A Comparison of 7 Oncology External Control Arm Case Studies: Critiques From Regulatory and Health Technology Assessment Agencies

Jaksa, A.; Louder, Anthony; Vondeling, G.; Martin, Laura Díaz; Gatto, Nicolle M.; Richards, Eric; Yver, Antoine; Rosenlund, Mats

doi:10.1016/j.jval.2022.05.016

Cited by 24 publications

(28 citation statements)

References 11 publications

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“…Conducting external control studies is methodologically challenging and there are many examples of evidence generated using external controls being rejected by regulatory agencies and HTA agencies due to concerns relating to confounding and bias [10]. Before embarking on a study using external control data, it is essential to conduct a comprehensive feasibility assessment to establish the suitability of available data sources to act as external control arms, to consider the availability of objective and indisputable outcomes, and to consult with the relevant regulatory agency to confirm the appropriateness of the proposed approach.…”

Section: Methodological Considerationsmentioning

confidence: 99%

External control arms for rare diseases: building a body of supporting evidence

Khachatryan¹,

Read²,

Madison

2023

J Pharmacokinet Pharmacodyn

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Comparator arms in randomized clinical trials may be impractical and/or unethical to assemble in rare diseases. In the absence of comparator arms, evidence generated from external control studies has been used to support successful regulatory submissions and health technology assessments (HTA). However, conducting robust and rigorous external control arm studies is challenging and despite all efforts, residual biases may remain. As a result, regulatory and HTA agencies may request additional external control analyses so that decisions may be made based upon a body of supporting evidence.This paper introduces external control studies and provides an overview of the key methodological issues to be considered in the design of these studies. A series of case studies are presented in which evidence derived from one or more external controls was submitted to regulatory and HTA agencies to provide support for the consistency of findings.

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Section: Methodological Considerationsmentioning

confidence: 99%

External control arms for rare diseases: building a body of supporting evidence

Khachatryan¹,

Read²,

Madison

2023

J Pharmacokinet Pharmacodyn

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show abstract

“…To ensure all eligible submissions were appropriately included, the final list of products for data extraction was compared against products included in other reviews (noting that eligibility criteria differed between studies). 41,42,44,74 Whereas systematic in nature, we limited our scope to products with regulatory pathways (e.g., accelerated approval and breakthrough designation). This may have resulted in the exclusion of some submissions utilizing an external control.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions

Solà-Morales

Curtis

Heidt

et al. 2023

Clin Pharma and Therapeutics

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Real‐world data (RWD)‐derived external controls can be used to contextualize efficacy findings for investigational therapies evaluated in uncontrolled trials. As the number of submissions to regulatory and health technology assessment (HTA) bodies using external controls rises, and in light of recent regulatory and HTA guidance on the appropriate use of RWD, there is a need to address the operational and methodological challenges impeding the quality of real‐world evidence (RWE) generation and the consistency in evaluation of RWE across agencies. This systematic review summarizes publicly available information on the use of external controls to contextualize outcomes from uncontrolled trials for all indications from January 1, 2015, through August 20, 2021, that were submitted to the European Medicines Agency, the US Food and Drug Administration, and/or select major HTA bodies (National Institute for Health and Care Excellence (NICE), Haute Autorité de Santé (HAS), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), and Gemeinsamer Bundesausschuss (G‐BA)). By systematically reviewing submissions to regulatory and HTA bodies in the context of recent guidance, this study provides quantitative and qualitative insights into how external control design and analytic choices may be viewed by different agencies in practice. The primary operational and methodological aspects identified for discussion include, but are not limited to, engagement of regulators and HTA bodies, approaches to handling missing data (a component of data quality), and selection of real‐world endpoints. Continued collaboration and guidance to address these and other aspects will inform and assist stakeholders attempting to generate evidence using external controls.

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“…Situations where existing data are not available or suitable for an indication, a necessary exposure, an outcome, or a key covariate to measure confounding from sources, can pose a major limitation to conducting comparative efficacy studies to support regulatory decisions. As other researchers have stated, a common external control arm critique is about the mitigation of confounding [ 16 ]. Unfortunately, there are limits to ascertain real-world data proxies for variables in historically collected databases.…”

Section: Solutions: How Can Challenges Be Minimized?mentioning

confidence: 99%

“…As the majority of criticism from regulatory and reimbursement agencies on applications using real-world data has so far focused predominantly on data features (type, quality, and frequency) and confounding and selection bias limitations, appropriate curation and evaluation of these sources are critical components of any exercise using external evidence [ 16 ]. In this paper, we provide an overview of the challenges in identifying data suitable for external control arms, including common pseudonyms, such as synthetic control arms and historical controls, when evaluating comparative efficacy, and provide solutions for researchers to consider.…”

Section: Introductionmentioning

confidence: 99%

Data Challenges for Externally Controlled Trials: Viewpoint

Velummailum¹,

McKibbon²,

Brenner³

et al. 2023

J Med Internet Res

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The preferred evidence of a large randomized controlled trial is difficult to adopt in scenarios, such as rare conditions or clinical subgroups with high unmet needs, and evidence from external sources, including real-world data, is being increasingly considered by decision makers. Real-world data originate from many sources, and identifying suitable real-world data that can be used to contextualize a single-arm trial, as an external control arm, has several challenges. In this viewpoint article, we provide an overview of the technical challenges raised by regulatory and health reimbursement agencies when evaluating comparative efficacy, such as identification, outcome, and time selection challenges. By breaking down these challenges, we provide practical solutions for researchers to consider through the approaches of detailed planning, collection, and record linkage to analyze external data for comparative efficacy.

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A Comparison of 7 Oncology External Control Arm Case Studies: Critiques From Regulatory and Health Technology Assessment Agencies

Cited by 24 publications

References 11 publications

External control arms for rare diseases: building a body of supporting evidence

External control arms for rare diseases: building a body of supporting evidence

Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions

Data Challenges for Externally Controlled Trials: Viewpoint

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