Consultation outcome

Public feedback and detail of outcome

Updated 16 December 2021

Following the consultation, the MHRA has published two guidance documents.

The document MHRA Guidance on the use of Real-World Data in Clinical Studies to Support Regulatory Decisions provides an introduction to the MHRA’s real-world data (RWD) guideline series, and points to consider when evaluating whether a RWD source is of sufficient quality for the intended use.

The MHRA Guideline on Randomised Controlled Trials using Real-World Data to Support Regulatory Decisions provides points to consider when planning a prospective randomised trial using RWD sources with the intention of using the trial to support a regulatory decision. The guideline covers clinical trial authorisation (if applying for approval to run such a trial wholly or in part in the UK), and clinical trial design including choice of endpoints and safety data requirements.

The consultation invited comments from stakeholders on the MHRA draft guidance on randomised controlled trials generating real-world evidence to support regulatory decisions. Responses were received from 10 pharmaceutical companies, 6 academic groups, 5 trade associations, 4 patient organisations/charities, 3 CROs, 3 healthcare providers/regulatory organisations, 3 professional bodies, and 3 individuals. The majority of responses were from UK based individuals/organisations, but comments were received from other European countries and the USA. This feedback helped the MHRA, in collaboration with the Commission on Human Medicines Real-World Data ad hoc group, to finalise and publish this guidance.

All the comments received were carefully considered during revision of the guidance, and when relevant they were implemented in the final guidance. Some of the areas which attracted the most comment are discussed below, along with the MHRA response.

The majority of comments were positive and supportive of the guideline objectives of encouraging greater use of RWD in regulatory applications.

Many comments stated that the scope of the guideline was not clear; or revealed it to be so by asking why there wasn’t more information on topics intended to be outside the scope such as observational studies. The intention was that the guideline addressed only issues related to running randomised, controlled trials (RCTs) using real-world data, and not issues related to other types of study designs. In response to these comments the content from the draft guideline was split into two documents each with a much clearer scope; one containing a general introduction to the MHRA RWD guidance and points to consider on data quality, and another document containing only content related to RCTs.

Stakeholders were unsure whether trials using RWD that were conducted outside of the UK would be acceptable to the MHRA. The answer to this question is ‘yes’ but the comments led to the realisation that the discussion related to clinical trial approval (which is UK specific) had been intertwined with the general points on trial design, leading to a lack of clarity. In the revised guideline these two aspects have been clearly separated.

Similarly, there were questions over whether the guidance was applicable to devices. While many of the general principles would be applicable to trials in any area, given the ongoing revisions to devices regulations, at this time the sections on trial approval are specific to medicines. This aspect has been clarified. Once the new framework for medical devices is developed this will be part of the considerations going forward.

Several comments provided philosophical discussion which provoked much debate. Many commenters were of the view that RCTs use RWD but do not produce real world evidence (RWE), and there were views on whether the trials under discussion provided evidence of efficacy or effectiveness. While these debates were interesting it was ultimately decided that the purpose of the guideline was simply to provide information to those thinking of running a RCT using RWD, and how the resulting evidence might be classified was ultimately not a critical point for regulatory decision making. Therefore, in response to these comments, the title of the guideline was changed to refer to RWD rather than RWE and almost all references to RWE were removed from the document along with references to and discussions of ‘effectiveness’.

Requests were made for specific discussion of issues related to non-inferiority trials, for more emphasis to be placed on blinding, and for incorporation of the estimand framework from the ICH E9 addendum ; edits were made to address all these points. There was a general preference from commenters to refer to ‘traditional’ RCTs rather than ‘conventional’ as we had done when describing RCTs not using RWD, so the former term was adopted.