Mind the Gap: EMA Guidance on Diversity in Clinical Trials
Overview of Relevant Guidance
Demonstrating its commitment to aligning global standards in clinical trials, the European Medicines Agency (EMA) has adopted three International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines that are particularly relevant to diversity in clinical trials. The adopted guidelines include ICH E5, focusing on Ethnic Factors in the Acceptability of Foreign Clinical Data; ICH E17, emphasizing Multi-Regional Clinical Trials; and ICH E8(R1), addressing General Considerations for Clinical Trials. Alongside these ICH guidelines, the EMA has adopted EU Clinical Trial Regulation No 536/2014 which is designed to facilitate and optimize the efficiency of clinical trials within the European Union, fostering a uniform and transparent approach to the execution of clinical research.
Countries within the EU may have their own individual diversity regulations in addition to those endorsed by the EMA. However, Germany and France have indicated that they will be following the EMA’s lead in this area.
What the Guidance Says
The EMA guidance that is most relevant for diversity in clinical trials is also the most recently implemented: ICH E8(R1) and EU Clinical Trial Regulation No 536/2014. This newsletter will focus on these two documents.
ICH E8(R1)
ICH E8(R1) came into effect in April 2022, and it identifies four specific groups that deserve special consideration in clinical trial planning:
Pregnant individuals
Lactating individuals
Pediatric populations
Geriatric populations
Outside of these groups, there is limited mention of other populations that deserve additional consideration. This may be because which groups are under-represented likely vary across countries within the EU.
Notably, the adopted guideline does emphasize the importance of engaging patients and other stakeholders in trial design. While this does not necessarily impact diversity in clinical trials, the involvement of patients and other stakeholders may lead to improvements in participant representativeness.
EU Clinical Trial Regulation No 536/2014
The EU Clinical Trial Regulation No 536/2014 was passed in 2014, but it was not applied until January 2022. The regulation’s application depended on the development of a fully functional online portal and database for the EU clinical trials. This portal, called the Clinical Trials Information System, went live on January 31, 2022, and then the regulation was applied.
Regulation No 536/2014 is a significant regulatory framework designed to enhance and streamline the conduct of clinical trials within the European Union. One notable aspect of this regulation is its attention to addressing the representation of underrepresented populations in clinical trials. Recognizing the importance of diversity in trial participants, the regulation emphasizes the need for inclusive enrollment strategies to ensure that the study population is reflective of the broader patient demographic. This approach is vital for generating robust and generalizable data that accurately represents the safety and efficacy of medicinal products across various population groups. By explicitly highlighting the importance of including underrepresented populations, the regulation aims to improve the overall validity and applicability of clinical trial results, contributing to more informed and equitable healthcare decisions. In addition to the four population groups highlighted in the ICH E8(R1) guidance, Regulation No 536/2014 outlines specific considerations for trials with incapacitated subjects.
Importantly, the regulation doesn’t just highlight the need for representative clinical trials, it goes one step further and requires trial sponsors to justify non-representative samples:
“Unless otherwise justified in the protocol, the subjects participating in a clinical trial should represent the population groups, for example gender and age groups, that are likely to use the medicinal product investigated in the clinical trial”
Furthermore, the regulation requires sponsors to justify non-inclusion. That is to say, that trial sponsors must justify study exclusion criteria that may limit the representativeness of the clinical trial.
The regulation also improves transparency by requiring trial sponsors to make available trial results stratified by age and gender.
EMA Guidance Has Significant Gaps and How it Will be Enforced is Unknown
Although these are important steps forward, the EMA’s adopted guidelines and regulation has some important gaps. Specifically, while the EMA regulation says that trials should represent the population groups that are likely to use the medicinal product, aside from age and gender, it does not indicate what other sociodemographic characteristics should be considered. Furthermore, unlike the FDA guidance, the EMA does not provide direction on how relevant sociodemographic characteristics should be identified. Without these components, it is difficult to know how these regulations will be enforced and to what degree.
Similarly, the regulation requires justification for non-representative samples and for non-inclusion, but the EMA does not provide any insight as to what would be considered adequate justification, and how this may vary by trial phase. The ICH E8(R1) guidance, which was adopted more recently, states that:
“As more information is known about the drug, clinical studies may expand in size and duration, may include more diverse study populations, and may include more secondary endpoints in addition to the primary measures of efficacy.”
suggesting that representativeness of trials can vary with trial phase, with earlier trials being less representative, in line with current practice.
For these regulations to meaningfully improve diversity in clinical trials, the EMA will need to operationalize “representativeness” and provide details on what constitute acceptable justifications for non-representativeness and non-inclusion.