Written by Michelle Conway

Estimated reading time: 8 minutes

Those of you who know me, or who have read my previous columns here on RARE Revolution will know that I am passionate about making sure lived experience is at the heart of every conversation, every process and every policy that has the potential to improve and shape that experience.  After all, it is the unmet need and the patient voice that drives so much innovation!  However, I am often left wondering if we are really capturing the right data at the right time and presenting them in the right way, particularly when I speak to families and patient advocacy group leaders, who at times may feel that their lived experience and data isn’t bridging the gaps as well as it could and should be. 

In the ideal scenario for any clinical development programme, their voices and lived experiences should sit at the heart of every conversation and every strategic decision.  In a traditional approach to patient engagement in clinical development we might expect to see the patient voice informing development in different ways at different stages as outlined in the below table.  Although in my experience I don’t believe this is happening across the board and there are opportunities for improved engagement at the discovery and target ID and trial design phases, where some patient advocates have expressed a feeling of tokenism rather than true engagement—but that is perhaps for another day!

Stage	Patient Role
Discovery & target ID	Define unmet needs, shape targets
Trial design	Input on endpoints, feasibility, inclusion criteria
Clinical trials	Advise on burden, help recruit, improve retention
Regulatory submission	Provide testimony, influence benefit-risk assessment
HTA and accessccess	Value definition, real-world impact, participate in deliberations
Post-market surveillance	Contribute to real-world evidence (RWE), report side effects, support ongoing data collection

However, even when the patient voice and lived experience is captured and informs all these touch points, we may still be missing some vital information that can inform how a medicine will impact the community in the real world.  Real-world data and real-world evidence are terms we are hearing more often in discussions about the regulation and approval of medicines.  So, what is meant by real-world data (RWD) and real-world evidence (RWE)? 

The MHRA suggests that real-world data is collected “while patients go about their regular lives” from various sources including their electronic health records, patient registries or wearable devices and is collected outside of a clinical trial situation.  Real-world evidence is the analysis of such data¹.  Often considered as complimentary to clinical trial data, some of the noted benefits include; the ability to capture data from people who may otherwise have been excluded from the clinical trial due to strict inclusion/exclusion criteria, the opportunity to include diversity of voice, capturing lived experience from populations who may not have engaged in a formal clinical trial and the inclusion of a far broader range of clinical settings and comparators/ standard of care².  

The inherent challenges associated with clinical development programmes in rare disease have certainly resulted in a huge interest in the use of RWE and it is unlikely that you will attend a conference about orphan medicines, rare diseases or access to medicines these days without hearing at least one keynote or panel discussion focused on how we can harness data derived from lived experience in RWE. 

Over recent years regulatory agencies have also clearly seen the value in RWE, with the FDA⁴, EMA⁵ and the MHRA¹ all producing guidance on its inclusion in regulation.  Its collection can span the full clinical development process and has the potential to inform discussions both pre and post marketing approval.  However, I think it would be a fair assessment to suggest that most RWE programmes still tend to land in the post marketing phase, which means that we are potentially missing that opportunity to “see effective medicines being approved more quickly or even see programmes which were previously thought to be unfeasible becoming feasible…”¹.  This is something that has clearly not gone unnoticed by the regulators themselves and at the start of this year, while researching opportunities for the use of RWE, I discovered the recent launch of a pilot programme- the MHRA Real-World Evidence Scientific Dialogue Programme. 

The MHRA have said this programme has been “designed to help innovators refine their evidence generation strategies” which will aid decision making across both regulatory and reimbursement processes⁶. 

My attention was immediately peaked, knowing that evidence generation strategies and methodologies have been an area of particular focus during conversations with industry colleagues in the past.  A reluctance to develop methodologies that may not have been accepted and a level of ambiguity about what was required are perhaps the main reasons behind the limited use of RWE in regulatory decisions.  Therefore, I am sure that many across the rare disease ecosystem are watching this pilot with great interest to understand how and if it can help to address the numerous challenges.

MHRA were accepting expressions of interest for the pilot programme between February and April this year, with those companies selected receiving notification in early May.  The programme was only open to medicinal products that would be regulated through the medicine’s pathway and excluded any product that was already under active regulatory procedures, such as-marketing authorisations, variations, major safety reviews or other statutory procedures. 

Applications were invited for medicines that met a range of criteria, many of which I believe have the potential to improve our understanding of how we use RWE in regulation for rare diseases.  I was particularly interested to note the inclusion of external control arm studies and pragmatic clinical trials as well as those using evidence generation relative to claims of both safety and effectiveness.  This certainly helps to address some of the barriers of not having randomised double-blind placebo-controlled trials, which are often very difficult to achieve in rare diseases due to both ethical and clinical constraints. 

Medicines meeting these criteria were then prioritised for selection based on a number of core criteria: it addresses a public health challenge that is aligned to government policy; it addresses an area of significant unmet need; it is a preventative medicines;  it is a medicine using an approach including genomic data, biomarkers or precision medicines and has methodologies that are considered innovative and that have the ability to advance knowledge in the field.

It seems that by creating this programme the MHRA hopes to be able to strengthen its approach to RWE by standardising methodologies and outlining practical examples that ensure the quality of data is aligned with its rigorous safety, efficacy and public health protection requirements.  It provides those companies selected with an opportunity to engage in strategic, confidential discussions that aim to clarify regulatory expectations in relation to data, analysis, and endpoints. What it also appears to offer, that many would argue has been lacking previously, is an opportunity to clarify and align these requirements to meet the needs of NICE, with joint reflective papers and workshops coming later in the year.  We will all be eagerly watching for the outcomes of these discussions to understand what RWE is required that will satisfy the needs of both stakeholders. 

Having the opportunity to get this right, early, has the potential to speed up patient access and remove some of the lengthy delays we sometimes see as companies try and address their data gaps for NICE.

As I write this article, there does not appear to be a published list of the medicines included in the pilot, there are no outcomes available and no tangible data to show whether the pilot is able to create a framework for future guidance.  However, I do feel hopeful that this pilot may provide opportunities in the future by demonstrating what can be done and how we can still make innovation available when the traditional approaches to clinical development are not always possible!

But for me, we are still missing a key piece of the puzzle.  As I said at the start of this piece, the unmet need and the patient voice is often what drives the innovation.  So many parents, advocates and patient support groups I speak to are driving forward some incredible research within their own communities, completely independent of any industry input.  They are driving technologies to support improved diagnosis, establishing registries and natural history models and even models to capture quality of life.  So, although they may not be directly linked to a product, these outcomes will certainly influence the sphere of RWE and may in the future impact on regulatory decisions. 

Therefore, I would have liked to have seen some specific engagement opportunities within this pilot for patient organisations.  They need to ensure their data could have maximum impact on decision making and their voice needs to be heard in these discussions.  There should have been a call through the MHRA public involvement team as part of the pilot to really include and incorporate their voice within this pilot.  As we advance our thinking on inclusion of lived experience, we must make sure they are active participants at the tale and not by standers looking on!

References
1. MHRA guidance on the use of real-world data in clinical studies to support regulatory decisions – GOV.UK
2. The Expanding Role of Real-World Evidence Trials in Health Care Decision Making – PMC
3. Overcome Rare Disease Drug Development Challenges with RWD | PPD
4. Advancing Real-World Evidence Program | FDA
5. Real-world evidence | European Medicines Agency (EMA)
6. MHRA Real-World Evidence Scientific Dialogue Programme – GOV.UK

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