Surrogate Markers in AIDS: Where Are We? Where Are We Going? Uuring the last several years, extensive research has been done on surrogate markers in patients with the acquired immunodeficiency syndrome (AIDS) (1). However, many questions remain about the use of these markers in the design and implementation of clinical trials for early approval of new drugs to combat the human immunodeficiency virus (HIV), and for patient management. For example, can short-term treatment effects on CD4 cell counts observed during comparative clinical trials of new drugs be reliably used to predict long-term clinical effects? Should the Food and Drug Administration (FDA) use laboratory markers as surrogates for clinical effect in the approval process for new anti-HIV drugs? How can a marker be used to monitor the benefit to a patient receiving an anti-HIV drug? Clearly, the potential value of surrogate markers in these endeavors is enormous. If such markers are used inappropriately, however, ineffective drugs could be adopted as part of standard medical care, and effective drugs could be mistakenly deemed ineffective or used suboptimally. What properties, therefore, should we expect of surrogate markers, and how do we proceed in the face of imperfect information? Drug Evaluation In a large-scale comparative clinical trial, the essential question is whether a new drug is more efficacious

than a standard therapy for the patient population under consideration. For a marker to be a valid surrogate for clinical progression in such trials, any effect of the drug on the risk for clinical progression should be predictable through its effect on the marker. How can a marker be validated for this property? The potential marker must first be biologically plausible as a measure central to the pathogenesis of disease, symptoms, or both. If this plausibility is satisfied, it is not enough that pretreatment values of the marker are predictive of the risk for clinical progression; rather, two empiric conditions must exist to satisfy a formal definition of a surrogate marker (2). First, changes in the marker values over time must correlate with the shortterm risk for clinical progression. Second, after controlling for the treatment's effect on the marker, no residual effect of treatment on the risk for clinical progression should exist (2). This latter condition ensures that any clinical benefit of the drug can be fully explained by its effect on the marker. These conditions establish a qualitative link between the marker effect and the clinical effect of treatment. The treatment's effect on the marker should also produce a clinically meaningful effect (3). To date, the only marker for which these conditions appear to have been evaluated is the CD4 lymphocyte

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count, based on results from placebo-controlled trials of zidovudine in persons with AIDS (Tsiatis A., presentation to FDA Antiviral Advisory Committee, 13 February 1991, Bethesda, Maryland) and those with asymptomatic HIV infection (Choi S. and Volberding P. Personal communication). Both studies confirm that a patient's current CD4 cell count is significantly correlated with the risk for disease progression in both treated and untreated patients. However, both studies also indicate that CD4 cell count can explain only a portion of zidovudine's beneficial effect on clinical progression. That is, a substantial component of zidovudine's beneficial effect does not appear to be manifested through its effect on CD4 cell count. Because of the central role of CD4 count in the pathogenesis of HIV disease, however, CD4 responses may more fully explain the clinical effects of drugs having other mechanisms of action. In retrospect, it seems unrealistic to expect that any single marker can fully explain all of a drug's clinical effects. The CD4 cell count, for example, does not measure functionality of CD4 cells and therefore reflects only one aspect of a patient's immune system. A more realistic possibility is that several markers will be identified that collectively explain most of a treatment's effect on clinical progression. Even if such a battery of markers were found, for example, based on trials involving zidovudine, the use of such markers to predict another drug's effect on clinical progression would entail a leap of faith, although perhaps one acceptable to the scientific community. Laboratory markers have been used in small phase I and II trials to select new drugs that should be candidates for evaluation in large-scale, phase III comparative efficacy trials. However, based on current knowledge about surrogate markers, we cannot confidently abandon clinical end points as the basis for judging efficacy in these large trials. A problem then arises because, in trials of HIV-infected persons who have not yet developed AIDS, clinical event rates can be quite low, implying that larger sample sizes or trials of longer duration are needed. It is therefore important that we continue to conduct comparative efficacy trials that collect data on both clinical outcomes and surrogate markers to establish CD4 count or other markers as valid surrogates for clinical effect. Drug Approval The use of surrogate markers for regulatory purposes requires a different perspective because drug approval decisions must be made in the face of public health exigencies. The FDA's recent approval of dideoxyinosine (ddl) for persons with advanced HIV infection is a case in point. The decision was based on the drug's effect on CD4 count, at a time well before clinical efficacy data from the ongoing controlled clinical trials were available. Despite the evident limitations of using CD4 count as a surrogate marker for clinical progression, the FDA and its Antiviral Advisory Committee recognized the tremendous clinical need for effective therapies for patients with advanced HIV infection for whom zidovudine no longer provides any clinical ben600

efit. We believe that this reality outweighed any reservations about the reliability of CD4 counts to assess potential clinical efficacy. It was also clear, however, that these considerations were not sufficient for unconditional approval of ddl. Central to this decision is that the most critical questions, that is, the clinical outcomes of the controlled trials as well as their correlation with CD4 counts, will be answered by mid-1992, thus providing reassurance that the scientific basis for the approval will be confirmed (or not) within a reasonable time. The potential value of surrogate markers in the drug approval process is especially critical for persons with early asymptomatic HIV infection because this population currently comprises the majority of HIV-infected persons in the United States and worldwide, and because all these persons are expected to eventually develop symptomatic disease. Among these apparently healthy individuals, the rates of developing opportunistic infections and other clinical manifestations of HIV are small, and trials based on clinical end points currently in common use may require thousands of patients and many years to complete. Clearly, the potential gains from early approval of drugs based on surrogate markers could be enormous. However, early approval based on an inappropriate marker could result in many persons receiving ineffective therapies. Intensive efforts to define valid surrogates for this population are in progress. Patient Management Ideally, the CD4 count and other markers could be used in patient management to indicate to clinicians when a therapy should be initiated; when it is no longer effective; when alternative therapies ought to be introduced; and, by the magnitude of the effect on the marker, how much clinical benefit a patient is deriving. Unfortunately, little is known about the value and use of any markers for these purposes. The best mechanism for clarifying these issues is that of controlled clinical trials which investigate differing treatment strategies and which collect marker data to help elucidate the value of markers in the management of individual patients. To date, the CD4 count has been evaluated in persons receiving zidovudine and has been found only partially to explain the drug's beneficial effects on mortality and clinical disease progression. Correlative studies involving other nucleoside analogs should be completed within the next year. However, the applicability of these results to drugs that are believed to act differently from zidovudine and ddl is unclear. Other molecules of immune origin have been shown to predict the risk for clinical progression (4), but their value in predicting drug efficacy has not yet been elucidated. Researchers are currently examining whether markers that more directly measure the extent of circulating HIV (such as quantitative plasma culture, quantitative RNA, and DNA polymerase chain reaction) might more fully characterize a drug's ultimate clinical effect. The success of these investigations could have enormous effects

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on the drug evaluation process and thereby on our ability to effectively combat this epidemic.

Annals of Internal Medicine. 1992;116:599-601. References

Stephen W. Lagakos, PhD Harvard University Boston, Massachusetts 02115 Daniel F. Hoth, MD National Institutes of Health Bethesda, Maryland 20892 Requests for Reprints: Stephen W. Lagakos, PhD, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115.

1. Institute of Medicine. Surrogate endpoints in evaluating the effectiveness of drugs against HIV infection and AIDS: September 11-12, 1989 Conference Summary. Robin Weiss and Leah Mazade; eds. Washington, D.C.: National Academy Press; 1990. 2. Prentice R. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431-40. 3. Machado SG, Gail MH, Ellenberg S. On the use of laboratory markers in the evaluation of treatment for HIV infection. J Acquir Immune Defic Syndr. 1990;3:1065-73. 4. Osmond DH, Shiboski S, Bacchetti P, Einger EE, Moss AR. Immune activation markers and AIDS prognosis. AIDS. 1991;5:505-11.

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Surrogate markers in AIDS: where are we? Where are we going?

Surrogate Markers in AIDS: Where Are We? Where Are We Going? Uuring the last several years, extensive research has been done on surrogate markers in p...
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