Second Opinion: Trial Design Regulation is Coming – Are You Ready?

2023-02-23 |  Shrinivas Anikhindi

Welcome back to Second Opinion. 

Representation is a beautiful thing, and yet so often escapes recognition. In a world of seven billion, representation takes us from being unheard voices to being whole people who can create real change that affects so many. 

The healthcare industry was built by loud voices; by those who recognised what needed to be done, what needed to change, and making it happen for so many patients around the world. That being said, there are so many voices that remain unheard – in our industry, in our meeting rooms, and most crucially, in our clinical trials. 

Clinical trial cohorts which do not accurately reflect the demographics of the diseases they are working to solve means that we are creating medicines which do not effectively treat broad groups of patients. In fact, this lack of diversity in clinical trials may even harm patients in the long term.

Recognising the risks of low clinical diversity, clinical authorities around the world are now bringing about regulations which focus on how trials are designed, with an aim to promote clinical diversity. First up among them is an upcoming regulation from the FDA. 

Stick around to read about why clinical trial diversity is so important, and what the FDA and other authorities are doing to jumpstart it.

I also got to sit down with the author of this piece, Amy Hannaford to dig deeper into why we’re talking about clinical trial diversity – and why we should be optimistic about this trend. Look out for that next week on our usual channels via Spotify, Apple and Soundcloud!


Clinical trial diversity has been a growing priority within the pharma industry over the last three decades. We have reached the point where every pharma organisation needs to start acting now, making their commitments to clinical trial diversity a reality. 

Attempts by sponsors to improve clinical trial diversity over the years have often fallen short of having the impact that the industry had hoped for. To some extent, there has been a belief within the industry that this is a broader societal problem that pharma cannot solve, or in some cases, that addressing diversity in clinical development will result in costlier, slower trials.

This misconception highlights the need for an industry-wide shift in mindset, as it ignores the significant value that improved clinical trial diversity delivers not only for patients and society, but for business and for science. You can read more on this here.

What is the FDA doing to promote clinical trial diversity?

The FDA has been issuing comprehensive guidance for sponsors to improve clinical trial diversity, where diversity is defined by recruiting trial cohorts that accurately reflect the populations who will use the drug. In more recent years, this guidance has outlined expectations for collecting race and ethnicity data, as well as recommendations to increase the enrollment of underrepresented groups.

However, the industry has failed to make the level of changes that the FDA is looking for. As a result, in April 2022, the FDA issued draft guidance on the creation of diversity plans, recommending that sponsors demonstrate evidence that they have considered the real-world disease population and have rendered their strategies to recruit underrepresented populations into a concrete plan. 

The FDA has also gone one step further. On 29th December 2022, the FDA was granted a “new set of teeth” by Congress to move the creation of a Diversity Action Plan from a recommendation to a ‘regulatory requirement’. 

The key implication of the new legislation is that sponsors will have to submit Diversity Action Plans (DAP) for all Phase III and other pivotal studies, including device studies and paediatric studies. This requirement will take effect 180 days after the FDA has finalised the guidance.

Although many organisations have already started developing diversity plans in line with the draft guidance, there are still many questions to be answered. 

What questions do we need to answer for a comprehensive DAP?

  • Who needs to be involved? 
  • When do we start the DAP and how long does it take? 
  • What targets do we set? Do we do this for every study? 
  • When are there exceptions? 
  • How do we monitor against targets and when do we need to update the plan?

What should the Diversity Action Plan comprise?

Finalisation of the FDA guidance should help answer many of these questions, but from industry experience to date, there are five key things that need to be considered when approaching a Diversity Action Plan (DAP):

  1. A DAP should be the culmination of clinical trial diversity considerations from a number of preceding clinical development processes and documents, such as the epidemiology report and the protocol
  2. In this vein, diversity and the content of the DAP should be considered early in clinical trial development, embedded into key governance and planning meetings
  3. The DAP requires cross-functional collaboration from stakeholders across the clinical development process. It may well highlight broader challenges in this process, such as a lack of cross-functional input into study design, especially from an operational perspective
  4. It starts with the data – because connecting epidemiology to enrolment goals is key, but so is the real-world situation; sponsors should consider behavioural and sociological patient insights, such as access to healthcare
  5. And ends with the data, as sponsors must have a plan to proactively monitor the enrolment targets set out in the DAP and pivot recruitment tactics accordingly

Ensuring your organisation is set up to create Diversity Action Plans, and indeed to actually deliver on these plans, may require a lot of internal change.

However, it’s important to remember that as an industry, we are on this journey together. There will be much to learn from continued engagement with the FDA, and shared experience across organisations as sponsors monitor the impact of their actions to improve clinical trial diversity.


Aside from the FDA, other regulatory bodies are also building strategies to promote diversity in clinical trials. The new European Medicines Agency’s (EMA) directive on clinical trials (536/2014), which took effect in January 2022, mentions that participants should reflect the population likely to use the medicinal product.

Meanwhile, in the UK, the Medicines and Healthcare products Regulatory (MHRA) conducted a public consultation in January 2022 with questions relating to the legislative requirement for diversity of participants. While the outcomes of this consultation have not yet been published, they could have the potential to reframe the UK legislation for clinical trials. The UK government has also recently published the Women’s Health Strategy for England, which includes a commitment for new research and data on gender in clinical trials.

In addition to these countries, Canada and Australia have also taken some steps towards promoting greater diversity in clinical trials. In Australia, health service organisations with a clinical trial service must conform to NSQS standards that require them to identify the diversity of their consumers and any patients at high risk of harm, and incorporate this information into the planning and delivery of care. In addition, sponsors in Canada putting forward a new drug submission containing clinical data are required to answer a questionnaire on whether data is disaggregated by sex, age and race or ethnicity.

Despite these efforts, there are discrepancies with clinical trial diversity regulations in different countries and regions. Other countries researched, including China, Japan and Brazil, do not appear to have any initiatives or regulations aimed at promoting diversity in clinical trials.

And while there is growing recognition of the importance of diversity, as well as an increasing number of global regulations aimed at promoting this, there is still a long way to go. In a recent analysis of 35 cardiometabolic drugs between 2008 and 2017, women represented only 36% of the 290,000 participants, yet women account for 51% of the US population.

There are also discrepancies between race and global population levels in clinical trials. In a 2020 analysis of around 290,000 participants in clinical trials globally, 76% were white, 11% were Asian, and only 7% were Black. In comparison, the global population is composed of around 60% of the population in Asia, 16% in Africa, 10 % in Europe and around 8% in Latin America.

Addressing this gap will require a collaboration between the industry, regulatory bodies, patient advocacy groups and other stakeholders.


As differences in genetic, cultural, socioeconomic, and environmental factors influence heterogeneity in drug responses, underrepresentation of specific subpopulations can lead to suboptimal efficacy and adverse effect profiles, which are not accounted for in clinical trials.

Specific subpopulations are known to be at higher risk of some diseases, yet they continue to face severe underrepresentation in clinical trials. In turn, this can lead to poorer drug responses and higher deaths among these groups.

An example of this is the racial disparity in drug responses to albuterol, the most commonly prescribed asthma medication in the world. Puerto Rican and African American children have the highest prevalence of asthma in the US but respond the least well to this life-saving drug. This can primarily be attributed to the inapplicability of trial findings to these minority groups, as 95% of lung disease studies are comprised mostly of European-descent participants. This issue is also apparent in older populations, where, for example, individuals aged >70 years represent only 13% of oncology trial participants, despite comprising approximately 50% of cancer patients.

Instances of suboptimal dosing being prescribed to ethnic minorities due to underrepresentation is manifold. For example, as of May 2020, of the 191 pharmacogenomic studies focused on improving dosing algorithms for warfarin patients, only 24% and 18% of the algorithms were applicable to Black and Mixed/Other populations respectively, due to less than 5% of trial participants being from these populations. This in turn led to poorer drug responses in African Americans. 

Similar repercussions were seen with Bristol-Myers Squibb and Sanofi-Adventis U.S. LLC’s clopidogrel. The drug had little to no effect on an estimated 30% of Hawaii’s population due to 75% of Pacific Islanders having a genetic trait that makes them poor responders. This led to two lawsuits being filed against the companies; the first in 2015 by the Hawaiian state attorney general who sued for false, unfair, and deceptive marketing, and the second in 2016 by the Attorney General of New Mexico.

While representation of women in trials is progressing, women from ethnic minorities continue to face underrepresentation. Furthermore, a ‘domino effect’ of severe adverse event profiles in women has resulted from biases towards male representation in pre-2000 and other early trials. This issue was brought to life from a 2001 official audit of medicines from the American market, which disclosed that 80% of the medicines posed a greater risk of adverse events for women than men.

While some pharma companies have started addressing the lack of diversity in clinical trials to avoid the devastating consequences of ignoring this, we will soon see all regulatory bodies get on board to collaborate and hold our industry accountable to ensure all populations are represented and treated equally. 

Are you ready for the changes this will bring?

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