Drug developers and their research partners aim to achieve diverse patient populations in their clinical studies. The US Food and Drug Administration (FDA) has demonstrated an interest in supporting this goal, offering resources like the guidance Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices and Trial Design.
Still, achieving acceptable diversity and equity in their trials is something sites and sponsors continue to struggle with. Outsourcing-Pharma (OSP) recently discussed with Verantos CEO Dan Riskin (DR) about how his firm, which specializes in real-world evidence (RWE) generation, helps its pharma and biotech firms harness the power of RWE and other tools to increase trial diversity, and why it’s important.
OSP: Please share some of the reasons why diversity and inclusion are important in trials.
DR: By design, randomized clinical trials (RCTs) tend to include healthier and wealthier patients and exclude some patient sub-groups, often biased by race, ethnicity, age, gender, socio-economic status, and specific comorbidities. This means that the final RCT results will not adequately represent how the new therapy is likely to perform among diverse sub-groups in the real world. For example, many treatments require intensive patient engagement, such as daily visits to a hospital.
Others are relatively low intensity, such as an oral medication. An RCT may demonstrate that high-intensity therapy is more effective than low-intensity therapy; however, patients who do not have access to a car, need to work, or are homeless may come to only a fraction of their appointments. It seems likely that, for example, a high-intensity cancer treatment that has a 10% benefit in an RCT over less intensive treatment may be less effective than the low-intensity cancer treatment for patients with limited healthcare access.
These gaps in knowledge impact prescribing practices, which undermines the patients’ ability to access the most appropriate therapy option. This is especially true in a therapeutic category for which there may be several competing therapy options.
OSP: Why are RCTs currently not built to be as diverse/inclusive as they should be?
DR: RCTs are the gold standard for demonstrating safety and efficacy of therapies and vaccines. The RCT results define the drug’s label indications and influence the standard of care; however, RCTs cannot adequately do so in all patients as they use strict inclusion and exclusion criteria as part of the study protocol to optimize the cohort of trial participants.
OSP: Could you please share your perspective on what efforts to broaden the diversity of a trial’s patient population typically look like, and how they fall short?
DR: Pharmaceutical firms have recently begun sponsoring studies that aim to improve diversity and equity during trial enrollment. This is driven, in part, by payers and prescribers asking for more evidence of effectiveness and knowledge of which patients benefit most from a particular therapy.
These efforts usually involve adding a small number of targeted patients. While this is a step in the right direction, it will often not yield statistically significant insights. Moreover, the cost and logistics make it impractical to massively expand the size and scope of RCTs to include every potential patient subpopulation.
OSP: What are some of the problems associated with RCTs that you feel RWE can help solve?
DR: RWE, which meets patients where they receive routine care, can help close the gaps in understanding and support more equitable healthcare. RWE can help drug sponsors to develop broader insights related to the clinical and safety impact of a given therapy within specific patient subgroups that may have been underrepresented in the original RCT.
Additionally, they provide insight into outcomes in real-world scenarios, where the high level of structure and patient support found in RCTs may not be available. Pharmaceutical companies can analyze and model real-world data that is gathered during actual healthcare delivery from such sources as EHR structured data, EHR unstructured data, claims data, patient-reported outcomes and more. RWE helps create data-driven insights beyond RCT constraints.
OSP: What other technologies can be harnessed to increase trial diversity/inclusivity?
DR: Verantos specializes in designing studies that can yield clinically relevant insights that can be used with confidence to influence decisions at the point of care. RWE studies should be designed and conducted with the same level of scientific rigor as RCTs. We leverage data science and artificial intelligence along with advanced data sources, such as EHR unstructured data, to generate research-grade RWE capable of supporting clinical assertions.
Inaccurate, incomplete or “bad” data allowed into regulatory or reimbursement pathways can have unintended and dangerous consequences. It is our obligation as an industry to ensure fit-for-purpose data and fit-for-purpose design.
Data validity including accuracy measurement, should be viewed as a necessary element. This is particularly true when looking at underrepresented populations, or patients that may have less complete care and documentation, such as seen in routine care delivery.
OSP: Is there anything you’d like to add not touched upon above?
DR: Research-grade RWE can not only help close diversity and equity gaps, support precision medicine and improve outcomes, but also inform negotiations related to formulary placement, drug pricing and reimbursement. For example, when RWE studies can demonstrate clinical advantages among particular patient sub-groups, that information can be used to negotiate more favorable terms during the commercialization effort; such business outcomes can help the pharmaceutical company to support preferential data-driven prescribing for patients in those groups, differentiating the therapy in a crowded field and increasing market share. In these ways, incentives can align with patients, payers, and pharmaceutical firms all benefiting from high-quality, personalized RWE.
OSP: How does the FDA guidance document on diversity in trials help sites and sponsors? What content do you think is most helpful, and do you think there are areas the document could add to?
DR: FDA guidance is an excellent step to address this critical challenge. But, as mentioned in the guidance, despite decades of efforts to increase diversity in RCTs, “challenges to participation in clinical trials remain, and certain groups continue to be underrepresented in many clinical trials.”
Given that structural barriers in the RCT system make diversity so difficult to achieve, it’s worth expanding the perspective to see what other approaches can provide insight into underrepresented subgroups. The FDA is already making progress toward this goal by applying significant resources and attention to alternative evidence sources such as RWE.