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RWE Guidance Watch: MHRA draft guidance on RCTs generating RWE to support regulatory decisions

Nick Honig
Senior Analyst, Marketing, Aetion

Nirosha Mahendraratnam Lederer, Ph.D.
Director, RWE Strategy, Aetion

Image for RWE Guidance Watch:  MHRA draft guidance on RCTs generating RWE to support regulatory decisions
Image for RWE Guidance Watch:  MHRA draft guidance on RCTs generating RWE to support regulatory decisions

With real-world evidence (RWE) growing in influence across health care, regulatory and health technology assessment (HTA) bodies continue to issue recommendations for biopharma to articulate standards around RWE generation and use. 

However, as discussed during the session “RWE guidance and frameworks: What elements are necessary to promote quality, transparency, and validity in RWE?” at Virtual ISPOR 2020, these recommendations are often fragmented, and pose challenges for sponsors as they navigate different stakeholders’ nuanced definitions of “high quality RWE.” 

In our series,“ RWE Guidance Watch, we alert readers to recent, influential RWE guidances issued by standard-setting organizations, and what they mean for biopharma as organizations develop plans for RWE generation. This entry examines a recent draft guidance from the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA); read on to learn more. 

MHRA draft guidance on randomized controlled trials (RCTs) generating RWE to support regulatory decisions
On October 30, 2020, MHRA released a draft guidance on RCTs generating RWE to support regulatory decisions. This is the first in a series of guidance documents on RWE aimed to “further support the clinical development programmes of Sponsors,” and each guidance document will address a different trial design.  

MHRA developed this document with input from the Commission on Human Medicines Real-World Data working group. A comment period is open until December 11, 2020.

Below, we share a summary of the key takeaways from this guidance document.

MHRA actively encourages the use of RWE for a variety of regulatory purposes
This guidance focuses on prospective RCTs using an RWD source. Trial designs meeting this definition include practical trials*, large simple trials**, pragmatic trials***, and hybrid trials****. MHRA is the latest in a series of organizations considering RWE for pragmatic trials. ICER and the Innovative Medicines Initiative’s GETREAL Initiative have also published on this topic.

MHRA states that RWE studies from these trials “are most likely to be considered for label changes for already approved products, including drug repurposing.” The agency adds that it will also consider alternative use cases. MHRA also declares that “RWE from such trials 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 well designed.”

MHRA’s recommendations reflect consideration of principled epidemiology
Similar to the EMA’s recent guidance on registry-based studies, MHRA places an emphasis on many of the tenants of principled epidemiology as they relate to RCTs using an RWD source. The agency states that a sponsor conducting such trials must prespecify its protocol, determine what data will be collected, clearly define endpoints, and preselect analysis methods.

MHRA emphasizes data quality
MHRA dedicates a substantial portion of the guidance to data quality considerations. The agency recommends that a sponsor conduct a feasibility analysis to assess whether the RWD can accurately capture study variables prior to initiating a practical RWE study. According to the guidance, the feasibility analysis should utilize the guidelines laid out in this paper. Other considerations include:

  • whether the database will be used as the source population of recruitment or if will supplement other data sources;
  • the frequency and regularity of measurement of baseline characteristics;
  • the capture detail of interventions and outcomes, and potential for bias;
  • pre-specification of how the sponsor will handle changes in data collection;
  • lag time between occurrence of events and availability of data for analysis; 
  • consideration of methods for linking to other data sources and the reliability of such methods; and
  • data quality checks by a data custodian and additional checks required by the trial at hand.

These recommendations do not constitute a comprehensive roadmap for selecting a data source, but rather serve as a general guideline for sponsor considerations. MHRA also recommends that sponsors include a description of planned tools and methods, and that they detail how they were validated.

MHRA outlines the ideal situation for a practical RWE study
MHRA discusses when a randomized RWE study would provide a strong evidentiary base, laying out a number of considerations. First, the agency states “the more involvement outside of routine care that is required, the smaller the advantage of running a RWD based trial becomes, and not all the evidence generated by the trial would be classified as RWE.” MHRA also provides four criteria that would lead to a high-quality RWE study:

  1. the study examines an intervention that is “embedded in routine practice with a well-established EHR database;”
  2. the sponsor selects an objective endpoint that is “routinely and consistently collected in the EHR database;”
  3. the intervention of focus is already licensed, has a defined safety profile, and is combined with standard of care and evaluated against standard of care; and
  4. the intervention is being evaluated in a milder version of the disease for which it is already indicated.

MHRA provides a deep dive into the second point, citing all-cause mortality as an ideal endpoint. The guidance states that not only should the endpoint be objective, it should not require patient action to record, not be based on a time schedule, and should have a consistent method of recording.

MHRA recommends sponsors seek scientific advice
MHRA recommends sponsors take advantage of the MHRA Innovation Office’s regulatory advice and its general scientific advice pathways. Sponsors can discuss any aspect of clinical trial design with the agency, which can provide clarity on regulatory requirements and expectations.

Impact on biopharma
This guideline focuses solely on one type of study design, but signals the agency’s openness to accept RWE in regulatory decision-making. 

Research and development, value and access, and safety groups should consider using randomized RWE trials for label expansions and other product evaluations. These groups should review MHRA’s cited case studies, such as the Salford Lung Study to better understand the agency’s standards for these types of trials. Sponsors should also plan to leverage MHRA’s scientific advice pathways to ensure alignment with the core pillars of principled epidemiology.

* MHRA defines a practical trial as “any investigation in human subjects, other than a non-interventional trial, intended to (1) discover or verify the clinical, pharmacological, or other pharmacodynamic effects of one or more medicinal products, (2) identify any adverse reactions to one or more such products, or (3) study absorption, distribution, metabolism and excretion of one or more such products, with the object of ascertaining the safety or efficacy of those products.

** MHRA defines a simple trial as “a randomised, controlled trial using a RWD source [involving] patients in the database being randomised to one of a choice of interventions which could include standard clinical care alone. They are then followed as is routine practice for the database concerned. The interventions to be compared could be the intervention of interest added to standard of care, compared to standard of care alone. It could also be an active controlled comparison of an intervention of interest to another intervention.”

*** MHRA defines pragmatic trials as “trials which aim to investigate the effectiveness of a treatment in routine clinical practice. They contrast with  explanatory trials, which investigate whether an intervention can have an effect in a carefully controlled situation.”

**** MHRA defines a hybrid trial as “a trial where some of the data collected are RWD, and some are collected specifically for the trial outside of the RWD source.”

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