Clinical trials surrogate endpoints

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

Exposure-response data, using short-term biomarkers or surrogate endpoints, can sometimes make further exposure-response studies from clinical endpoints xmnecessary. For example, if it can be shown that the short-term effect does not increase beyond a particular dose or concentration, there may be no reason to explore higher doses or concentrations in the clinical trials. Similarly, short-term exposure-response studies with biomarkers might be used to evaluate early (i.e., first dose) responses seen in clinical trials. 

Surrogate endpoints, a subset of biomarkers, are laboratory measurements or physical signs used in therapeutic trials as a substitute for clinical endpoints expected to predict the effect of the therapy. A fully validated, surrogate endpoint predicts the clinically meaningful endpoint of a therapy consistently. ... 

In clinical trials, biomarkers are used to indicate a particular disease state and its progression. They may be used as surrogate markers in the evaluation of the effectiveness of a drug as representative of the natural endpoint such as survival rate or irreversible morbidity. 

The limitations of the use of biomarkers in healthy volunteers must be recognised. For example, although there have been attempts to simulate migraine headache in volunteers, to date none of these models can be considered adequate to serve as a surrogate endpoint. Patients with migraine are not difficult to recruit and are usually healthy apart from their migraine. In this case, it maybe more appropriate to establish tolerability and pharmacokinetics in healthy volunteers and then to select a maximum well-tolerated dose with which to perform a small proof of principle clinical trial in patients. This will need to be followed by larger trials to establish the dose-response relationship. 

There are many examples of biomarkers, which have been used as surrogates in prominent clinical trials that have been subsequently formd to be inadequate, illustrating the difficulty in identifying a surrogate endpoint. One notable scenario is that of a biomarker that responds to therapy and is highly predictive of survival, but does not predict the effect of treatment on survival. The use of CD4-I- counts in HIV trials is an example of such a biomarker. ... 

There are of course practical considerations in clinical research. We may find patient recruitment difficult in single centre studies and this is one of the major drivers to multicentre and multinational trials. Alternatively, we may need to relax the inclusion/exclusion criteria or lengthen the recruitment period. Unfortunately, while each of these may indeed increase the supply of patients they may also lead to increased variability that in turn will require more patients. A second issue is the size of the CRD which, if it is too small, will require a large number of patients. In such circumstances we may need to consider the use of surrogate endpoints (Section S.3.3.2). Finally, the standard deviation may be large and this can have a considerable impact on the sample size - for example, a doubling of the standard deviation leads to a four times increase in the... 

Fleming TR, DeMets DL. Surrogate endpoints in clinical trials are we being misled Ann Intern Med 1996 125 605-13. 

Prentice RL. Surrogate endpoints in clinical trials definition and operational criteria. Stat Med 1989 8 431 0. 

Surrogate endpoints are usually used when it is not possible within the timeframe of the trial to measure true clinical benefit. Many examples exist as seen in Table 1.3. 

CHOI BASIC IDEAS IN CLINICAL TRIAL DESIGN Table 1.3 Surrogate variable and clinical endpoints... 

Treatment effects on surrogate endpoints therefore do not necessarily translate into treatment effects on clinical endpoints and the validity of the surrogate depends not only on the variable itself but also on the disease area and the mode of action of the treatment. Establishing new valid surrogates is very difficult. Fleming and DeMets conclude that surrogates are extremely valuable in phase II proof of concept studies but they question their general use in phase III confirmatory trials. 

Further support for using blood pressure as a surrogate endpoint is provided by the concordance of evidence from a number of clinical trials in which blood pressure lowering with low-dose diuretics and P-blockers was shown to reduce the incidence of stroke/ coronary artery disease/ and congestive heart failure in hypertensive patients (19). Of particular interest is a meta-analysis that was conducted to compare the extent of blood pressure reduction achieved in different clinical trials with the maximum benefit that was anticipated on epidemiolgic grounds (Table 17.3) (20). The decrease in stroke incidence anticipated for a 5- to 6-mm Hg average reduction in diastolic blood pressure was fully realized with only 2 to 3 years of antihypertensive therapy. 

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