The UK MHRA has issued draft guidance on randomised controlled trials generating real-world evidence (RWE) that is used to support regulatory decisions. It is intended to be the first in a series of guidance documents addressing RWE. The guidance is part of the MHRA’s push to reinforce the view of the MHRA as a pro-innovative regulatory authority, and that the UK is a leading country in which to conduct clinical research, post-Brexit.

Real World Evidence

Real world data (RWD) is broadly defined as routinely collected health data. Sources of RWD include electronic healthcare records, disease registries and observational studies, and data collected via wearable devices. This data, when analysed to make inferences about treatments, produces real world evidence (RWE).

Interest in RWE has increased, with the view that generating such data can be a cheaper alternative to costly randomised controlled trials. RWD is also regarded as more representative of the population as a whole and of the real life use of a product, compared to data produced in a conventional, and somewhat sanitised, clinical trial. Indeed, it was said at the “Global regulatory workshop on COVID-19 real-world evidence and observational studies” in July 2020 that “Evidence generated by high-quality observational research is fundamental to understanding the safety and effectiveness of medicines in everyday use by patients and doctors.”

However, up to now, the use of such data in regulatory submissions has been largely limited to safety data, for post-marketing follow-up to explore areas where there is insufficient evidence pre-authorisation, or to support pricing and reimbursement approval. The use of RWE in regulatory submission for new products or indications has been confined to a limited number of orphan products, where randomised controlled trials are more difficult to conduct. Regulatory authorities maintain some caution about relying on RWE, given the wide range of ways in which it is collected and the questions over the quality of the data.

Increasingly, companies are exploring RWE for a wider range of products and to support a broader set of regulatory submissions. While there have been lots of discussion and pilot schemes about using RWE, the call from industry has been for concrete guidance about how and when such data will be accepted by authorities. The EMA has acknowledged in the HMA-EMA Joint Big Data Taskforce Phase II report, “Evolving Data-Driven Regulation”, that “It is clear that the data landscape is evolving and that the regulatory system needs to evolve as well.” The MHRA is seeking to answer that call.

MHRA consultation

The current draft guidance document sets out points to be considered when planning a randomised clinical trial using RWD sources, and where the sponsor intends to submit this trial for regulatory approval.

The guidance covers simple trials and hybrid trials:

  • Simple trials are trials that are set up to generate RWE. An example may be a randomised controlled trial involving patients in a database that are randomised to one of a choice of interventions, and are then followed up as is routine practice for the database concerned.
  • Hybrid trials are trials where some of the data collected is RWD, and some is collected for the trial outside of the RWD source. An example may be where patients and/or healthcare professionals provide trial specific data, such as patient reported outcomes or additional clinical assessments, as well as the routinely collected data that may be entered into the registry.

As patients are randomised into cohorts in these trials, they will be classed as interventional trials. However, they will likely be low interventional trials, where the potential risk associated with the investigational medicinal product is considered no higher than that of standard medical care. The guidance categorises these trials as “Type A trials”.

The guidance sets out the factors that need to be considered when collecting RWD as part of a clinical trial. In terms of safety, monitoring and reporting requirements will vary depending on the proposed population and adverse event profile. The fact the trial is set up to collect RWE does not change the legal requirement to report adverse events as set out in the legislation.

In terms of using RWE for regulatory submissions, the MHRA says there is nothing barring the use of RWE to gain an initial approval or approval of a new indication – it is not the source of the data that is the critical question, but whether the data quality is “robust” and the trial is “designed in a way which allows it to provide the evidence required to answer the regulatory question”. For Type A trials, or low interventional trials, the MHRA will accept the data for regulatory purposes “if the key endpoints necessary to make the regulatory decision are routinely collected in the database and are sufficiently objective such that they would not be subject to meaningful bias from the knowledge of treatment allocation in an open-label setting”. Notwithstanding this, the consultation states that a RWE approach is likely to be most suited to decisions regarding labelling changes and adding a new indication.

The MHRA is consulting on this draft until 11 December 2020 to get feedback from stakeholders on the clarity and wording of this first piece of guidance; you can provide comments on this form.

EMA consultation

The EMA is also running a consultation on RWE; this time on the use of registry-based studies. The guidance aims to optimise the use of registry-based studies as a source of RWE that can be used in the context of the benefit-risk evaluation of medicinal products. Stakeholders are invited to send their comments via an online form by 31 December 2020.