Statistical Issues Arising in AIDS Clinical Trials: CommentAuthor(s): Stephanie GreenSource: Journal of the American Statistical Association, Vol. 87, No. 418 (Jun., 1992), pp. 571-572Published by: American Statistical AssociationStable URL: http://www.jstor.org/stable/2290293 .

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Green: Comment 571

demonstrating safety and efficacy in broad and heterogeneous groups of patients who represent the ultimate target groups in practice.

Again, I would like to compliment the authors on an ex- tremely interesting and timely report. I hope that it will stim- ulate further work by statisticians, and that the authors themselves will be able to facilitate such work through further

communication and by helping interested statisticians gain access to data in order to hasten such work toward productive application.

ADDITIONAL REFERENCE Gehan, E. A., and Freireich, E. J. (1974), "Non-Randomized Controls in

Cancer Clinical Trials," New England Journal of Medicine, 290, 198- 203.

Comment STEPHANIE GREEN*

The authors present clearly some of the difficult statistical issues being addressed in the AIDS clinical trials program. These issues are not new, but the critical need to identify effective AIDS therapies has generated new urgency for methodological research. Clinical cancer research shares many of the problems addressed by the authors.- This dis- cussion will examine the issues following the same organi- zation as the paper.

First, consider cancer natural history. Care practices, di- agnostic definitions and techniques, and primary and ancil- lary treatments are changing continuously. Although more historical information is available for most cancers than for AIDS, for some subtypes this is not true-such as hairy cell leukemia, which was rarely recognized before the late 1 970s. Even when historical information is extensive, it is inade- quate for use in assessment of new treatments. The magni- tude of change over time cannot be assumed smaller than the modest expected effects of treatment.

Evaluating drug efficacy in the presence of standard therapy is problematic in cancer research as well. There are few can- cers for which a placebo-controlled trial is considered ethical. At the time when "no treatment" arms would have been acceptable, trials often were inadequately controlled, leading to standard treatments of unknown effectiveness. The active control design addressed in Fleming (1987), for example, estimates the effect of doxorubicin (Adriamycin) based not on placebo-controlled trials, but on trials of combination chemotherapy with and without Adriamycin. Generally, negative trials must be interpreted to mean that the new agent should not be used in the patient population studied; questions about effectiveness in patients intolerant to stan- dard therapy or in combination with standard therapy must be addressed directly. In many cancers, the difficulties are compounded by the existence of multiple effective treatments for both early stage and advanced disease. By the time it is considered ethical to treat a patient with a new agent, pre- treatment is often extensive and the probability of demon- strating activity, even for an active agent, is low.

* Stephanie Green is Associate Member, Fred Hutchinson Cancer Re- search Center, Seattle, WA 98104-2092.

As for AIDS, no adequate surrogate endpoints have been identified for any cancer. Candidate markers, such as CEA, have been found to be nonspecific and too variable. Tumor regression is used as an endpoint for new agents in advanced disease to indicate biologic activity, but it is recognized that regression will not necessarily translate into a survival ad- vantage and that active agents can be missed using this strat- egy. The aim of response trials is to identify agents that should be studied further in randomized settings with longer-term endpoints; CD4 or dose-response trials might eventually serve a similar role in AIDS.

We base early stopping of randomized cancer trials on survival whenever possible. If survival is prohibitively long, progression-free survival is used with conservative stopping rules (similar to use of development of opportunistic infection instead of survival in AIDS). Earlier markers are not used, even when the relapse rate is low, as this risks compromising the ability to answer the primary study questions later. It is difficult to see how auxiliary outcomes can improve the abil- ity to draw conclusions concerning the primary endpoints without making unverifiable model assumptions. Early out- come information might be useful in designing new trials, but not in stopping current ones.

Multiple questions in the same patient population are common in cancer. Issues in bone marrow transplantation, for instance, include timing of the transplant, optimal in- duction regimen, management of graft-versus-host disease, and infection prophylaxis, all of which impact on survival. In many other cancers, issues arise concerning optimal use of multiple treatment modalities: radiotherapy, surgery, chemotherapy, hormonal therapy, and biologic response modification. We occasionally use factorial designs for treat- ments directed at the same endpoint, but experience has proven that assumptions of no interaction are not always correct. For instance, a recent Southwest Oncology Group study of chemotherapy and prophylactic cranial irradiation in limited non-small cell lung cancer resulted in a detrimental

? 1992 American Statistical Association Journal of the American Statistical Association

June 1992, Vol. 87, No. 418, Review Paper

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572 Journal of the American Statistical Association, June 1992

effect of radiotherapy and, consequently, an inadequate sample size for addressing the chemotherapy question. Sub- sequent factorials have been designed to have adequate power without assuming there are no interactions.

Examples of studies directed at different endpoints include antiemetic and pain management trials. Co-enrollment on cancer trials with different endpoints generally has not been considered a problem, although clearly it could be (e.g., if an experimental antiemetic treatment allows higher doses of drugs to be administered on one of the treatment arms). A recent issue involves the use of colony-stimulating factors for managing chemotherapy-induced neutropenia. The po- tential for interaction of treatment with colony-stimulating factors appears sufficiently high to lead us to recommend standardized administration specified in treatment protocols rather than to allow entry of study patients onto randomized CSF protocols.

We too wrestle with the problems of early stopping on multiarm studies, efficient management of patients on mul- tiple studies, and when to double-blind. Because time to fail- ure and survival are fairly objective endpoints, and treat- ments usually are not available over the counter, we rarely decide that double-blinding is sufficiently advantageous to warrant the inconvenience or, given current budget con- straints, the cost.

In cancer as well as in AIDS, treatment modifications due to toxicity are routine. Patient noncompliance is common as well. For instance, head and neck cancer patients often are alcoholics and are uncooperative. Analysis according to dose received ("dose intensity" analysis) recently has become fairly common. Because there are no studies for which it is reasonable to assume compliance is unrelated to the primary endpoint, however, the inevitable results of these analyses are heated (and unproductive) disagreements concerning "correct" methods and interpretation. Perhaps there are more appropriate applications in AIDS, but we find that if the intent to treat analysis becomes meaningless (i.e., the treatment strategy is not followed), then little is salvageable from the trial. It seems unlikely that any amount of modeling will resolve the issue of ZDV benefit in the context of PCP prophylaxis; only further randomization of prophylaxis vs. prophylaxis plus ZDV (if this had been possible) would have settled the question.

Outcome summary poses similar problems in cancer as in AIDS. Time to failure for both diseases includes more than one type of failure, plus competing risks difficulties. In addition to objective tumor increase, cancer patients may die or discontinue treatment due to toxicity, may deteriorate and go off treatment without objective evidence of progres- sion, may develop new primaries, or may die of other causes. Multiple events of the same type are also a problem for both cancer and AIDS. For instance, rate of occurrence of pap- illary tumors is of interest in bladder cancer. Long-term tox-

icity assessment in patients receiving long-term adjuvant therapy presents the same problems as in patients receiving years of antiviral agents. A suggestion similar to time without treatment complications-time without symptoms or tox- icity (TWIST)-has been proposed for use in adjuvant breast cancer studies (Gelber and Goldhirsch 1986). Cancer also has similar long-term outcome modeling applications; for instance, bone mineral density changes during adjuvant therapy.

Statistical issues may be similar in cancer and AIDS, but political and sociological issues are much more intense for AIDS. It is not that there have not been cancer patient ad- vocates (e.g., Rose Kushner in breast cancer) or that there are not important issues in cancer (e.g., cancer patients do not participate in unacceptable trials either, access to care is a problem for many patients, minorities are underrepresented on clinical trials, and more women's issues need to be ad- dressed). But cancer patient response is largely passive; rather than demand access to studies that suit them, they simply do not participate. Cancer clinical trialists have not had to interact with critical activist groups or discuss design issues with patient representatives.

Educating the community regarding principles of clinical trials and adjusting certain aspects of studies without com- promising these principles is a good approach. It is not so clear that other changes will be beneficial. The "parallel track" approach has potential for compromising scientific standards. How complete is the adverse effective information collected? Are patients willing to be followed indefinitely? What will be compared in these simple randomized trials, and will patients accept randomization? Given the compli- ance problems in carefully monitored trials, how likely is it patients will comply on these trials? What conclusions can be made if results on a parallel track trial disagree with re- search protocol results? Is the cost prohibitive? Cancer sta- tisticians may be inclined to be overly cautious due to limited success in identifying useful cancer therapies, but AIDS is bound to have its laetriles and "magic bullets" too. The best way to guarantee that future patients receive effective treat- ment is through well controlled and carefully monitored trials.

AIDS clinical research is enormously challenging. The clinical trials program has developed rapidly over the last five years under very difficult circumstances and is already producing important results. The dedication and effort of the authors and other statisticians working in AIDS research is to be commended.

ADDITIONAL REFERENCE

Gelber, R. D., and Goldhirsh, A., for the Ludwig Breast Cancer Study Group (1986), "A New Endpoint for the Assessment of Adjuvant Therapy in Postmenopausal Women with Operable Breast Cancer," Journal of Clinical Oncology, 4, 1772-1779.

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