Lagakos SW 1. Affiliations 1 author 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract The identification of surrogate markers for clinical end points has important implications for the conduct of AIDS clinical trials, the approval of drugs for the treatment of infection with human immunodeficiency virus HIV , and the management of HIV infection.
In this paper, the concept of a surrogate marker and the properties of an ideal marker are discussed. The steps required for the empirical verification of a potential marker are then addressed, and current information on surrogate markers for AIDS is reviewed. Studies conducted to date indicate that the effects of a new drug on numbers of CD4 lymphocytes account only partly for its ultimate impact on the clinical progression of HIV infection.
Consequently, the potential benefits of early approval of a drug based on its effect on CD4 lymphocytes must be weighed against the uncertainty about its ability to actually delay clinical progression. Full text links Read article at publisher's site DOI : Smart citations by scite. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
Explore citation contexts and check if this article has been supported or disputed. The predictive value of several markers in the progression to acquired immunodeficiency syndrome. AIDS clinical trials. Is there access for all? Similar Articles To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.
Surrogate markers in AIDS and cancer trials. Funding Funders who supported this work. These limitations underscore the importance of continued evaluation in the post-market phase when products are approved based upon surrogate endpoints that have not been validated, as well as the need to rigorously evaluate and sometimes re-evaluate surrogate endpoints clinically.
Despite such caveats, as science and technology advance, it is hoped that the increased use of biomarkers and surrogate endpoints will facilitate the more efficient development of safe and effective medical products. What are biomarkers? What are endpoints when used in a clinical trial? What are examples of validated surrogate endpoints used in medical product development? Are surrogate endpoints that have not been validated useful in medical product approvals? Why are surrogate endpoints important for medical product development?
What is the challenge of using biomarkers and surrogate endpoints in medical product development? This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.
Abstract Available from publisher site using DOI. A subscription may be required. Search articles by 'T R Fleming'. Fleming TR 1. Affiliations 1 author 1. Department of Biostatistics, University of Washington, Seattle Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract There is significant need for rapid yet reliable evaluation of promising new interventions for the treatment of patients with cancer or HIV infection.
Considerable attention has been given to identifying replacement or 'surrogate' endpoints for the true clinical efficacy endpoints, in order to reduce the cost, size and duration of clinical trials. We discuss issues which affect the validity of surrogate markers. The reliability of the CD4 lymphocyte count marker is carefully considered in clinical trials of anti-retroviral agents in HIV infected individuals. The nature of surrogate markers and their reliability is discussed in cancer prevention, screening and treatment trials.
Some suggested uses of marker information are also considered. Full text links Read article at publisher's site DOI : Title not supplied Fleming Statistical Science Title not supplied The Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmia's during the year after acute myocardial infarction: the CAPS Title not supplied The Preliminary Report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction Title not supplied The A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease Surrogate end points in clinical trials.
Surrogate markers in AIDS: where are we? Where are we going? Surrogate endpoints in clinical trials: definition and operational criteria. Further, the preamble explicitly states that when a clinical benefit can clearly be shown in reasonable clinical trials, the Agency will not rely on an effect on a surrogate to support approval.
The regulations impose numerous requirements on sponsors of drug products approved under these provisions, e. If the attempt to validate the surrogate fails or no reasonable attempt is made , the drug may be removed from the market. Although these and all regulations have the force of law, they were adopted via the process of rule-making as are all regulations , which does not require the action of Congress.
In fact, the Agency has approved drug products on the basis of their effects on surrogate markers for many years before the adoption of these regulations examples include anti-hypertensives, cholesterol-lowering agents, and treatments for glaucoma.
In each of these cases, drugs have been shown to have a beneficial effect on the surrogate of interest blood pressure, serum cholesterol, and intra-ocular pressure, respectively without a requirement that they be shown to have an effect on the relevant, desired clinical outcomes heart attacks, strokes, death in the first two cases, and visual loss in the last. It is worth noting that the FDA does not have a monolithic position on the approval of drugs under the Accelerated Approval regulations.
Clearly, there are units in the Agency in which such approvals are routinely granted; for example, some anti-cancer treatments are approved under the Accelerated Approval regulations. In these cases, however, the drugs are considered to be reasonably likely to predict the desired clinical benefit, and the labeling adopted at the time of the approval indicates the treatment for patients with the clinical condition studied, with accompanying language describing that the approval was based on the effects of the treatment on tumor size, and that there is no evidence of a clinical effect.
The labeling is changed to include a description of the documented effect on survival only when the subsequent studies are done that demonstrate the effect on the clinical outcome.
To date, however, no treatments for neurologic or psychiatric diseases have been approved on the basis of an effect on a surrogate marker, validated or unvalidated.
Most, if not all, recently approved treatments for neurologic and psychiatric disease are considered to have symptomatic effects; that is, there is no clinical evidence that these treatments have any effect on the underlying pathologic substrate of the disease under study.
Although, of course, some of them may have such an effect on the underlying pathology, the clinical studies performed to support the approval of these treatments are not capable of detecting such an effect. In the typical study conducted to support approval, patients are randomized to treatment or control usually placebo , observed throughout the time course depending upon the condition under study, the duration of the study may be 3 weeks to 2 years , and assessed on a relevant clinical outcome, as described above.
Effectiveness is determined by the difference in outcome between patients who received the drug and those who received the control treatment. This design is incapable of detecting whether or not the effect is symptomatic or structural and enduring. Typically, indications for such treatments in approved product labeling are silent about the nature of the effect for example, a drug approved on the basis of its effect in reducing, relative to control, the frequency of partial seizures, will be indicated as a treatment for partial seizures , but no implication that the effect is structural either in labeling or advertising is permitted.
Clearly, for the treatments approved to date, practical study designs exist in terms of duration, size, and available clinical measures , and are capable of detecting treatment effects. It is explicitly in these circumstances that the use of surrogate markers as primary outcome measures is unwarranted, as discussed in the preamble to the regulations, and described above.
It is important to recognize this, because the advantages often ascribed to reliance on the effect of a drug on a surrogate marker are that trials can be considerably shorter in duration and smaller in size number of patients enrolled if the primary outcome is a surrogate rather than the clinical outcome of interest e.
There are now a number of pharmaceutical sponsors that have begun to develop treatments that they believe might have an effect on the progression of the disease i.
It is possible to imagine, for example, that for a particular treatment that produced an effect on the underlying progression of an illness, studies of reasonable duration or size might not be practical to conduct. That is, it might not be possible to detect a difference between the treatment and control on an obvious clinical outcome in a trial of reasonable duration or size. It is in the context, then, of attempting to demonstrate the effect of a drug on the underlying progression of the disease when a clinical effect would be unexpected to be easily detectable that there has begun to be serious discussion about the use of surrogate markers as primary measures of drug effect.
Clinical trial designs have been proposed, however, that are capable of detecting the effect of a drug on the underlying progression of disease, and these trials are unambiguously interpretable. However, in this design, patients initially treated with active drug are withdrawn from treatment patients initially treated with placebo are continued on placebo. In this withdrawal period, if patients initially treated with active drug approach the status of patients initially treated and continuing to be treated with placebo, this is taken as evidence that the active treatment had only a symptomatic effect that is, when the treatment is removed, patients approach where they would have been had they never received treatment.
If, on the other hand, patients initially treated with active drug do not approach the continuing placebo patients that is, the slope of their decline is at least parallel to that of the placebo patients this implies that the treatment had a structural effect that is, when the treatment is removed, there is a persistent difference compared to how they would have fared had they not been treated.
Although these designs appear to be able to provide clear evidence for either a symptomatic or structural effect that is, they provide unambiguous evidence for either conclusion , they are difficult to perform adequately, for at least two reasons.
It is typically not clear how long the withdrawal observation period should be. It would be inappropriate to conclude that the post-treatment slopes of the two groups were parallel, for example, if the patients were followed for too short a period to adequately assess the slope.
In addition, the goal of such a study assuming the goal is to demonstrate a structural effect is to demonstrate parallel slopes. This leads to a situation in which equivalence of slopes is the goal; demonstration of equivalence of outcomes ordinarily requires large numbers of patients.
Perhaps for these reasons, these trials are rarely performed. Given that the clinical trials designed to detect a progression effect are difficult, and given the appearance of many new investigational treatments designed to affect the underlying pathology of various diseases, there has been renewed interest in relying on the effect of a drug on surrogate markers to support approval.
However, there are a number of important issues that need to be addressed before such use can be contemplated. As discussed above, the Agency recognizes that basing an approval on the effect of a drug on an unvalidated surrogate introduces additional uncertainty into the approval process. Clearly, this uncertainty is considered acceptable under certain circumstances. As noted earlier, however, current and past treatments for neurologic and psychiatric drugs have all been approved on the basis of relatively simple clinical trials.
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