Pragmatic randomized clinical trials: a proposal to enhance evaluation of new cancer therapies with early signs of exceptional activity

Koehler, Maria; Donnelly, Erling T.; Kalanovic, D.; Dagher, Ramzi; Rothenberg, Mace L.

doi:10.1093/annonc/mdw143

Cited by 13 publications

(9 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, all clinical studies being enriched does not mean that the clinical utility is low but that there is no clinical evidence. Moreover, some of the drugs included in this study exhibited what some have called “exceptional activity” 42 and they have great value for biomarker-positive patients.…”

Section: Discussionmentioning

confidence: 91%

Evidence for Treatment-by-Biomarker interaction for FDA-approved Oncology Drugs with Required Pharmacogenomic Biomarker Testing

Vivot

Boutron

Béraud-Chaulet

et al. 2017

Sci Rep

View full text Add to dashboard Cite

For oncology drugs that were approved by the US Food and Drug Administration (FDA) and required pharmacogenomic biomarker testing, we describe 1) the use of enrichment (biomarker-positive patients) and a randomized controlled design by pre-approval trials and 2) the treatment-by-biomarker interaction. From the 137 drugs included in the FDA table, we selected the 22 oncology drugs with required genetic testing in their labels. These drugs corresponded to 35 approvals supported by 80 clinical studies included in the FDA medical officer reviews of efficacy. For two thirds of approvals (24/35, 69%), all clinical studies were restricted to biomarker-positive patients (enriched). Among the 11 remaining approvals with at least one non-enriched trial, for five approvals, the non-enriched studies were non-randomized. The treatment-by-biomarker interaction was statistically significant for three approvals and missing for two. Among the six approvals with a non-enriched randomized controlled trial, three featured a statistically significant treatment-by-biomarker interaction (p < 0.10), for an enhanced treatment effect in the biomarker-positive subgroup. For two thirds of FDA approvals of anticancer agents, the requirement for predictive biomarker testing was based on clinical development restricted to biomarker-positive patients. We found only few cases with clinical evidence that biomarker-negative patients would not benefit from treatment.

show abstract

Section: Discussionmentioning

confidence: 91%

Evidence for Treatment-by-Biomarker interaction for FDA-approved Oncology Drugs with Required Pharmacogenomic Biomarker Testing

Vivot

Boutron

Béraud-Chaulet

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Additional studies are then required to confirm the clinical benefits of these changes; such "confirmatory" studies increasingly involve novel clinical trial designs (e.g., pragmatic trials) that incorporate RWE. 55,56 Analyses of RWD can be used to assess the feasibility of pragmatic RWE trials before they are discussed with regulators. 57 For example, a systematic literature review analyzed published data from multiple sources (e.g., clinical trials and RWE from registries) to understand how hemoglobin concentration (a biomarker) is related to various clinical endpoints, such as stroke, cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in patients with sickle cell disease.…”

Section: Selection Of Endpoints and Identification Of Surrogate Endpointsmentioning

confidence: 99%

Use of Real‐World Evidence to Drive Drug Development Strategy and Inform Clinical Trial Design

Dagenais

Russo

Madsen

et al. 2021

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Interest in real-world data (RWD) and real-world evidence (RWE) to expedite and enrich the development of new biopharmaceutical products has proliferated in recent years, spurred by the 21st Century Cures Act in the United States and similar policy efforts in other countries, willingness by regulators to consider RWE in their decisions, demands from third-party payers, and growing concerns about the limitations of traditional clinical trials. Although much of the recent literature on RWE has focused on potential regulatory uses (e.g., product approvals in oncology or rare diseases based on single-arm trials with external control arms), this article reviews how biopharmaceutical companies can leverage RWE to inform internal decisions made throughout the product development process. Specifically, this article will review use of RWD to guide pipeline and portfolio strategy; use of novel sources of RWD to inform product development, use of RWD to inform clinical development, use of advanced analytics to harness "big" RWD, and considerations when using RWD to inform internal decisions. Topics discussed will include the use of molecular, clinicogenomic, medical imaging, radiomic, and patient-derived xenograft data to augment traditional sources of RWE, the use of RWD to inform clinical trial eligibility criteria, enrich trial population based on predicted response, select endpoints, estimate sample size, understand disease progression, and enhance diversity of participants, the growing use of data tokenization and advanced analytical techniques based on artificial intelligence in RWE, as well as the importance of data quality and methodological transparency in RWE.

show abstract

“…This approach also ensures that the sorts of interventions tested can be plausibly rolled out in clinical practice and that the outcomes used to assess effectiveness are valid and easily understood by a range of users, including clinicians, patients, policy makers, and health commissioners (14). Furthermore, when novel cancer drugs meet specific criteria (i.e., conditional approval), PCTs may provide sufficient evidence for verification of clinical benefit and lead to full approval (15).…”

Section: Pragmatic Clinical Trials (Pcts)mentioning

confidence: 99%

The essence of real-world study in cancer research

Li¹,

Shi²,

Fan³

et al. 2020

Transl Breast Cancer Res

View full text Add to dashboard Cite

BackgroundDespite the rapid development of gene engineering and other novel therapies, advanced cancer is still a largely intractable disease, and its high mortality necessitates the development of better treatment (1). In general, the regulatory approval of new cancer treatment is built on the objective criteria of efficacy and safety derived from randomized controlled trials (RCTs). However, with advances in genetic and molecular treatment, the number of patients available for a specific clinical trial may be too small for proper assessment of a benefit-risk paradigm (2). As a result, drug developers and regulators have become increasingly interested in data external from clinical trials, and there is growing need to rethink the traditional approaches to treatment development and approval (3). One potential solution to this may be to further extend and validate the results from RCTs with the wider experience of real-world data (RWD) or real-world evidence (RWE).Compared to the rigorous admission criteria and strict research conditions of RCTs, RWD is collected from the real world to provide evidence for clinical and policyrelevant questions that cannot be addressed with data from RCTs, such as patient health status, cancer incidence and mortality, quality of and access to care delivered in routine practice, rare cancers, and rare adverse events and toxicities

show abstract

Pragmatic randomized clinical trials: a proposal to enhance evaluation of new cancer therapies with early signs of exceptional activity

Cited by 13 publications

References 14 publications

Evidence for Treatment-by-Biomarker interaction for FDA-approved Oncology Drugs with Required Pharmacogenomic Biomarker Testing

Evidence for Treatment-by-Biomarker interaction for FDA-approved Oncology Drugs with Required Pharmacogenomic Biomarker Testing

Use of Real‐World Evidence to Drive Drug Development Strategy and Inform Clinical Trial Design

The essence of real-world study in cancer research

Contact Info

Product

Resources

About