The European Medicines Agency (EMA) has published a reflection paper discussing key considerations for single-arm clinical trials that are used as pivotal evidence in regulatory filings.
A public consultation on the paper, which is the first guidance document by an international medicine regulator outlining the considerations and challenges associated with this type of clinical trial, is open until 30 September.
Randomised clinical trials are the standard for providing confirmatory evidence on the efficacy of a new treatment, with a large number of patients usually included to generate robust data.
However, in certain therapeutic areas where target populations are often very small, such as rare diseases, a proportion of marketing authorisation applications are submitted to the EMA using data from single-arm trials as pivotal evidence.
Because there is no randomised comparator in a single-arm trial, all patients receive the experimental treatment and only the outcomes under the experimental treatment can be observed.
‘If results derived from single-arm trials are to be used as pivotal evidence for approval, it is essential that their adequacy is systematically addressed in terms of their characteristics, limitations and remaining uncertainties,’ the guidance states.
The reflection paper discusses the choice of endpoints used in single-arm trial designs, the target and trial population, the role of external information, statistical principles and sources of bias and potential mitigation.
‘It aims to stimulate the scientific discussion around key concepts and challenges associated with single-arm trials and to improve their design and conduct,’ the agency said in a statement.
The reflection paper has been adopted by EMA’s human medicines committee, with contributions from the Committee for Advanced Therapies, the Methodology Working Party and the Oncology Working Party.
Following the public consultation, comments from stakeholders will be analysed and considered in the final document that is planned to be published in 2024.
The publication comes just a month after the US Food and Drug Administration issued new draft guidance aimed at improving oncology clinical trials used to support accelerated approval applications.
The guidance, Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics, discusses a potential advantage of randomised clinical trials over single-arm studies.