefit not only to both parties, but also to all others involved in AIDS research. The insights of the statisticians have benefitted the activists and helped us gain new abilities to affect the direction and design of research, and the vociferous empowerment effected by the activists has helped raise the methodologists to new prominence.

Too often, in clinical research as elsewhere, statisticians are regarded by clinical trialists as mere technicians, called in at the last moment to mumble incomprehensible formulae over completed data, validating it as "significant" and thus providing the benediction of objectivity. Yet statisticians

must be involved from the very outset of the research en- terprise. Many clinical trials-certainly in AIDS and most likely elsewhere-are doomed from the start by inadequate sample size, unnecessary restrictions, and incoherent design. Moreover, guidelines for clinical care often are based on misinformed interpretation of past clinical trial results. To ensure that such mistakes are avoided in future studies, statisticians must make their voices heard early and often. If AIDS activists have had the opportunity to teach AIDS statisticians the lesson of empowerment, then statisticians have a chance to pass on that lesson to their profession by teaching colleagues how to work with advocates concerned with other serious and life-threatening diseases. For at their best methodologists are the referees in games of truth called clinical trials, and the truths constructed from clinical trials are ex- pressed as lives lengthened and lives saved.

ADDITIONAL REFERENCE Fauci, A. S., Schnittman, S. M., Poli, G., Koenig, S., and Pantaleo, G.

(1991), "Immunopathogenetic Mechanisms in Human Immunodeficiency Virus (HIV) Infection," Annals of Internal Medicine, 114, 678-693.

Comment THOMAS A. LOUIS*

Ellenberg, Finkelstein, and Schoenfeld (hereinafter re- ferred to as EFS) provide an informative and compelling perspective on current approaches and challenges in AIDS research. Their examples show how this epidemic, with its rapid spread, morbid and fatal consequences, and demands on the health care system, has broken paradigms of clinical research and heightened the urgency in addressing long- standing issues. I have no essential points of disagreement with EFS. Therefore, I shall expand on some of their points and add a few of my own, including proposals that should generate discussion. I avoid technical details, although these pose substantial challenges.

1. CHOOSING TREATMENTS FOR STUDY

Byar et al. (1990) stressed the central role of "the uncer- tainty principle" in deciding whether to enter patients into a clinical trial. Freedman (1987) used the term "equipoise" to describe this phenomenon. The principle posits that a clinician can enter a patient into a trial if he or she is sufficiently uncertain as to benefit. Although the principle reads well and is consistent with a branch of ethics called proba- bilism, implementation brings complications. The idea applies most directly when an individual clinician is uncertain.

* Thomas A. Louis is Professor and Head, Division of Biostatistics, Uni- versity of Minnesota School of Public Health, Minneapolis, MN 55455. Partial support was provided by National Institute of Allergy and Infectious Diseases Contract NOI-AI-05073 and by National Cancer Institute Grant POI-CA50305.

But to take an extreme case, how should society deal with the situation in which each clinician is virtually certain about which treatment is superior but there is much heterogeneity of opinion? Patients and medical science would benefit from a formal study of the clinical question, but no single clinician is sufficiently uncertain to trigger the principle. Is "societal equipoise" sufficient to justify a trial? And if so, what mechanism will get the trial going?

2. USES OF A PLACEBO OR STANDARD THERAPY

The initial trials of zidovudine (AZT) have been criticized for including a placebo arm. This concern is driven by AZT's successes. If the trials had shown otherwise, the use of a placebo would have been praised. The same concern applies to the use of standard therapy in evaluating innovative treatments (placebo may be the current standard). Currently, discussion boils around the decision to include an AZT-only arm in trials investigating combinations of treatments. Without this baseline arm, any comparisons among the in- novations are floating in midair. Whatever the result, the study will beg the question of whether either is better than the standard.

This said, strict adherence to including the control arm can be inefficient and possibly unethical. In a situation where "nothing works," where disease staging is a minor issue, and

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statistical issues arising in aids clinical trials: comment

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