MHRA guidance on the use of RWD
Leveraging real-world evidence in clinical development
Commentary on the MHRA guidance on the use of real-world data in clinical studies to support regulatory decisions (1) and the MHRA guideline on randomized controlled trials using real-world data to support regulatory decisions (2), both recently published (December 16, 2021)
MHRA acknowledges that evidence from randomized trials using RWD is not generally considered of more or less value for regulatory decision making than evidence from conventional RCTs provided the data quality is robust and the trial is well-designed.
MHRA guidance on the use of RWD:
General principles excerpted from the original document:
– Data quality processes must be detailed in the study protocol, and these must be appropriately validated to ensure that any process is fit for its intended use.
– Data quality checks should be conducted to ensure all data values are recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.
– Data should meet agreed specifications and requirements defined by the sponsor to support the study requirements to ensure that any received data contains only expected data files and that all data elements are structured correctly as per the agreed specification.
In summary, data quality and assurance requirements for RWD should be in line with the standard expectations for conventional RCTs.
MHRA guideline on randomized controlled trials using RWD:
Salient points adapted from the original document:
Scope: The guideline has limited scope. It only covers randomized, controlled clinical trials primarily using RWD sources. It covers drugs, not devices. It does not cover other types of studies that could be run using RWD such as observational studies, or clinical trials using RWD as a control arm.
Additional requirements: Running a trial using RWD is attractive because of reductions in patient and healthcare professional burden. If the clinical situation necessitates that many additional requirements outside of routine practice need to be incorporated in the trial, then there may be few advantages over a conventional RCT. In other words, the more involvement required outside of routine care, the smaller the advantage of running a RWD based trial. Randomized trials using a RWD source may be most commonly used (but not exclusively) for label changes for already approved products, including:
– Use in a new population (different age group, different disease severity, etc. to what is already licensed
– Change in dose, or route of administration
– Adding a new indication (repurposing)
Blinding: Trials should be blinded whenever possible. This is especially needed when the primary endpoint is not sufficiently objective, or if unblinding results in different management practices depending on the drug the patient receives.
Hybrid trials: RWD can be supplemented by additional trial specific data such as additional clinical assessments or interventions.
Assay sensitivity: Assay sensitivity in non-inferiority trial needs to be carefully examined: The efficacy of the comparator is usually estimated from past conventional RCTs that compared it with placebo, where noise was reduced to a tolerable level by forcing participating physicians to treat all the trial participants with the same protocol. This reduces the sample size needed to detect the differential efficacy signal. In the real-world physicians do not treat all their patients with the same protocol; noise is increased, and the sample size must be adjusted upwards to avoid a false non-inferiority conclusion.
EHR based endpoints: Completeness and validity of the recording of potential endpoints in electronic health records should not be assumed. In the UK, acute myocardial infarction, which is generally considered as a reliable endpoint, was found to be recorded with poor completeness in primary care, secondary care admissions data, and a disease specific registry, with each data source missing 25-50% of events (3).
(1) https://www.gov.uk/government/publications/mhra-guidance-on-the-use-of-real-world-data-in-clinical-studies-to-support-regulatory-decisions/mhra-guidance-on-the-use-of-real-world-data-in-clinical-studies-to-support-regulatory-decisions
(2) https://www.gov.uk/government/publications/mhra-guidance-on-the-use-of-real-world-data-in-clinical-studies-to-support-regulatory-decisions/mhra-guideline-on-randomised-controlled-trials-using-real-world-data-to-support-regulatory-decisions
(3) https://www.bmj.com/content/346/bmj.f2350
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