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Assessing risk/benefit for trials using preclinical evidence: a proposal.

ABSTRACT: Moral evaluation of risk/benefit in early phase studies requires assessing the clinical promise of a candidate intervention using preclinical evidence. Yet, there is little to guide ethics committees, investigators, sponsors or other stakeholders morally charged with making these assessments ('evaluators'). In what follows, we draw on published guidelines for preclinical study design to develop a structured process for assessing the clinical promise of new interventions. In the first step, evaluators gather all relevant preclinical studies, assess the magnitude of treatment effects and determine clinical promise in light of various threats to valid clinical inference. In the second step, evaluators adjust the assessments of clinical promise from preclinical studies by examining how other agents in the same reference class-and supported by similar evidence-have fared in clinical development. Assessments of clinical promise can then be fed into the moral evaluation of risk and benefit in early phase trials. Though our approach has limitations, it offers a systematic and transparent method for assessing risk/benefit in early phase trials of novel interventions.

SUBMITTER: Kimmelman J

PROVIDER: S-EPMC4854630 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Assessing risk/benefit for trials using preclinical evidence: a proposal.

Kimmelman Jonathan J Henderson Valerie V

Journal of medical ethics 20151013 1

Moral evaluation of risk/benefit in early phase studies requires assessing the clinical promise of a candidate intervention using preclinical evidence. Yet, there is little to guide ethics committees, investigators, sponsors or other stakeholders morally charged with making these assessments ('evaluators'). In what follows, we draw on published guidelines for preclinical study design to develop a structured process for assessing the clinical promise of new interventions. In the first step, evalu ...[more]

PMID: 26463620

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Project description:BackgroundEvidence based medicine aims to integrate scientific evidence, clinical experience, and patient values and preferences. Individual health care professionals need to appraise the evidence from randomized trials and observational studies when guidelines are not yet available. To date, tools for assessment of bias and terminologies for bias are specific for each study design. Moreover, most tools appeal only to methodological knowledge to detect bias, not to subject matter knowledge, i.e. in-depth medical knowledge about a topic. We propose a unified framework that enables the coherent assessment of bias across designs.MethodsEpidemiologists traditionally distinguish between three types of bias in observational studies: confounding, information bias, and selection bias. These biases result from a common cause, systematic error in the measurement or common effect of the intervention and outcome respectively. We applied this conceptual framework to randomized trials and show how it can be used to identify bias. The three sources of bias were illustrated with graphs that visually represent researchers' assumptions about the relationships between the investigated variables (causal diagrams).ResultsCritical appraisal of evidence started with the definition of the research question in terms of the population of interest, the compared interventions and the main outcome. Next, we used causal diagrams to illustrate how each source of bias can lead to over- or underestimated treatment effects. Then, we discussed how randomization, blinded outcome measurement and intention-to-treat analysis minimize bias in trials. Finally, we identified study aspects that can only be appraised with subject matter knowledge, irrespective of study design.ConclusionsThe unified framework encompassed the three main sources of bias for the effect of an assigned intervention on an outcome. It facilitated the integration of methodological and subject matter knowledge in the assessment of bias. We hope that graphical diagrams will help clarify debate among professionals by reducing misunderstandings based on different terminology for bias.

Project description:BackgroundRamucirumab is a widely used cancer drug having gained six regulatory approvals in various advanced solid tumors. Thus, assessing the risk-benefit profile of such a commonly used drug across multiple tumor types is necessary to inform clinical and reimbursement decisions. To objectively assess the risks and benefits of ramucirumab in patients with advanced solid tumors, we performed a systematic review and meta-analysis of published randomized controlled trials (RCTs).MethodsA systematic search of PubMed, the Cochrane Library, Google Scholar and conference abstracts for all RCTs of ramucirumab in patients with advanced solid cancer was conducted according to the PRISMA guidelines. Data on treatment-related serious adverse events (SAEs), fatal adverse events (FAEs), primary endpoint, gains in median overall survival (OS), progression-free survival (PFS) with their hazard ratios (HR) and 95% confidence intervals (CIs) and quality of life (QOL) were extracted from each RCT. Summary relative risks (RR) with 95% CI for SAEs and FAEs were calculated by pooling data across the RCTs using random-effects model. Treatment benefit was evaluated descriptively in terms of median and HR with 95% CI of OS and PFS gains as well as improvements in QOL. ESMO-Magnitude of Clinical Benefit Scale (MCBS), a validated tool, was used to objectively quantify clinical benefit of ramucirumab in approved settings.FindingsTen RCTs met our inclusion criteria. Compared with the control arm, the use of ramucirumab was associated with a significantly increased risk of developing SAE (RR 1.13, 95% CI 1.05-1.21, incidence 37.5% v 33.5%). The increase in risk of FAE (RR 1.41, 95% CI 0.96-2.07, incidence 1.8% v 1.3%) was not statistically significant. Using the ESMO MCBS tool, clinical benefit with ramucirumab was not substantial in any indication, five of six approvals scoring a "negligible benefit" score of 1 or 2. QOL was either not reported (30%) or not improved (70%) in these RCTs.InterpretationIn this meta-analysis of RCTs, use of ramucirumab in patients with advanced cancer was associated with increased risk of treatment related serious and possibly fatal adverse events but the magnitude of clinical benefit from ramucirumab was mostly negligible with no trial reporting an improvement in QOL. These relative risks and benefits should be considered in clinical and regulatory decision making.FundingNone.

Project description:BACKGROUND:Flubendazole, originally developed to treat infections with intestinal nematodes, has been shown to be efficacious in animal models of filarial infections. For treatment of filarial nematodes, systemic exposure is needed. For this purpose, an orally bioavailable amorphous solid dispersion (ASD) formulation of flubendazole was developed. As this formulation results in improved systemic absorption, the pharmacokinetic and toxicological profile of the flubendazole ASD formulation have been assessed to ensure human safety before clinical trials could be initiated. METHODS & FINDINGS:Safety pharmacology, toxicity and genotoxicity studies have been conducted with the flubendazole ASD formulation. In animals, flubendazole has good oral bioavailability from an ASD formulation ranging from 15% in dogs, 27% in rats to more than 100% in jirds. In in vivo toxicity studies with the ASD formulation, high systemic exposure to flubendazole and its main metabolites was reached. Flubendazole, up to high peak plasma concentrations, does not induce Cmax related effects in CNS or cardiovascular system. In repeated dose toxicity studies in rats and dogs, flubendazole-induced changes were observed in haematological, lymphoid and gastrointestinal systems and in testes. In dogs, the liver was an additional target organ. Upon treatment cessation, at least partial recovery was observed for these changes in dogs. In rats, the No Observed Adverse Effect Level (NOAEL) was 5 mg (as base)/kg body weight/day (mg eq./kg/day) in males and 2.5 mg eq./kg/day in females. In dogs, the NOAEL was lower than 20 mg eq./kg/day. Regarding genotoxicity, flubendazole was negative in the Ames test, but positive in the in vivo micronucleus test. CONCLUSIONS:Based on these results, in combination with previously described genotoxicity and reproductive toxicity data and the outcome of the preclinical efficacy studies, it was concluded that no flubendazole treatment regimen can be selected that would provide efficacy in humans at safe exposure.

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Assessing risk/benefit for trials using preclinical evidence: a proposal.

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Assessing risk/benefit for trials using preclinical evidence: a proposal.

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