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W-29: Single Pivotal Trial Characteristics Supporting Regulatory Approval of Non-orphan, Non-oncology Drugs in EU and US, 2012 – 16

Poster Presenter

Vivien Jagalski

Regulatory Intelligence Professional
Lundbeck
Denmark

Objectives

The clinical evidence of efficacy submitted in support of non-oncology, non-orphan novel therapeutics in EU and US approved based on one pivotal clinical trial was characterized in terms of design and results of the pivotal trial, requests for post-approval efficacy, and evidence from other trials.

Method

This is a retrospective, descriptive, cross-sectional study including public information from FDA and EMA websites, such as review documents and approval letters, US prescribing Information, and European Public Assessment Reports. All data were reviewed and verified by two independent authors.

Results

The historically established standard for new drug approvals by regulators are two positive, adequate and well-controlled clinical trials to demonstrate the efficacy of a new drug in the targeted patient population with a primary outcome measure supporting the intended therapeutic indication. However, one third of all new drugs approved by the FDA and EMA are supported by a single pivotal trial. While oncology and rare diseases account for the majority with somewhat regulatory flexibility in terms of efficacy requirement, less is known about approvals based on a single pivotal trial that are not rare nor immediately life threatening. Hence, our aim was to increase the understanding of evidence supporting the non-orphan and non-oncology approvals based on a single pivotal trial. Excluding oncology and orphan drugs, 23 novel therapeutic drugs were approved in EU and/or US from 2012 to 2016 for one or more indications (27 indications in total) supported by a single pivotal clinical trial. The majority of pivotal trials were randomized and included a control arm (85%), i.e. randomized controlled trials (RCTs). Thirteen RCTs (48%) were placebo-controlled while 10 (37%) included an active comparator. Four pivotal trials (15%) were open-label and uncontrolled. In these uncontrolled trials, the primary outcomes were established as very convincing responses to treatment or changes from baseline. Most of the primary outcome measures in the single pivotal trials were overall objective efficacy measures (clinical outcomes or surrogate markers in 22 out of 27 pivotal trials). In almost all cases, evidence from one or more non-pivotal trials submitted as part of the application were classified as ‘supportive’ for the assessment of efficacy. Moreover, in only a few instances, post-approval studies were requested by the regulatory agencies to confirm efficacy.

Conclusion

While it has been widely discussed whether approvals of oncology and orphan drugs are too often based on limited evidence of efficacy, our analysis shows that single pivotal trial approvals for novel therapeutic drugs targeting other disease areas are generally based on data from a randomized and controlled trial with a statistically very compelling result of the primary analysis. Our analysis also suggests that the seriousness of the disease and the availability of supportive evidence of efficacy from other clinical trials play an important role when approvals of new treatments are based on a single pivotal trial. These learnings may supplement the available FDA and EMA guidance pertaining to applications with a single pivotal trial and inform sponsors with considerations of the clinical development plan. This work has been peer-reviewed and accepted for publication in Clinical and Translational Science in Dec.2018: https://doi.org/10.1111/cts.12617