Comparison of External Control Arm (ECA) Critiques in Regulatory and Health Technology Assessment (HTA) Oncology Submissions
Author(s)
Jaksa A*1;Vondeling G2;Martin L3;Draganigos A3;Louder A1, Rosenlund M3
1Aetion, Inc, Boston, MA, USA, 2Daiichi Sankyo Europe GmbH, Munich, BY, Germany, 3Daiichi Sankyo Europe GmbH, Munich, Germany
OBJECTIVES: With the rise in accelerated approvals in oncology, reliance on single-arm studies in regulatory and HTA decision-making has increased. Regulatory and HTA agencies are recognizing that high-quality ECAs, built using real-world data (RWD), can reduce uncertainties in single-arm studies. This review compared regulatory and HTA agencies’ evaluations of oncology ECAs to determine success factors.
METHODS: FDA multi-disciplinary reviews for oncology submissions from 2014-2019 were screened to identify four therapy-indication analogues with ECAs to support efficacy claims. Regulatory (FDA, EMA, PMDA, HC) and HTA (pCODR, NICE, G-BA, HAS, and PBAC) submissions for these analogues were reviewed. The decision-makers’ critiques on ECAs were analyzed and categorized using a pre-specified extraction table.
RESULTS: ECAs were reviewed for blinatumomab (2 indications), avelumab, and erdafitinib. Ten regulatory and 13 HTA decisions were reviewed. Across drugs, selection bias was the most common ECA critique by regulatory and HTA agencies. HTAs also criticized naive comparisons and inconsistency in standard-of-care over time frames of RWD collection. However, agreement was low in critiques of ECAs within an analogue across regulators and HTAs; for example, for blinatumomab (Ph- ALL), the FDA and NICE noted that key differences between ECA and single-arm trials were accounted for however, HAS and pCODR disagreed. ECA influence on agencies’ decisions also varied across agencies; G-BA dismissed all ECAs due to methodological issues, while PBAC readily incorporated ECAs into reimbursement assessments.
CONCLUSIONS: Despite evaluating the same ECA evidence, agencies came to different conclusions on the quality of the ECA for decision-making. Regulators and HTAs preferred ECAs with formal statistical comparisons and raised issues around methods (e.g. selection bias). When designing ECAs, manufacturers should be aware of differing criteria and priorities that are likely to be raised from various stakeholders and attempt to address these critiques in their ECA design and submissions.
METHODS: FDA multi-disciplinary reviews for oncology submissions from 2014-2019 were screened to identify four therapy-indication analogues with ECAs to support efficacy claims. Regulatory (FDA, EMA, PMDA, HC) and HTA (pCODR, NICE, G-BA, HAS, and PBAC) submissions for these analogues were reviewed. The decision-makers’ critiques on ECAs were analyzed and categorized using a pre-specified extraction table.
RESULTS: ECAs were reviewed for blinatumomab (2 indications), avelumab, and erdafitinib. Ten regulatory and 13 HTA decisions were reviewed. Across drugs, selection bias was the most common ECA critique by regulatory and HTA agencies. HTAs also criticized naive comparisons and inconsistency in standard-of-care over time frames of RWD collection. However, agreement was low in critiques of ECAs within an analogue across regulators and HTAs; for example, for blinatumomab (Ph- ALL), the FDA and NICE noted that key differences between ECA and single-arm trials were accounted for however, HAS and pCODR disagreed. ECA influence on agencies’ decisions also varied across agencies; G-BA dismissed all ECAs due to methodological issues, while PBAC readily incorporated ECAs into reimbursement assessments.
CONCLUSIONS: Despite evaluating the same ECA evidence, agencies came to different conclusions on the quality of the ECA for decision-making. Regulators and HTAs preferred ECAs with formal statistical comparisons and raised issues around methods (e.g. selection bias). When designing ECAs, manufacturers should be aware of differing criteria and priorities that are likely to be raised from various stakeholders and attempt to address these critiques in their ECA design and submissions.
Conference/Value in Health Info
2020-11, ISPOR Europe 2020, Milan, Italy
Value in Health, Vol. 4, No. 6 (November/December 2001)
Code
ON3
Topic
Health Policy & Regulatory, Health Technology Assessment, Study Approaches
Topic Subcategory
Approval & Labeling, Decision & Deliberative Processes, Literature Review & Synthesis, Reimbursement & Access Policy
Disease
Oncology