Showing papers on "Surrogate endpoint published in 2006"

Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials.

Abstract: Background. Target of rapamycin inhibitors (TOR-I) have a novel mode of action but uncertain clinical role. We performed a systematic review of randomized trials where immunosuppressive regimens containing TOR-I were compared with other regimens as initial therapy for kidney transplant recipients. Methods. Databases (inception, June 2005) and conference proceedings (1996-2005) were searched. Two independent reviewers assessed trials for eligibility and quality. Results at 1 year, are expressed as relative risk (RR), where values < 1 favor TOR-I, or lower dose of TOR-I, and for continuous outcomes are expressed as weighted mean difference (WMD), both expressed with 95% confidence intervals (CI). Results. Thirty-three trials (142 reports) were included (27 trials of sirolimus, 5 ofeverolimus, and 1 of head-to-head comparison). When TOR-I replaced calcineurin inhibitors (CNI) (8 trials with 750 participants), there was no difference in acute rejection (RR, 1.03; 95% CI, 0.74-1.44), but serum creatinine was lower (WMD, -18.31 μmol/L; 95% CI, - 30.96 to -5.67) and bone marrow more suppressed (leukopenia: RR 2.02; 95% CI, 1.12-3.66; thrombocytopenia: RR, 6.97; 95% CI, 2.97-16.36; and anaemia: RR, 1.67; 95% CI, 1.27-2.20). When TOR-I replaced antimetabolites (11 trials with 3966 participants), acute rejection and cytomegalovirus infection (CMV) were reduced (RR, 0.84; 95% CI, 0.71-0.99; RR, 0.49; 95% CI, 0.37-0.65, respectively), but hypercholesterolemia was increased (RR, 1.65; 95% CI, 1.32-2.06). When low- was compared with high-dose TOR-I, with equal CNI dose (10 trials with 3,175 participants), rejection was increased (RR, 1.23; 95% CI, 1.06-1.43) but calculated glomerular filtration rate (GFR) higher (WMD, 4.27 mL/min; 95% CI, 1.12-7.41), and when lower-dose TOR-I and standard-dose CNI were compared with higher-dose TOR-I and reduced CNI, acute rejection was reduced (RR, 0.67; 95% CI, 0.52-0.88), but calculated GFR was also reduced (WMD, - 9.46 mL/min; 95% CI, -12.16 to - 6.76). There was no significant difference in mortality, graft loss, or malignancy risk for TOR-I in any comparison. Conclusions. TOR-I have been evaluated in four different primary immunosuppressive algorithms: as replacement for CNI and antimetabolites, in combination with CNI at low and high doses, and with a variable dose of CNI. Generally, surrogate endpoints for graft survival favor TOR-I (lower risk of acute rejection and higher GFR), and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression and lipid disturbance). Long-term hard-endpoint data from methodologically robust randomized trials are still required.

Reported Outcomes in Major Cardiovascular Clinical Trials Funded by For-Profit and Not-for-Profit Organizations: 2000-2005

Abstract: ContextIn surveys based on data available prior to 2000, clinical trials funded by for-profit organizations appeared more likely to report positive findings than those funded by not-for-profit organizations. Whether this situation has changed over the past 5 years or whether similar effects are present among jointly funded trials is unknown.ObjectiveTo determine in contemporary randomized cardiovascular trials the association between funding source and the likelihood of reporting positive findings.DesignWe reviewed 324 consecutive superiority trials of cardiovascular medicine published between January 1, 2000, and July 30, 2005, in JAMA, The Lancet, and the New England Journal of Medicine.Main Outcome MeasureThe proportion of trials favoring newer treatments over the standard of care was evaluated by funding source.ResultsOf the 324 superiority trials, 21 cited no funding source. Of the 104 trials funded solely by not-for-profit organizations, 51 (49%) reported evidence significantly favoring newer treatments over the standard of care, whereas 53 (51%) did not (P = .80). By contrast, 92 (67.2%) of 137 trials funded solely by for-profit organizations favored newer treatments over standard of care (P<.001). Among 62 jointly funded trials, 35 (56.5%), an intermediate proportion, favored newer treatments. For 205 randomized trials evaluating drugs, the proportions favoring newer treatments were 39.5%, not-for-profit; 54.4%, jointly funded; and 65.5%, for-profit trials (P for trend across groups = .002). For the 39 randomized trials evaluating cardiovascular devices, the proportions favoring newer treatments were 50.0%, not-for-profit; 69.2%, jointly funded; and 82.4%, for-profit trials (P for trend across groups = .07). Regardless of funding source, trials using surrogate end points, such as quantitative angiography, intravascular ultrasound, plasma biomarkers, and functional measures were more likely to report positive findings (67%) than trials using clinical end points (54.1%; P = .02).ConclusionsRecent cardiovascular trials funded by for-profit organizations are more likely to report positive findings than trials funded by not-for-profit organizations, as are trials using surrogate rather than clinical end points. Trials jointly funded by not-for-profit and for-profit organizations appear to report positive findings at a rate approximately midway between rates observed in trials supported solely by one or the other of these entities.

Evaluation of Prostate-Specific Antigen Declines for Surrogacy in Patients Treated on SWOG 99-16

Abstract: Background: The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial. Methods: Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/ prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%-90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice's criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided. Results: Three-month PSA level declines of 20%-40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio [HR]= 0.43, 95% confidence interval [CI] = 0.34 to 0.55; P<.001), and the increased risk of death for men treated with M/P compared with D/E (HR = 1.24, 95% CI = 1.02 to 1.51; P =.032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy. Conclusions: Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.

Nutrition support in acute pancreatitis : A systematic review of the literature

Abstract: Background: Failure to use the gastrointestinal (GI) tract in patients with acute pancreatitis may exacerbate the stress response and disease severity, leading to greater incidence of complications and prolonged hospitalization. The objectives of this study were to determine the optimum route for nutrition support, whether nutrition therapy is better than no artificial nutrition support, whether specific additives to enteral or parenteral therapy can further enhance their efficacy, and whether methodologic differences in delivery of enteral nutrition (EN) influence tolerance. Methods: A computerized search was performed of MEDLINE, Cochrane database, EMBASE, and reference lists of pertinent review articles for prospective randomized trials in adult patients with acute pancreatitis that evaluated interventions with nutrition therapy. Primary outcome data and surrogate endpoint parameters (for nutrition indices, stress markers, and measures of the inflammatory/immune response) were extracted in duplicate in...

Statistical evaluation of biomarkers as surrogate endpoints: a literature review

Abstract: A valid surrogate endpoint allows correct inference to be drawn regarding the effect of an intervention on the unobserved true clinical endpoint of interest The perceived practical and ethical advantages of substituting a surrogate endpoint for a clinical endpoint have led to a considerable number of statistical methods being proposed for the evaluation of a biomarker as a surrogate endpoint We review the main statistical schools of thought which have developed and consider how the validation process might be arranged within the regulatory and practical constraints of the drug development process We conclude by assessing which of the candidate statistical methods offer the best approach for surrogate endpoint evaluation

Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis.

Abstract: Summary Background The duration and cost of cancer clinical trials could be reduced if a surrogate endpoint were used in place of survival. We did a meta-analysis to assess the extent to which two surrogates, tumour response and time to progression, are predictive of mortality in metastatic colorectal cancer and non-small-cell lung cancer. Methods Summary data (median time to progression, proportion of patients responding to treatment, and median overall survival) from randomised trials of first-line treatment in colorectal cancer (146 trials) and lung cancer (191 trials) were identified. Data were extracted and analysed by linear regression. We used prediction bands for trials with 250, 500, and 750 patients to identify the surrogate threshold effect that would predict a significant difference in survival. Findings Response to treatment and time to progression correlated with improvement in survival for both lung cancer (p Interpretation Irrespective of trial size, large differences in tumour response rate are needed to predict a significant survival benefit. If surrogates are chosen as the primary endpoint in a clinical trial, time to progression is the preferred measure because more modest and achievable differences are needed for a significant survival benefit. Trials in metastatic lung cancer and colorectal cancer should measure survival as their primary outcome unless the surrogate outcome difference is anticipated to exceed the threshold effect size.

Surrogate threshold effect: an alternative measure for meta-analytic surrogate endpoint validation.

Abstract: In many therapeutic areas, the identification and validation of surrogate endpoints is of prime interest to reduce the duration and/or size of clinical trials. Buyse et al. [Biostatistics 2000; 1:49-67] proposed a meta-analytic approach to the validation. In this approach, the validity of a surrogate is quantified by the coefficient of determination Rtrial2 obtained from a model, which allows for prediction of the treatment effect on the endpoint of interest ('true' endpoint) from the effect on the surrogate. One problem related to the use of Rtial2 is the difficulty in interpreting its value. To address this difficulty, in this paper we introduce a new concept, the so-called surrogate threshold effect (STE), defined as the minimum treatment effect on the surrogate necessary to predict a non-zero effect on the true endpoint. One of its interesting features, apart from providing information relevant to the practical use of a surrogate endpoint, is its natural interpretation from a clinical point of view.

Carotid intima-media thickness as a surrogate marker for cardiovascular disease in intervention studies.

Abstract: Background: Cardiovascular trials using clinical endpoints to assess efficacy typically require followup of large numbers of participants for 3–5 years. This disadvantage has encouraged the search for well-validated surrogate markers for cardiovascular disease (CVD). These markers may provide earlier indications of efficacy in trials involving fewer participants. One approach gaining interest in recent years is the measurement of atherosclerotic progression, a major underlying cause of CVD.Scope: This review article aims to further substantiate the evidence supporting the use of measurement of carotid intima-media thickness (CIMT) as a surrogate marker for atherosclerosis and cardiovascular risk.Findings: CIMT has consistently been related to future CVD events in population studies. CIMT is significantly related with other markers for CVD risk, such as elevated levels of risk factors and presence of atherosclerosis in the coronary arteries. Furthermore, almost all lipid-lowering trials and a large...

End Points for Adjuvant Therapy Trials: Has the Time Come to Accept Disease-Free Survival as a Surrogate End Point for Overall Survival?

Abstract: The intent of adjuvant therapy is to eradicate micro-metastatic residual disease following curative resection with the goal of preventing or delaying recurrence. The time-honored standard for demonstrating efficacy of new adjuvant therapies is an improvement in overall survival (OS). This typically requires phase III trials of large sample size with lengthy follow-up. With the intent of reducing the cost and time of completing such trials, there is considerable interest in developing alternative or surrogate end points. A surrogate end point may be employed as a substitute to directly assess the effects of an intervention on an already accepted clinical end point such as mortality. When used judiciously, surrogate end points can accelerate the evaluation of new therapies, resulting in the more timely dissemination of effective therapies to patients. The current review provides a perspective on the suitability and validity of disease-free survival (DFS) as an alternative end point for OS. Criteria for establishing surrogacy and the advantages and limitations associated with the use of DFS as a primary end point in adjuvant clinical trials and as the basis for approval of new adjuvant therapies are discussed.

Adapting the sample size planning of a phase III trial based on phase II data.

Abstract: Traditionally, in clinical development plan, phase II trials are relatively small and can be expected to result in a large degree of uncertainty in the estimates based on which Phase III trials are planned. Phase II trials are also to explore appropriate primary efficacy endpoint(s) or patient populations. When the biology of the disease and pathogenesis of disease progression are well understood, the phase II and phase III studies may be performed in the same patient population with the same primary endpoint, e.g. efficacy measured by HbA1c in non-insulin dependent diabetes mellitus trials with treatment duration of at least three months. In the disease areas that molecular pathways are not well established or the clinical outcome endpoint may not be observed in a short-term study, e.g. mortality in cancer or AIDS trials, the treatment effect may be postulated through use of intermediate surrogate endpoint in phase II trials. However, in many cases, we generally explore the appropriate clinical endpoint in the phase II trials. An important question is how much of the effect observed in the surrogate endpoint in the phase II study can be translated into the clinical effect in the phase III trial. Another question is how much of the uncertainty remains in phase III trials. In this work, we study the utility of adaptation by design (not by statistical test) in the sense of adapting the phase II information for planning the phase III trials. That is, we investigate the impact of using various phase II effect size estimates on the sample size planning for phase III trials. In general, if the point estimate of the phase II trial is used for planning, it is advisable to size the phase III trial by choosing a smaller alpha level or a higher power level. The adaptation via using the lower limit of the one standard deviation confidence interval from the phase II trial appears to be a reasonable choice since it balances well between the empirical power of the launched trials and the proportion of trials not launched if a threshold lower than the true effect size of phase III trial can be chosen for determining whether the phase III trial is to be launched.

Blood pressure as an example of a biomarker that functions as a surrogate.

Abstract: There are many important uses of biomarkers in drug development. An area of particular interest is the use of biomarkers as surrogate end points. Only a small minority of biomarkers are established surrogate end points. Blood pressure is an example of a surrogate end point accepted by both clinicians and regulators. It was a plausible surrogate because of the large epidemiologic databases demonstrating a correlation between elevated blood pressures and adverse cardiovascular outcomes. That plausibility has been supported, however, by the numerous placebo-controlled outcome studies evaluating several pharmacologically distinct agents that showed an effect on stroke and coronary heart disease outcomes from lowering blood pressure.

Clinical results of vaccine therapy for cancer: learning from history for improving the future.

Abstract: Active, specific immunotherapy for cancer holds the potential of providing an approach for treating cancers, which have not been controlled by conventional therapy, with very little or no associated toxicity. Despite advances in the understanding of the immunological basis of cancer vaccine therapy as well as technological progress, clinical effectiveness of this therapy has often been frustratingly unpredictable. Hundreds of preclinical and clinical studies have been performed addressing issues related to the generation of a therapeutic immune response against tumors and exploring a diverse array of antigens, immunological adjuvants, and delivery systems for vaccinating patients against cancer. In this chapter, we have summarized a number of clinical trials performed in various cancers with focus on the clinical outcome of vaccination therapy. We have also attempted to draw objective inferences from the published data that may influence the clinical effectiveness of vaccination approaches against cancer. Collectively the data indicate that vaccine therapy is safe, and no significant autoimmune reactions are observed even on long term follow-up. The design of clinical trials have not yet been optimized, but meaningful clinical effects have been seen in B-cell malignancies, lung, prostate, colorectal cancer, and melanoma. It is also obvious that patients with limited disease or in the adjuvant settings have benefited most from this targeted therapy approach. It is imperative that future studies focus on exploring the relationship between immune and clinical responses to establish whether immune monitoring could be a reliable surrogate marker for evaluating the clinical efficacy of cancer vaccines.

Surrogate Endpoints: Wishful Thinking or Reality?

Abstract: More than 100 years ago, the noted French mathematician Henri Poincare quoted the following remark about the assumption of a normal distribution: “ Everybody fi rmly believes in it because the mathematicians imagine it is a fact of observation, and observers that it is a theory of mathematics ” ( 1 ) . A similar generalization could be made about methods to validate surrogate endpoints: Biostatisticians believe that the methods they propose are useful because clinicians adopt them, and clinicians believe that the methods proposed by biostatisticians are useful because they have the “ imprimatur ” of mathematical statistics. Given this state of affairs, a critical examination of methods to validate surrogate endpoints is needed. However, before delving further it is necessary to precisely state the role of surrogate endpoints. The purpose of a surrogate endpoint is to draw conclusions about the effect of intervention on true endpoint without having to observe the true endpoint. If this purpose could be achieved, clinical research would be greatly accelerated. Unfortunately it is a tall order, and many proposed surrogate endpoints have subsequently been shown to have led to incorrect conclusions about the effect of intervention on the true endpoints ( 2 ) . Therefore, before a surrogate endpoint can be used with confi dence, it must be validated. Part of the controversy with the use of surrogate endpoints is that there is no agreed-upon defi nition of a validated surrogate endpoint. Essentially, validation of a surrogate endpoint consists of whatever the investigators think will make them and others feel confi dent about the use of the surrogate endpoint in a future trial. Validation measures must ensure that this confi dence is grounded more in reality than wishful thinking.

Posttreatment prostatic-specific antigen doubling time as a surrogate endpoint for prostate cancer-specific survival: an analysis of Radiation Therapy Oncology Group Protocol 92-02.

Abstract: Purpose: We evaluated whether posttreatment prostatic-specific antigen doubling time (PSADT) was predictive of prostate cancer mortality by testing the Prentice requirements for a surrogate endpoint. Methods and Materials: We analyzed posttreatment PSA measurements in a cohort of 1,514 men with localized prostate cancer (T2c-4 and PSA level n = 761), or in combination with 24 months of adjuvant androgen deprivation ( n = 753). Using an adjusted Cox proportional hazards model, we tested if PSADT was prognostic and independent of randomized treatment in this cohort. The endpoints were time to PSADT (assuming first-order kinetics for a minimum of 3 rising PSA measurements) and cancer-specific survival (CSS). Results: After a median follow-up time of 5.9 years, randomized treatment was a significant predictor for CSS (p Cox = 0.002), PSADT Cox Cox Cox Cox = 0.4). The significant posttreatment PSADTs were also significant predictors of CSS (p Cox Conclusions: Prostatic specific antigen doubling time is significantly associated with CSS, but did not meet all of Prentice's requirements for a surrogate endpoint of CSS. Thus, the risk of dying of prostate cancer is not fully explained by PSADT.

Imaging biomarkers as surrogate endpoints for drug development.

Abstract: The employment of biomarkers (including imaging biomarkers, especially PET) in drug development has gained increasing attention during recent years. This has been partly stimulated by the hope that the integration of biomarkers into drug development programmes may be a means to increase the efficiency and effectiveness of the drug development process by early identification of promising drug candidates—thereby counteracting the rising costs of drug development. More importantly, however, the interest in biomarkers for drug development is the logical consequence of recent advances in biosciences and medicine which are leading to target-specific treatments in the framework of “personalised medicine”. A considerable proportion of target-specific drugs will show effects in subgroups of patients only. Biomarkers are a means to identify potential responders, or patient subgroups at risk for specific side-effects. Biomarkers are used in early drug development in the context of translational medicine to gain information about the drug’s potential in different patient groups and disease states. The information obtained at this stage is mainly important for designing subsequent clinical trials and to identify promising drug candidates. Biomarkers in later phases of clinical development may—if properly validated—serve as surrogate endpoints for clinical outcomes. Regulatory agencies in the EU and the USA have facilitated the use of biomarkers early in the development process. The validation of biomarkers as surrogate endpoints is part of FDA’s “critical path initiative”.

Perfusion and diffusion MRI of glioblastoma progression in a four-year prospective temozolomide clinical trial

Abstract: Purpose: This study was performed to determine the impact of perfusion and diffusion magnetic resonance imaging (MRI) sequences on patients during treatment of newly diagnosed glioblastoma. Special emphasis has been given to these imaging technologies as tools to potentially anticipate disease progression, as progression-free survival is frequently used as a surrogate endpoint. Methods and Materials: Forty-one patients from a phase II temolozomide clinical trial were included. During follow-up, images were integrated 21 to 28 days after radiochemotherapy and every 2 months thereafter. Assessment of scans included measurement of size of lesion on T1 contrast-enhanced, T2, diffusion, and perfusion images, as well as mass effect. Classical criteria on tumor size variation and clinical parameters were used to set disease progression date. Results: A total of 311 MRI examinations were reviewed. At disease progression (32 patients), a multivariate Cox regression determined 2 significant survival parameters: T1 largest diameter (p < 0.02) and T2 size variation (p < 0.05), whereas perfusion and diffusion were not significant. Conclusion: Perfusion and diffusion techniques cannot be used to anticipate tumor progression. Decision making at disease progression is critical, and classical T1 and T2 imaging remain the gold standard. Specifically, a T1 contrast enhancement over 3 cmmore » in largest diameter together with an increased T2 hypersignal is a marker of inferior prognosis.« less

Atrial fibrillation predicts appropriate shocks in primary prevention implantable cardioverter-defibrillator patients.

Abstract: AIMS: Atrial fibrillation (AF) is often present in patients with left ventricular dysfunction who receive an implantable cardioverter-defibrillator (ICD). The purpose of this study was to investigate whether AF is associated with appropriate shocks and cardiovascular mortality in primary prevention ICD patients with left ventricular dysfunction. METHODS AND RESULTS: We included 80 primary prevention ICD patients with left ventricular dysfunction and compared the outcome between patients with a history of AF (n=29) and patients with no history of AF (n=51). The primary endpoint was occurrence of appropriate shocks. Secondary endpoints were: (1) the composite of cardiovascular mortality/appropriate shocks; and (2) inappropriate shocks. During follow-up (median 8 months, range 1-60), patients with a history of AF more often received appropriate shocks than patients with no history of AF (24 vs. 6%, P=0.03). The composite endpoint of cardiovascular mortality/appropriate shocks was also more likely to occur in patients with a history of AF (34 vs. 12%, P=0.02). History of AF predicted appropriate shocks (HR 6.9, 95% CI 1.7-27.5, P=0.006) and the composite endpoint of cardiovascular mortality/appropriate shocks (adjusted HR 5.1, 95% CI 1.7-15.1, P=0.003). There were no differences in occurrence of inappropriate shocks. CONCLUSION: Our study demonstrates that history of AF is associated with increased risk of appropriate shocks and cardiovascular mortality in primary prevention ICD patients with left ventricular dysfunction.

A simple meta-analytic approach for using a binary surrogate endpoint to predict the effect of intervention on true endpoint.

Abstract: A surrogate endpoint is an endpoint that is obtained sooner, at lower cost, or less invasively than the true endpoint for a health outcome and is used to make conclusions about the effect of intervention on the true endpoint. In this approach, each previous trial with surrogate and true endpoints contributes an estimated predicted effect of intervention on true endpoint in the trial of interest based on the surrogate endpoint in the trial of interest. These predicted quantities are combined in a simple random-effects meta-analysis to estimate the predicted effect of intervention on true endpoint in the trial of interest. Validation involves comparing the average prediction error of the aforementioned approach with (i) the average prediction error of a standard meta-analysis using only true endpoints in the other trials and (ii) the average clinically meaningful difference in true endpoints implicit in the trials. Validation is illustrated using data from multiple randomized trials of patients with advanced colorectal cancer in which the surrogate endpoint was tumor response and the true endpoint was median survival time.

Use and misuse of surrogate outcomes in arrhythmia trials.

Abstract: Rigorous design and careful execution of clinical trials have led to major advances in cardiovascular medicine over the past few decades. A pivotal design feature of any trial is the choice of outcomes. We place great value on reduction of mortality and somewhat less on outcomes, such as myocardial infarction, that lead to major morbidity and death. Changes in quality of life and functional capacity are harder to measure but are clinically meaningful in many situations. On the other hand, surrogate outcomes have very low status in this hierarchy. These are outcomes that “stand in” for more clinically relevant outcomes. The key feature of a surrogate outcome is that unproven assumptions are necessary to connect a change in the surrogate to a change in the accepted clinical outcome. The problem of using surrogate outcomes has been highlighted by situations in which the assumptions have been subsequently discredited. In the early 1980s, on the basis of numerous studies that demonstrated an association between ventricular premature depolarization (VPD) frequency and mortality in post-myocardial infarction (MI) patients, VPD suppression became an accepted method for antiarrhythmic drug selection in clinical practice. Even though VPDs were usually asymptomatic, VPD suppression served as a primary outcome measure in clinical trials that resulted in regulatory approval of antiarrhythmic drugs.1 The underlying assumption that VPD suppression was associated with a reduction in mortality was totally upended when the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that several drugs, which were highly effective at VPD suppression, actually increased mortality after MI.2 Article p 776 It is not always possible or desirable to perform a full-scale trial with the most highly clinically relevant outcomes. Surrogate outcomes are particularly useful in the early stages of development of a new drug or device when the main goal is to prove a …

The use of MRI as an outcome measure in clinical trials.

Abstract: Because the changes on MRI likely reflect various aspects of the underlying pathology of multiple sclerosis, MRI outcome measures have become an important component of most MS clinical trials, providing objective, supportive evidence for the clinical endpoints. Although there is currently insufficient evidence to support any single or combination of MRI measures as a fully validated surrogate, it is now generally accepted that if the aim of a new therapy is to prevent relapses, new Gd-enhancing and T2 lesions can be considered an appropriate surrogate outcome measure of relapses, and MRI activity outcomes can be recommended as the primary measure of treatment efficacy.

Coronary Artery Calcium Should We Rely on This Surrogate Marker

Abstract: Surrogate markers of atherosclerosis such as treadmill time, serum tests, coronary artery calcium, and carotid intimal thickness enjoy considerable attention and the promise of yielding answers at much less cost and time than clinical trials using hard clinical outcomes such as myocardial infarction and cardiac death. Indeed, only studies with large sample sizes and long follow-up periods can provide meaningful data on hard outcomes. Of course, from a patient care perspective, the value of a surrogate marker derives solely from its ability to predict a cardiac event giving rise to either death or physical impairment that could be prevented. What is important to patients is whether a new therapy can make one feel better or live longer (or both). Few patients would eagerly undergo a new treatment if it would merely change a measurement but would not also improve how they felt, would not reduce their risk of heart attacks, and/or would not help them to live longer. Article p 427 Cardiologists’ recent experience with hormone replacement therapy (HRT) once again illustrated the dangers of relying too heavily on surrogate markers. Multiple studies of HRT using surrogate markers showed a benefit on cardiovascular disease.1 The Postmenopausal Estrogen/Progestin Intervention (PEPI) trial, for example, showed that HRT had beneficial effect on serum markers of atherosclerosis, with lower low-density lipoprotein (LDL) and fibrinogen levels and higher high-density lipoprotein.2 The Rancho Bernado Study found that women taking HRT had lower coronary artery calcium (CAC) scores and concluded that there was antiatherogenic effect of postmenopausal estrogen (but nevertheless called for …

A new and rapid scoring system to assess the scientific evidence from clinical trials.

Abstract: Guidelines are based on a scientific analysis from existing data of randomized controlled trials (RCTs), registry trials, simple registries, case reports, and the personal experience of the task force members. Furthermore, meta-analyses and subgroup analyses are used to derive the strengths of recommendations. Fortunately, the major cardiac societies, i.e., the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC), are essentially using the same definitions for the levels of recommendations. In the expanding field of cardiology, however, the overwhelming and increasing number of clinical studies reveals the limitations of the traditional ranking of these studies: Applying the standard definitions of the ACC/AHA/ESC criteria for the levels of recommendation, almost every PCI procedure would easily reach the level of evidence A, even with two small, underpowered studies and a surrogate endpoint. Although meta-analyses are important tools for creating an overview of major diagnostic or treatment modalities, they are bound to severe limitations. The compilation of several underpowered, small trials can generate a statistically artificial "significant" result. This is especially important because only two meta-analyses containing almost identical studies could easily yield an evidence level A. RCTs are usually designed and conducted according to a power calculation, for which a primary clinical or surrogate endpoint can be chosen. Surrogate endpoints, however, do not necessarily correlate with the clinical outcome. The history of medicine is full of errors introduced by underpowered studies with surrogate endpoints. Many investigators and companies attempt to tease out treatment effects in specific subpopulations of patients. These subgroup analyses are usually underpowered. Another major limitation of the ACC/AHA/ESC scoring system is that neither the power of a study nor the choice of a primary clinical endpoint is included in their definitions. Yet another limitation of the ACC/AHA/ESC grading system is that two "simple" registries may already lead to a level of evidence B. A new scoring system is presented addressing most of these limitations: a primary clinical endpoint receives three points, whereas all of the following receive one point: double-blind design, evaluation interval of primary endpoint > or = 6 months, multicenter (at least three centers), independent data and safety monitoring, power of > or = 80% for primary endpoint achieved, and follow-up > or = 80% for a surrogate primary endpoint or follow-up of > or = 95% for a clinical primary endpoint. Thus, the maximum achievable points is 10. This scoring system can also be applied for high-quality registry controlled trials using a predefined control group and power calculation. For simple registry studies and subgroup analyses, a modified scoring system has been developed (maximum achievable points is 5). The advantage of the suggested new scoring system is its transparency, reproducibility, and ease of use by quickly answering the key quality questions for clinical trials. The new scoring system suggested here should help make decisions regarding which treatment to use and stimulate discussions.

Biomarker-driven care in asthma: Are we there?

Abstract: Clinical asthma management is limited by the lack of straightforward and clinically applicable techniques to assess control and appropriately adjust therapy. The availability of biomarkers associated with airway caliber, responsiveness, or inflammation has prompted interest in the application of these measures as surrogate asthma end points in clinical trials. Use of a biomarker as a surrogate outcome in practice is most appropriate in settings in which the effects of therapy on clinical disease, as experienced by patients, are fully captured by that biomarker. Recent studies suggest that although asthma therapies can alter various biomarkers, the relationship between these biomarker changes and important clinical outcomes is inconsistent. Because symptom-driven titration of therapy is feasible and effective, additional data demonstrating clinically important benefits of biomarker-driven care in asthma are needed to justify the logistic and economic burdens associated with clinical dissemination of these techniques.

Surrogate outcomes in neurology, psychiatry, and psychopharmacology.

Abstract: A surrogate outcome can be defined as an outcome that can be observed sooner, at lower cost, or less invasively than the true outcome, and that enables valid inferences about the effect of intervention on the true outcome. There is increasing interest in the use of surrogate out comes of treatment efficacy measurement in investigational drug trials. However, the significance of surrogate markers of treatment outcome in neurology and psychiatry has not yet been sufficiently demonstrated. Few such markers have been adequately “validated, ” that is, shown to predict the effect of the treatment on the clinical outcome of interest. In this article, evidence that would support the validation of such markers is discussed, Biomarkers used during early clinical development programs of new psychotropic compounds are considered in the contexts of Parkinson's disease, affective disorder, and schizophrenia. The particular case of neuroprotective trials is exemplified by Parkinson's disease, where a biomarker substituting for a clinical measure of progression could be considered as a surrogate treatment outcome.

Historic evidence and future directions in clinical trial therapy of solid tumors.

Abstract: Although improved survival is the "gold standard" for proving clinical benefit of oncologic therapy, the U.S. Food and Drug Administration (FDA) has accepted significant results in clinical trials using surrogate endpoints as the basis for drug approval. One surrogate is the amount of tumor reduction, or tumor response. Although tumor shrinkage would seem to be a necessary precondition for improved survival, clinical studies of a variety of oncologic agents have not consistently demonstrated a correlation between the two in patients with renal cell carcinoma. Moreover, tumor response may not be an appropriate endpoint for evaluating the effects of the new targeted therapies, whose putative mechanisms are generally cytostatic rather than cytotoxic. Clinical trials suggest that some patients with other solid tumors, such as lung cancer, may derive clinical benefit from treatment that helps stabilize their disease. There is also controversy as to whether the Response Evaluation Criteria in Solid Tumors (RECIST) provides the most appropriate instrument for assessing tumor burden. Ultimately, use of a variety of endpoints as well as different trial designs may provide an adequate basis for investigating the benefits/risks of newer therapies.

Evaluating Causal Effect Predictiveness of Candidate Surrogate Endpoints

Abstract: Frangakis and Rubin (2002, Biometrics) proposed a new definition of a surrogate endpoint (a “principal” surrogate) based on causal effects. We introduce an estimand for evaluating a principal surrogate, the causal effect predictiveness (CEP) surface, which quantifies how well causal treatment effects on the biomarker predict causal treatment effects on the clinical endpoint. While the CEP surface is not identifiable due to missing potential outcomes, it can be identified by incorporating a baseline covariate that predicts the biomarker. Given case-cohort sampling of such a baseline predictor and the biomarker in a single large blinded randomized clinical trial, we develop an estimated likelihood method for estimating the CEP surface. This estimation assesses the “surrogate value” of the biomarker for reliably predicting clinical treatment effects for the same or similar setting as the trial. A CEP surface plot provides a way to compare the surrogate value of multiple biomarkers. The approach is illustrated by the problem of assessing an immune response to a vaccine as a surrogate endpoint for infection.