Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies

Ladanie, Aviv; Speich, Benjamin; Briel, Matthias; Sclafani, Francesco; Bucher, Heiner C.; Agarwal, Arnav; Ioannidis, John P. A.; Pereira, Tiago; Kasenda, Benjamin; Hemkens, Lars G

doi:10.1016/j.jclinepi.2019.05.033

Cited by 21 publications

(17 citation statements)

References 32 publications

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“…A meta-epidemiologic study published in 2019 evaluated all single-arm studies used for FDA approvals and demonstrated that the number of single-arm studies leading to approval increased substantially. Furthermore, the majority was based on studies with small sample sizes, and did not provide any other verifying studies (17). Recently, the EMA and FDA have been increasing the number of approvals based on non-randomized trials.…”

Section: Discussionmentioning

confidence: 99%

U.S. Food and Drug Administration anticancer drug approval trends from 2016 to 2018 for lung, colorectal, breast, and prostate cancer

Ribeiro

Rodrigues

et al. 2019

Int J Technol Assess Health Care

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ObjectiveThis paper aims to describe the clinical and regulatory aspects of new drugs and indications that were approved for lung, breast, prostate, and colorectal cancer, from 2016 to 2018, in order to provide health technology assessment trends in oncology.MethodsData were collected from the US Food and Drug Administration (FDA) online database for new medications and indications approved for the above-mentioned types of cancer. Data regarding clinical study characteristics and regulatory information were collected.ResultsFrom 2016 to 2018, 53 percent of the FDA approvals of new drugs and indications for the most incident cancers were for oral protein kinase inhibitor monotherapy for advanced lung cancer. Since 2018, four drugs were approved as tumor-agnostic therapies. A biomarker was included in 72 percent of indications, and 58 percent of approvals were for targeted therapies, potentially heralding an end to research into conventional cytotoxic agents. A special designation for faster approval was granted in 78 percent of new approvals. The majority of the studies were open label randomized controlled trials (RCTs) (44 percent), followed by blind RCTs, single-arm clinical trials, and cohort studies. Only 14 percent of studies used overall survival as the primary end point; the vast majority used surrogate end points, and did not use patient-important outcomes. Three biosimilars were approved in the period.ConclusionAdvanced lung cancer therapy, mainly targeted drugs, accounted for 53 percent of approvals. Special designations for faster approval were used in 78 percent of FDA approvals, and four drugs were approved for tumor-agnostic treatment—a new form of approval.

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Section: Discussionmentioning

confidence: 99%

U.S. Food and Drug Administration anticancer drug approval trends from 2016 to 2018 for lung, colorectal, breast, and prostate cancer

Ribeiro

Rodrigues

et al. 2019

Int J Technol Assess Health Care

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show abstract

“…[9][10][11][12][13] On the other hand, healthcare professionals doi: 10.1136/bmj.n450 | BMJ 2021;372:n450 | the bmj collecting routine data during usual care might have more clinical expertise than research staff who often collect trial data only for a narrow time frame and scope, sometimes only for a few participants or even a single patient in each centre. 14 Since routine data are collected independently of the trial from people unaware of treatment allocations, biases related to outcome ascertainment might be even less likely than in traditional trials. Moreover, quality of routinely collected data can vary enormously for different outcomes.…”

Section: Introductionmentioning

confidence: 99%

Treatment effects in randomised trials using routinely collected data for outcome assessment versus traditional trials: meta-research study

Cord

Ewald

Agarwal

et al. 2021

BMJ

Self Cite

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Objective To compare effect estimates of randomised clinical trials that use routinely collected data (RCD-RCT) for outcome ascertainment with traditional trials not using routinely collected data. Design Meta-research study. Data source Studies included in the same meta-analysis in a Cochrane review. Eligibility criteria for study selection Randomised clinical trials using any type of routinely collected data for outcome ascertainment, including from registries, electronic health records, and administrative databases, that were included in a meta-analysis of a Cochrane review on any clinical question and any health outcome together with traditional trials not using routinely collected data for outcome measurement. Review methods Effect estimates from trials using or not using routinely collected data were summarised in random effects meta-analyses. Agreement of (summary) treatment effect estimates from trials using routinely collected data and those not using such data was expressed as the ratio of odds ratios. Subgroup analyses explored effects in trials based on different types of routinely collected data. Two investigators independently assessed the quality of each data source. Results 84 RCD-RCTs and 463 traditional trials on 22 clinical questions were included. Trials using routinely collected data for outcome ascertainment showed 20% less favourable treatment effect estimates than traditional trials (ratio of odds ratios 0.80, 95% confidence interval 0.70 to 0.91, I 2 =14%). Results were similar across various types of outcomes (mortality outcomes: 0.92, 0.74 to 1.15, I 2 =12%; non-mortality outcomes: 0.71, 0.60 to 0.84, I 2 =8%), data sources (electronic health records: 0.81, 0.59 to 1.11, I 2 =28%; registries: 0.86, 0.75 to 0.99, I 2 =20%; administrative data: 0.84, 0.72 to 0.99, I 2 =0%), and data quality (high data quality: 0.82, 0.72 to 0.93, I 2 =0%). Conclusions Randomised clinical trials using routinely collected data for outcome ascertainment show smaller treatment benefits than traditional trials not using routinely collected data. These differences could have implications for healthcare decision making and the application of real world evidence.

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Section: Discussionmentioning

confidence: 99%

“…The main variables were grouped into the following binary categories: RCT (blinded and open-label) vs single-arm; surrogate outcomes (OvRR, ORR and PFS) vs overall survival; sample sizes of≥200 vs <200 (following Ladanie et al, 2019 [ 18 ] recommendations); and magnitude of effect as large vs not large. Study characteristics were compared between accelerated and regular approvals and this analysis was repeated for BTD for approvals from 2012 onwards, comparing BTD vs non-BTD, the absolute number and percentage was presented.…”

Section: Methodsmentioning

confidence: 99%

Comparison of FDA accelerated vs regular pathway approvals for lung cancer treatments between 2006 and 2018

et al. 2020

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Regulatory agencies around the world have been using flexible requirements for approval of new drugs, especially for cancer drugs. The US Food and Drug Administration (FDA) is mostly the first agency to approve new drugs worldwide, mainly due to the faster terms of the accelerated pathway and breakthrough therapy designation. Surrogate endpoints and preliminary data (e.g. single-arm and phase 2 studies) are used for these new approvals, however larger effect sizes are expected. We aim to compare FDA Accelerated vs Regular Pathway approvals and Breakthrough therapy designations (BTD) for lung cancer treatments between 2006 and 2018 regarding study design, sample size, outcome measures and effect size. We assessed the FDA database to collect data from studies that formed the basis of approvals of new drugs or indications for lung cancer spanning from 2006 to 2018. We found that accelerated pathway approvals are based on significantly more single-arm studies with small sample sizes and surrogate primary endpoints. However, effect size was not different between the pathways. A large proportion of studies used to support regular pathway approvals also showed these characteristics that are related to low quality and uncertain evidence. Compared to other approvals, BTD were more frequently based on single-arm studies. There was no significant difference in use of surrogate endpoints or sample size. 44% of BTD were based on studies demonstrating large effect sizes, proportionally more than approvals not receiving this designation. In conclusion, based on the indicators of evidence quality we extracted, criteria's for granting accelerated approval and breakthrough therapy designation seen not clear. Faster approvals are in the majority full of uncertainties which should be viewed with caution and the patient have to be communicated to allow shared decision making. Post-marketing validation is essential.

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Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies

Cited by 21 publications

References 32 publications

U.S. Food and Drug Administration anticancer drug approval trends from 2016 to 2018 for lung, colorectal, breast, and prostate cancer

U.S. Food and Drug Administration anticancer drug approval trends from 2016 to 2018 for lung, colorectal, breast, and prostate cancer

Treatment effects in randomised trials using routinely collected data for outcome assessment versus traditional trials: meta-research study

Comparison of FDA accelerated vs regular pathway approvals for lung cancer treatments between 2006 and 2018

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