Clinical Trial Diversity: How to get to the finish line?

We cannot seem to get off the starting grid

Increasing the diversity of trial participants is one of those challenges that still haunts clinical research. For decades, the research community has recognised the importance of ensuring that clinical trial populations actually reflect the populations that will ultimately use a medicine. For example, already in 1993, the NIH Revitalisation Act included guidelines for the inclusion of women and minorities in clinical research.[1]

However, the progress to achieving more representative trial populations has been modest. Still today in the US, Black and Hispanic patients only make up 2-16% of clinical trials depending on the phase of the trial and the disease it is in, although representing 33% of the population.[2]

Hispanics are almost twice as likely to never have heard of a clinical trial compared to non-Hispanic Whites.[3]

Women are 51% of the population in the US, but are only 30% of the clinical trial participants.[4]  

The lack of progress has not been for a lack of trying. The FDA has released guidance over the years, trying to nudge sponsors and research organisations to take diversity seriously within their trials. First, guidance on Collection of Race and Ethnicity Data in Clinical Trials.[5] Then the guidance on Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs.[6] And now most recently the draft guidance that Congress asked FDA to turn into actual regulatory requirement, Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials.[7]

Sponsors have certainly tried. Although, when faced with the perceived risk of delaying a clinical trial or making it more expensive to run, the efforts may have been somewhat diluted. In fact, most initiatives seem to have focused on site-level tactics to drive increased recruitment of underrepresented groups. When these initiatives are analysed considering the academic research on barriers to trial participation, it is perhaps not surprising that they fail to more fundamentally move the needle.

Through our own research and literature review, the barriers cited for underrepresented groups to participate in trials fall in five broad categories that in different ways accentuate each other:

1. Bias which is inherent amongst many healthcare professionals and implicit within in different processes used to design and run a trial (e.g. it is quite common that lack of English proficiency is an exclusion criteria)
2. Experience patients have had previously in the encounters with the healthcare system and the trust (or lack thereof) that they may feel as a result
3. The complexity of the participation process and that underrepresented groups often are not reached by general information about clinical trials (e.g. lack of knowledge of clinical trials is significantly more pervasive in ethnic minority groups)[8]
4. Logistical and socio-economic barriers are also common, such as distance to trial site and the direct (e.g. transportation) and indirect (time out of work) costs of participating
5. Socio-cultural context of different groups can also in some instances be important

To really address these, pharma companies will likely need to take a different approach to their programs all together.

In the words of the CTTI, the public-private collaboration between the FDA and Duke University: “Research organizations must make systemic changes to how clinical trials are envisioned & implemented to achieve sustainable support for diversity”[9]

A clear case for firing off on all cylinders

The rationale for investing into improving clinical trial diversity is quite clear for a pharma company. Besides the obvious point that this is the right thing to do for patients and society at large, it is also scientifically sound. You will not be able to extrapolate the safety and efficacy of your treatment unless your study population is representative of the actual patients that will take the medicine.

For the more business-minded, there is also a clear commercial rationale. There are multiple examples of treatments that have had to be pulled from the market or ended up with limited or uncompetitive labels, because of ignoring the correlation between mode of action and ethnical or racial biomarkers.

Finally, and perhaps most topically, taking tangible actions to address inclusion of underrepresented populations and arguing for why these actions are the right ones, is now a regulatory requirement.

So why are we not getting to the finish line?

If the scientific, commercial and regulatory rationale is clear, why have we as an industry not been able to adequately address trial diversity?

From our work supporting companies to prepare for FDA guidance on diversity and building the operational capability to improve diversity in their trials, we see three main obstacles to why we are not getting to the finish line.

1. Building in restrictions into the design of the trial
2. Not engaging the right sites or the right investigators
3. Not having the right governance or funding mechanisms to enable real transformation

Using the analogy of a race car, we have a great vehicle, but we are only driving it in first gear. We don’t leverage the whole track, but rather spin around on a small part of it. And we don’t have enough gas in the tank to make it the whole way.

Driving only in first gear: Building in restrictions into the design

The challenge to clinical trial diversity is partly a design problem. It is difficult to achieve more diversity than the protocol ‘allows’.

One example is the way that inclusion/exclusion criteria might inadvertently limit the participation of different underrepresented groups. We have seen this in different clients where certain criteria are consistently used in all the protocols and almost seemed to be included out of habit. One such common criteria which explicitly introduce investigator judgement, instructing them to exclude patients that are deemed likely to be 'non-compliant.' This might seem reasonable, but in fact it opens up for investigator biases and preconceived ideas.

Another example is how metrics and KPIs are used within the protocol. Often the sponsor has the ambition to recruit underrepresented populations, but investigators feel hamstrung as the protocol may not specify this at all or does not provide clear targets for the sites. When this is the case, unsurprisingly, recruitment tends to be done with patients that the investigators feel would be the ‘easiest’.

Driving on a quarter of the circuit: Not having the right sites or the right investigators

Even if the study or programme design is fit-for-purpose for diversity, there are often limitations in what the sites and investigators actually are able to achieve. Many companies return to sites they have used in the past and there is sometimes a general reticence to using investigators with little or no clinical trial experience.

Another related challenge can be that site-facing colleagues are not confident enough to discuss diversity with the sites. Understandably, this can be a tricky topic to breach with a site, especially if the site is not performing as expected in terms of recruiting patients from underrepresented groups.

We have also seen that internal processes and systems are often not set up to support more decentralised approaches.

It is also worth noting that reaching underrepresented patient populations is not always easy and socio-economic barriers can often be very tangible, requiring more infrastructure and capability in the site. Therefore, the answer is not always, unambiguously smaller, more community-based sites.

Another related challenge can be that site-facing colleagues are not confident enough to discuss diversity with the sites. Understandably, this can be a tricky topic to breach with a site, especially if the site is not performing as expected in terms of recruiting patients from underrepresented groups.

There can be many reasons for this, but it usually boils down either lack of training/skills in having the conversation in the correct way or lack of ability to offer support once the discussion has been had. Understanding the root-cause here is important to be able to address the right issue.

Driving with half a tank of gas: Not having the right governance or funding mechanisms to enable real transformation

The final obstacle is that lack of appropriate governance or funding mechanisms to ensure that the objectives and execution of a trial, align to a clear strategic vision for ensuring diversity.

It is not uncommon that tactics are left for study teams to develop and implement, resulting in transactional, short-term and small-scale trial. In a number of occasions, we have seen that tactics are left for study teams to develop and implement, which means that they often end up transactional, short-term and small-scale.

Instead, the more successful companies seek to create mechanisms that allow study-requirements to be met through thoughtful, strategic external engagement and cross-therapeutic area interventions.  

Becoming the Formula One of clinical trial diversity

Continuing the analogy of the race car – how can we, not just get to the finish line, but become the Formula One of clinical trial diversity?

Through extensive research, comparisons of different frameworks already developed and conversations with Subject Matter Experts across the industry, we have developed a maturity framework that can help organisation understand where and how to improve their capabilities.

Diversity touches upon several fundamental components across the clinical development process. That said, it is important to recognise that diversity is not the only challenge a company is facing when designing, standing up and executing a clinical trial.

Therefore, the framework needed to strike a balance between being comprehensive enough to have an impact and being concrete enough to drive action.

The framework describes five critical capabilities:

1. Vision & strategy: Have an enterprise-wide vision, and clear set of ambitions, route to success, and accountability
2. Stakeholder engagement: Build credibility with the external ecosystem through non-transactional, long-term & sustained engagement 
3. Design & targeting: Design studies and programmes that target the right patients
4. Planning & delivery: Operationalise the design for the right patients
5. Governance: Establishing the right oversight and accountability at all levels
6. Measurement: Capture the right data and have feedback loops and mechanisms in place to learn from our progress.

The maturity framework is accompanied by a survey-based tool to assess the maturity across the dimensions of each capability. 

Using this maturity framework allows you to identify clearly the objective for diversity and the roadmap to getting there. With clear actionable insights on where to spend time and focus, you will be able to bring teams together and overcome silos to collaborate more effectively.

PEN is helping create the next generation pharma companies

At PEN, we are helping our clients reimagine how they engage with their patients and partners in healthcare to provide better outcomes and experiences.

If you are interested in learning more, please reach out to

Magnus Franzen (magnus.franzen@penpartnership.com)

Amy Hannahford (amy.hannaford@penpartnership.com)

Joice Lana (joice.lana@penpartnership.com)

[1] NIH, Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical Research (access here)

[2] ASCO, Enrollment of Racial Minorities in Clinical Trials: Old Problem Assumes New Urgency in the Age of Immunotherapy (access here)

[3] Deloitte, Broadening clinical trial participation to improve health equity (access here)

[4] NIH website, Diversity and Inclusion in Clinical Trials (access here)

[5] FDA 2016, https://www.fda.gov/media/75453/download

[6] FDA 2020, https://www.fda.gov/media/127712/download

[7] FDA 2022, https://www.fda.gov/media/157635/download

[8] Deloitte (access here)

[9] CTTI (access here)