In many clinical trials, sponsors and investigators struggle with the development of study eligibility criteria.
From a purely scientific perspective, the instinct is toward making the study population narrow enough to eliminate the presence of factors that can confound the assessment of study outcomes (excluding participants with co-morbidities, concomitant medications, complicated medical histories) so that the very specific study question can be answered as cleanly and confidently as possible and internal validity of the study is maximized.
However, in order to make the study results as useful as possible, the results need to be generalizable to a patient population that exists in the real world- a population that has other illnesses, takes other medicines, and is likely more diverse in many ways than the study population- which means that the study has external validity.
Importantly, our study populations often have less ethnic and racial diversity than patient populations. For years, we’ve seen that clinical trial study populations differ from actual patient populations in significant ways, but at the same time, we want to design studies where the population is consistent enough that we can actually identify and measure the effects of study interventions. In the last couple of years, the FDA and other research stakeholders have started to make concrete efforts to address these issues.
On July 12, the FDA released the report of their April 2018 public workshop on Evaluating Inclusion and Exclusion Criteria in Clinical Trials. In this concise 12-page report, the FDA briefly reviews the history of these study design challenges and prior efforts to address them. The body of the report includes three main sections.
In the first, FDA discusses specific patient groups (including those with organ dysfunction, multiple illnesses, older adults, children, pregnant women) and how eligibility criteria can be reconsidered to expand the possibility for those groups to participate in research when it is safe for them to do so.
The next section addresses barriers to enrollment which are separate from protocol eligibility criteria, such as geography, financial burdens, and historical mistrust of research.
The third section proposes specific strategies to re-examine eligibility criteria for each study and ensure that each is scientifically and ethically justified, as well as suggesting consideration of alternative study designs to allow broader population access.
The research community has often cited the low number of patients who participate in clinical trials, and has been frustrated by enrolment challenges in studies. Creative and focused thinking about what sponsors, researchers and IRBs can do to look carefully at protocols and study processes to address eligibility issues and study barriers is going to be essential as we move forward together.