Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review

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.

Keywords: external controls; non-randomised studies; regulatory submissions; systematic review.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram. EMA, European Medicines Agency; FDA, Food and Drug Administration; RCT, randomised controlled trial.

Figure 2

Proportions of disease targets of included submissions. ADA-SCID, adenosine deaminase deficiency-severe combined immunodeficiency; aHUS, atypical haemolytic uraemic syndrome; ASCT, autologous stem cell transplant; HSCT, haematopoietic stem cell transplant; sALCL, systemic anaplastic large cell lymphoma.

Figure 3

Study design features of included studies (total n=96). ‘Other’ study designs included: switchover studies (n=1), extensions or subset analyses from previous studies (n=3), dose escalation studies (n=4), pilot studies (n=1), compassionate use (n=2), retrospective studies (n=2), or consensus recommendations and other literature (n=1). N/R, not reported; RCT, randomised controlled trial.

Figure 4

Objective response rate in haematological oncology products, by indication. Colour coding reflects approval status: dark green=approved by both agencies; light green=approved by Food and Drug Administration (FDA) only; ‘−2’ indicates more than one estimate was available (second estimate). CLL, chronic lymphocytic leukaemia; CTCL, cutaneous T cell lymphoma; MCL, mantle cell lymphoma; MM, multiple myeloma; NHL, non-Hodgkin’s lymphoma; ORR, objective response rate; PTCL, peripheral T cell lymphoma; sALCL, systemic anaplastic large cell lymphoma; WM, Waldenström macroglobulinaemia. Note: Lenalidomide and pomalidomide were approved by European Medicines Agency (EMA) using randomised controlled trial (RCT) evidence.

Figure 5

Summary of approval status, and regulatory pathways and designations. Left: EMA submissions (n=34). Right: FDA submissions (n=41). EMA, European Medicines Agency; FDA, Food and Drug Administration.