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Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review.
BMJ Open. 2019 02 27; 9(2):e024895.BO

Abstract

OBJECTIVES

Non-randomised clinical trial designs involving comparisons against external controls or specific standards can be used to support regulatory submissions for indications in diseases that are rare, with high unmet need, without approved therapies and/or where placebo is considered unethical. The objective of this review was to summarise the characteristics of non-randomised trials submitted to the European Medicines Agency (EMA) or Food and Drug Administration (FDA) for indications in haematological cancers, haematological non-malignant conditions, stem cell transplants or rare metabolic diseases.

METHODS

We conducted systematic searches of EMA databases of conditional approvals, exceptional circumstances, or orphan drug designations and FDA inventories of orphan drug designations, accelerated approvals, breakthrough therapy, fast-track and priority approvals. Products were included if reviewed by at least one agency between 2005 and 2017, the primary evidence base was non-randomised trial(s) and the indication was for haematological cancers, stem cell transplantation, haematological conditions or rare metabolic conditions.

RESULTS

We identified 43 eligible indication-specific products using non-randomised study designs involving comparisons with external controls, submitted to the EMA (n=34) and/or FDA (n=41). Of the 43 indication-specific products, 4 involved matching external controls to the population of a non-randomised interventional study using individual patient-level data (IPD), 12 referred to external controls without IPD and 27 did not explicitly reference external controls. The FDA approved 98% of submissions, with 56% accelerated approvals; most required postapproval confirmatory randomised controlled trials (RCT). The EMA approved 79% of submissions, with a quarter of approvals conditional on completion of a postapproval RCT or additional non-randomised trials.

CONCLUSIONS

There has been a large increase in submissions to the EMA and FDA using non-randomised study designs involving comparisons with external controls in recent years. This study demonstrated that regulators may be willing to approve such submissions, although approvals are often conditional on further confirmatory evidence from postapproval studies.

Authors+Show Affiliations

Epidemiology, ICON, Vancouver, British Columbia, Canada.Global Outcomes Research, Takeda Pharmaceuticals International, London, UK.Epidemiology, ICON, Vancouver, British Columbia, Canada.Epidemiology, ICON, Vancouver, British Columbia, Canada.Epidemiology, ICON, Vancouver, British Columbia, Canada.Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada.Institute of Clinical Trials and Methodology, University College London, London, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Systematic Review

Language

eng

PubMed ID

30819708

Citation

Goring, Sarah, et al. "Characteristics of Non-randomised Studies Using Comparisons With External Controls Submitted for Regulatory Approval in the USA and Europe: a Systematic Review." BMJ Open, vol. 9, no. 2, 2019, pp. e024895.
Goring S, Taylor A, Müller K, et al. Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review. BMJ Open. 2019;9(2):e024895.
Goring, S., Taylor, A., Müller, K., Li, T. J. J., Korol, E. E., Levy, A. R., & Freemantle, N. (2019). Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review. BMJ Open, 9(2), e024895. https://doi.org/10.1136/bmjopen-2018-024895
Goring S, et al. Characteristics of Non-randomised Studies Using Comparisons With External Controls Submitted for Regulatory Approval in the USA and Europe: a Systematic Review. BMJ Open. 2019 02 27;9(2):e024895. PubMed PMID: 30819708.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review. AU - Goring,Sarah, AU - Taylor,Aliki, AU - Müller,Kerstin, AU - Li,Tina Jun Jian, AU - Korol,Ellen E, AU - Levy,Adrian R, AU - Freemantle,Nick, Y1 - 2019/02/27/ PY - 2019/3/2/entrez PY - 2019/3/2/pubmed PY - 2020/3/4/medline KW - external controls KW - non-randomised studies KW - regulatory submissions KW - systematic review SP - e024895 EP - e024895 JF - BMJ open JO - BMJ Open VL - 9 IS - 2 N2 - OBJECTIVES: Non-randomised clinical trial designs involving comparisons against external controls or specific standards can be used to support regulatory submissions for indications in diseases that are rare, with high unmet need, without approved therapies and/or where placebo is considered unethical. The objective of this review was to summarise the characteristics of non-randomised trials submitted to the European Medicines Agency (EMA) or Food and Drug Administration (FDA) for indications in haematological cancers, haematological non-malignant conditions, stem cell transplants or rare metabolic diseases. METHODS: We conducted systematic searches of EMA databases of conditional approvals, exceptional circumstances, or orphan drug designations and FDA inventories of orphan drug designations, accelerated approvals, breakthrough therapy, fast-track and priority approvals. Products were included if reviewed by at least one agency between 2005 and 2017, the primary evidence base was non-randomised trial(s) and the indication was for haematological cancers, stem cell transplantation, haematological conditions or rare metabolic conditions. RESULTS: We identified 43 eligible indication-specific products using non-randomised study designs involving comparisons with external controls, submitted to the EMA (n=34) and/or FDA (n=41). Of the 43 indication-specific products, 4 involved matching external controls to the population of a non-randomised interventional study using individual patient-level data (IPD), 12 referred to external controls without IPD and 27 did not explicitly reference external controls. The FDA approved 98% of submissions, with 56% accelerated approvals; most required postapproval confirmatory randomised controlled trials (RCT). The EMA approved 79% of submissions, with a quarter of approvals conditional on completion of a postapproval RCT or additional non-randomised trials. CONCLUSIONS: There has been a large increase in submissions to the EMA and FDA using non-randomised study designs involving comparisons with external controls in recent years. This study demonstrated that regulators may be willing to approve such submissions, although approvals are often conditional on further confirmatory evidence from postapproval studies. SN - 2044-6055 UR - https://neuro.unboundmedicine.com/medline/citation/30819708/Characteristics_of_non_randomised_studies_using_comparisons_with_external_controls_submitted_for_regulatory_approval_in_the_USA_and_Europe:_a_systematic_review_ L2 - https://bmjopen.bmj.com/lookup/pmidlookup?view=long&pmid=30819708 DB - PRIME DP - Unbound Medicine ER -