An overview of randomized clinical trials in metastatic breast cancer
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Abstract:
The aim of this study was to analyse trial variables affecting drug approval in metastatic breast cancer (MBC). A literature search from 2000 to 2012 retrieved 66 phase III randomized controlled trials with reported primary endpoints in MBC and known outcomes in terms of approval. The influence of the primary endpoint, the line of therapy, crossover and the sample size was analysed. The primary endpoints used most frequently were progression-free survival (PFS) and time to progression or time to treatment failure (N=47; 71%). Overall survival (OS) was a primary endpoint in nine trials (14%). In 26 trials (39%), statistically significant results were found with respect to the primary endpoint, and in 13 trials (20%), this was found with respect to the secondary endpoint. Gains in OS were found in 12 trials (18%), whereas a benefit to PFS was found in 30 trials (46%). The average median OS was 23.1 months. Postprogression survival accounted for 64% of OS. Trials with crossover did not have OS as the primary endpoint. Trials that resulted in drug approval had a more pronounced gain in OS or PFS and had more patients than those without regulatory consequences. PFS was the main primary endpoint in randomized clinical trials in MBC and was significantly associated with drug approval. OS benefit was rarely achieved in trials where this was not the primary endpoint. The number of randomized patients, the primary endpoint and crossover are factors linked to regulatory requirements for approval, which should be considered in future trial designs.Keywords:
Clinical endpoint
Surrogate endpoint
Progression-free survival
Drs. Manyara, Ciani, and Taylor make the important point that randomized controlled trials (RCTs) using a primary surrogate endpoint should be more transparent in their reporting details of biomarkers in trials. They suggest a clear statement concerning use of a surrogate primary endpoint and providing information on validity and limitations of the surrogate. They announce a new project to develop SPIRIT and CONSORT extensions specific to surrogate endpoints SPIRIT-SURROGATE and CONSORT-SURROGATE. There are no fully qualified and validated surrogate biomarkers for Alzheimer's disease (AD) RCTs and none that could serve as a primary RCT endpoint. As described by the US Food and Drug Administration (FDA) a surrogate endpoint is a clinical trial endpoint used as a substitute for a direct measure of how a patient feels, functions, or survives.1 A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict clinical benefit. Epidemiologic, therapeutic, pathophysiologic, or other scientific data provide the evidentiary basis for establishing a biomarker as a surrogate. A surrogate must change in response to multiple therapies across multiple RCTs and must explain the change in clinical outcome as well as correlate with it.2 Designation as a surrogate requires substantial statistical evidence based on trial meta-analyses.3 Robert Califf, US Commissioner of Food and Drugs, makes the point that “the single most common and serious error in the evaluation of biomarkers is the assumption that a correlation between the measured level of a biomarker and a clinical outcome means that the biomarker constitutes a valid surrogate.”2 The primary outcome of the RCTs of the aducanumab trials was the Clinical Dementia Rating–Sum of Boxes (CDR-SB; NCT02484547; NCT02477800) and the primary endpoint was the drug–placebo difference on this outcome at week 76. Accelerated approval of aducanumab was based on amyloid plaque lowering as shown by amyloid positron emission tomography (PET) considered reasonably likely to predict clinical benefit.4 Reasonably likely surrogate endpoints are supported by a strong mechanistic and/or epidemiologic rationale, but the amount of clinical data available is not sufficient to support them as a validated surrogate endpoint (defined above). Reasonably likely surrogate endpoints are used to support the FDA's Accelerated Approval program, which is intended to provide patients with serious diseases more rapid access to promising therapies.5 Accelerated approval is followed by post-marketing studies to determine whether the reasonably likely surrogate endpoint, in fact, predicts the clinical benefit. The aducanumab trials would not have been included in reporting requirements for trials using surrogate primary endpoints; their primary endpoints were drug–placebo differences on clinical measures; amyloid lowering was not a primary or a secondary endpoint and was not included in the sequential testing rank order implemented (NCT02484547; NCT024778006). I concur with Drs. Manyara, Ciani, and Taylor that biomarkers should be described in greater detail in the SPIRIT and CONSORT criteria. Using the FDA biomarker lexicon, these measures would be described as risk/susceptibility, diagnosis, monitoring, pharmacodynamic/response, predictive, prognostic, or safety biomarkers.7, 8 Candidate surrogate biomarkers or biomarkers that might be considered reasonably likely to predict clinical benefit are pharmacodynamic biomarkers. Biomarkers that have been qualified for a specific context of use in the RCT should be described in the SPIRIT and CONSORT reporting framework.9 The SPIRIT-SURROGATE and CONSORT-SURROGATE initiative is important and might be more broadly conceived as a SPIRIT-BIOMARKER and CONSORT-BIOMARKER initiatives. Another important adjustment to the SPIRIT and CONSORT criteria is to require the reporting of ethnicity and race among trial participants. These data are sometimes not collected and often omitted from clinical trial reports.10 They are critically important to assess our success in increasing the diversity of clinical trial populations. JC is supported by NIGMS grant P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P20AG068053; NIA grant P30AG072959; NIA grant R35AG71476; Alzheimer’s Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; and the Joy Chambers-Grundy Endowment. J.C. has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Biogen, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Resverlogix, Roche, Signant Health, Suven, and United Neuroscience pharmaceutical, assessment, and investment companies. Author disclosures are available in the supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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Abstract Investigators use a surrogate endpoint when the endpoint of interest is too difficult and/or expensive to measure routinely and when they can define some other, more readily measurable, endpoint, that is sufficiently well correlated with the first to justify its use as a substitute. A surrogate endpoint is usually proposed on the basis of a biologic rationale. In cancer studies with survival time as the primary endpoint, surrogate endpoints frequently employed are tumour response, time to progression, or time to reappearance of disease, since these events occur earlier and are unaffected by use of secondary therapies. In early drug development studies, tumour response is often the true primary endpoint. We discuss the investigation of the validity of carcinoembryonic antigen (a tumour marker present in the blood) as a surrogate for tumour response. In considering the validity of surrogate endpoints, one must distinguish between study endpoints that provide a basis for reliable comparisons of therapeutic effect, and clinical endpoints that are useful for patient management but have insufficient sensitivity and/or specificity to provide reproducible assessments of the effects of particular therapies.
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Background/aims Non-inferiority trials are increasing in cardiovascular medicine, with approval of many drugs and devices on the basis of such studies. Surrogate markers as primary endpoints have been also more frequently used for efficient assessment of cardiovascular interventions. However, there is uncertainty about their concordance with clinical outcomes. Non-inferiority design using a surrogate marker as a primary endpoint may pose particular challenges in clinical interpretation. We sought to explore the publication trends, methodology, and reporting features of non-inferiority cardiovascular trials that used a primary surrogate marker as the primary endpoint. Methods We searched six high-impact journals ( The New England Journal of Medicine, The Journal of the American Medical Association, The Lancet, The Journal of the American College of Cardiology, Circulation, and European Heart Journal) from 1 January 1990 to 31 December 2018 and identified non-inferiority cardiovascular trials that used a surrogate marker as the primary endpoint. We assessed the non-inferiority margin reported in the manuscript and other publicly available platforms (e.g. protocol, clinicaltrials.gov). We also determined whether the included non-inferiority trials with surrogate markers as primary endpoints were followed by clinical outcome trials. Results We screened 15,553 publications and identified 247 cardiovascular trials that used a non-inferiority design. Of these, 37 had a surrogate marker as a primary endpoint (18 drug trials, 13 device trials, 6 others). All of these non-inferiority trials with surrogate outcomes were published after 2000, mostly in cardiology journals (13 in The Journal of the American College of Cardiology, 9 in European Heart Journal, 8 in Circulation, 6 in The Lancet, 1 in The New England Journal of Medicine), and their publication rate increased over time (p < 0.001 for linear trend). The median number of patients in the primary analysis was 300 (interquartile range: 202–465). The study protocol or a methods paper was publicly available for only 13 (35.1%) trials, of which the non-inferiority margin was not reported in 4 trials. In 16 studies (43.2%), the manuscript did not acknowledge the limitations of using a surrogate endpoint or the need for a definitive clinical outcome trial. Thirty-four trials (91.9%) concluded that the tested intervention met non-inferiority criteria. However, only five (13.5%) were followed by clinical outcomes trials the results of which did not always confirm non-inferiority. Conclusion Non-inferiority trials that use a surrogate marker as the primary endpoint are being increasingly performed. However, these trials pose particular challenges with design, reporting, and interpretation, which are not systematically and consistently addressed or reported.
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Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints.
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PURPOSE: In cancer, it is vital to develop and validate surrogate endpoints so that long-term and costly Phase III trials for comparing treatments can be avoided. METHODS: We propose development of a new framework for assessing surrogacy in which the surrogate endpoint is considered to be validated if two criteria are satisfied: (1) the surrogate endpoint has to have positive probability of occurring before the true endpoint, conditional on treatment group; (2) the treatment effect on the surrogate endpoint, as part of a composite outcome with the true endpoint, must be associated with the treatment effect on the true endpoint more than expected by chance. RESULTS: Applying this to two cancer clinical trial datasets, we show that complete remission is a valid surrogate for survival in acute myelogenous leukemia, and time to progression is a valid surrogate for survival in advanced colorectal cancer. CONCLUSION: This new surrogacy paradigm will lead to surrogate endpoints that are composite outcomes that will occur more quickly than observing the true endpoint only. At the same time, treatment effects on these combined outcomes will be informative about those on the true endpoint.
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There are strong ethical and practical reasons for hastening decision-making about the efficacy of new treatments for human immunodeficiency virus (HIV) infection. One strategy is to use early markers of disease progression, such as CD4+ lymphocyte levels, as surrogates for ultimate clinical endpoints, such as the development of acquired immune deficiency syndrome (AIDS) or death, in the evaluation of new therapies. We used a simple model of transitions among three health states (well; alive but with an adverse marker; and having experienced a definitive clinical endpoint) to examine the extent to which treatment comparisons based on the surrogate endpoint predict ultimate clinical benefits. With parameters chosen to model the treatment of HIV infection, computer simulations of clinical trials demonstrated substantial time savings by use of the surrogate endpoint. However, reliance on the surrogate led to serious overestimates of ultimate clinical benefit if treatment entailed delayed toxicity or had only transient beneficial effects. Likewise, reliance on the surrogate led to serious underestimates of ultimate clinical benefit when the treatment had no effect on the transition from well to the marker state but did reduce the rates of transition from the marker state to the ultimate clinical endpoint and directly from the well state to the ultimate clinical endpoint.
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