30-31 - CLINICAL TRIALS: The human condition

The clinical research industry is increasingly prioritising diversity in clinical trials, though it has been a slow process over decades of regulatory guidance, with the latest from the FDA in April 2022.

Despite the increased attention from regulators, diverse patient populations are still underrepresented in rare disease clinical trials – to the detriment of the patients and the research. For many rare disease patients, clinical trials are their only access to potentially meaningful therapies because only about 5% of the known rare diseases have approved treatments.

Broadly speaking, rare disease clinical research faces compounding barriers to achieving diversity in trials. We map these systemic barriers across four key levels: disease strategy, protocol, trial site and always the most critical level – the patient. There are various steps that sponsors, CROs, sites and patient advocacy organisations can take to drive progress toward representative trial populations.

Historically, sponsors and CROs have shaped clinical trials. How can we reshape them with more human and patient-centric approaches to increase interest, trust and motivation for participation? These conversations inspire innovation in the way we approach and achieve diversity in clinical trials. With a patient-centric approach, the first step to achieving diversity is accessibility, followed by inclusion.

In recent discussions with sponsor, CRO, consultancy and patient advocacy organisation representatives in our Rare Disease Week webinar series, these stakeholders yielded a key question – how do we make rare disease clinical trials more human?

The first step towards diversity is accessibility, but accessibility is a big word in more ways than one. When we talk about accessibility in clinical trials, we often start the conversation talking about the location or the physical accessibility of the site.

Geographic location is a known barrier for diversity that compounds time and financial limitations for many patients, and we know that most of the world isn’t built for people with differing abilities – but accessibility is more than creating access by removing physical barriers.

When we talk about accessibility for clinical trials, we must start from the patient’s perspective to identify and dismantle as many of the invisible, social and cultural gates that would keep them from participating.

Translation services is a key component of more accessible trial design. Patients rely on sponsors and sites to communicate critical information to them regarding the investigational treatment being studied, the requirements of the clinical trial and how it will fit into their healthcare options. This information must be accessible in terms of:

Language and dialect – consider the vast differentiation between regional dialects and the way meaning is ascribed to certain words or phrases
Cultural translation – ensure conceptual equivalency that simple language-to-language translations don’t
Health literacy – the relative degree of complexity should accommodate a determined community baseline of health literacy
Mediums for transmission – the ways in which patients can receive this information and their ability to share it with their families and support systems
Different ability – for example, low-vision or hearing considerations.
Patients want access to more information, including the trial’s inclusion/exclusion criteria, to enable their decision-making. People don’t operate in a vacuum. Many people will want to take this information to their families to discuss the nuances of participation and how they can factor the trial into their daily lives.
This may especially be true for underserved and underrepresented communities with a historic distrust of the medical system that will want to consult with their loved ones.

The onus for accessible communication rests on sponsors and CRO partners to adapt to patient needs and go beyond the minimum requirements. CROs and sponsors can assist sites to overcome the barriers that would limit their ability to engage, inform and build trust in a clinical trial among patient populations.

Increasing diversity requires approaching outreach as relationship-building, developing trust within communities and offering value. Clinical research is beginning to adopt more of the public health model of community-based outreach, building mutually beneficial relationships to establish sustainability.

We must be willing to support patients through the process, and that starts at a community level. In collaboration with patient advocacy organisations and CROs, sponsors can identify the appropriate communities to approach, then provide information about not only the clinical trial, but about the disease itself.

This would emerge from sponsoring local organisations and events, attending those events as public health communicators, thereby fostering relationships and giving as well as receiving information.

Unfortunately, many patients go through a trial and are left asking what’s next. As clinical researchers, our patients provide invaluable data, which leads to potential breakthroughs and new therapies. However, after we get the data, patients may be met with silence during the analysis phase.

We can do more to support patients by maintaining our relationships, encouraging trust and leaving communities better off after each trial by working with patient advocacy organisations (PAOs) to continue support. A constructive initiative, that has the potential to benefit sponsors and patients both, would be to examine how we can best communicate with and engage the patients, via PAOs, in the data interpretation stage of clinical trials.

Rare disease is heterogeneous. Most of them, 80%, have a genetic cause. This means genetic testing is a primary gateway to proper diagnosis. Yet the critical genetic testing relies on genomic databases that are 80% white European ancestry, 10% Asian ancestry, 2% African ancestry and <2% of other ethnicities. This significant data gap creates blind spots in identifying pathogenic genetic variants in non-white populations, making diagnosis even more difficult. Data needs to diversify in other areas, as well.

Traditionally, clinical trials have been restrictively homogeneous in the pursuit of good, clean data. This perspective on objective data discouraged inclusion of diverse populations and often excluded the sickest patients that need those therapies the most.

We know, however, that disease doesn’t exist in silos. The variability that is inherent in the manifestations of rare disease across patients is a core feature of many conditions. It is worthwhile to recognise that, in rare disease indications, the patients who will be receiving that treatment post-approval, in the ‘real world’, are the very same population who are studied in phase 2/3 trials.

We are rewriting the definition of good data to be more diverse and include elements such as ethnicity, socioeconomic status, sexual orientation and gender identity and levels of ability that allow us to account for social determinants of health, comorbidities and concordance of disease.

Traditional outcome measures supported by regulators are site-centric, requiring patients to attend in-person visits, which exacerbates geographical barriers to achieving diverse trial populations.

As an industry, we are often trying to squeeze a proverbially square endpoint measure into a round trial, leading to restrictive inclusion/exclusion criteria to compensate for measures that are not designed for sensitivity to the rare disease being studied.

Developing bespoke outcome measures is possible with input from patient communities – helping define the ways diseases manifest within specific groups. Novel endpoints require robust disease natural history data and entail significant investments and risks for sponsors who bring them to regulators for review and potential validation.

Although there is risk in defining new outcomes and endpoints, there is also opportunity to develop measures that matter more to the patients and are more relevant to the trial.

Working together, we are shifting our perspectives and approach to be part of the solution to bring meaningful therapies to the diverse communities affected by rare disease.

We are engaging in these discussions across the industry and sharing tools like the RARE-X DE&I metrics toolkit for PAOs or the ‘What to ask when you’re interested in a clinical trial: A guide for rare disease patients and families’ that we developed with our Rare Disease Advisory Council.

There is no one right way to achieve diversity in clinical trials, and best practices are still being pressure-tested. But it is imperative that we continue to innovate and improve our approaches.

Through important conversations with stakeholders at every level, we are repositioning the people and patients at the heart of our diversity efforts and rethinking how we create accessible, inclusive trials for everyone.

The human condition

Access all areas

Translation and transparency

Reaching out

Good data paradigm

Outcome measures

More human