Finally, the guidance really starts to address the broad range of issues that challenge clinical trials to be more diverse. I am struck by the opening paragraph of the cover letter that Dr. Hahn attached to the release of this guidance:
Throughout my career as a cancer doctor and medical researcher, I have been concerned about and have sought to address issues related to health care disparities. One important step that researchers and medical product sponsors can take to confront health care disparities is to make sure that clinical trials for medical products are more inclusive of multiple populations.
In addition, the guidance itself opens with these paragraphs:
Over the past few decades, FDA has promoted enrollment practices that would lead to clinical trials that better reflect the population most likely to use the drug if the drug is approved, primarily through broadening eligibility criteria.
Despite these efforts, challenges to participation in clinical trials remain, and certain groups continue to be underrepresented in many clinical trials. This guidance recommends approaches that sponsors of clinical trials intended to support a new drug application or a biologics license application can take to increase enrollment of underrepresented populations in their clinical trials.
This guidance considers both demographic characteristics of study populations (e.g., sex, race, ethnicity, age, location of residency) and non-demographic characteristics of populations (e.g., patients with organ dysfunction, comorbid conditions, disabilities, those at the extremes of the weight range, and populations with diseases or conditions with low prevalence). Enrolling participants with a wide range of baseline characteristics may create a study population that more accurately reflects the patients likely to take the drug if it is approved and allow assessment of the impact of those characteristics on the safety and effectiveness of the study drug.
Both openings express frustration over the lack of movement in increasing diversity in clinical trials. I have always wondered why the FDA does not just come out and tell industry that it must comply and do whatever it takes to enhance diversity in clinical trials. Then I came across this paragraph in this guidance:
In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
So, I have learned something – the must/should is not the FDA’s intent, it is simply to recommend. Sadly, unless a thing supports ROI the thing is not going to happen in the life sciences industry. This is the case with diversity in clinical trials or patient engagement in general. However, I think that COVID has changed that perspective. COVID has put the importance of diversity in clinical trials in the every day conversation of the general public, it’s in the media every day…the motivation, now, is different.
We have all become more aware about the need to enhance diversity in clinical trials as we realized COVID is hitting non-white populations harder for a variety of reasons. These populations are usually underrepresented in clinical trials so the alarm bells have been going off. If the clinical trials don’t enroll the people who represent the demographics of the people being hit the hardest then two things happen:
- The public will not trust that the clinical trial data
- The public will not take vaccines and therapeutics
I sat in on the FDA Vaccine and Related Advisory Committee meeting on October 22, 2020. All day there was testimony from groups representing the people who are usually underrepresented in clinical trials. All were insisting that the FDA require the vaccine makes ensure the clinical trials be more inclusive. I was disappointed that the Advisory Committee decided against making this mandatory as Moderna had shown it was making some effort to be more inclusive. Thinking to myself I wondered why the Board did not know that effort has ALWAYS been made and it has rarely been effective. As long as the clinical trial sponsor does not require the clinical research organization (CRO) to ensure the people enrolled in the trial is more diverse it is just never going to happen.
I am reminded all the time that clinical trials are about money and time – get the trial placed at a site quickly, get the trial enrolled quickly, get the data back quickly. Every day that data is delayed, therefore the drug is not on the market, can cost a company $1MM. The incentive is to move fast. In order to make clinical trials more diverse a different, slower process is required. The CRO must build relationships with sites other than the old reliable highly academic centers. The CRO must work with sites that are in the community, that are trusted by the people who live there. Any change in process will cost time and money, at first. Over time the relationships will grow and the process will become more efficient.
Overall, the guidance does lay out the value and processes to enhance diversity in clinical trials. It provides plenty of examples of how to lessen the burden of participation in clinical trials. The guidance lays out nicely the various demographics that need more emphasis such as women who are pregnant, children, people outside of weight guidelines The guidance suggest changes in approaches to inclusion/exclusion criteria. Specifically the guidance says:
Sponsors should enroll participants who reflect the characteristics of clinically relevant populations with regard to age, sex, race, and ethnicity. Inadequate participation and/or data analyses from clinically relevant populations can lead to insufficient information pertaining to medical product safety and effectiveness for product labeling.
Although the FDA will not make any guidance compulsory there is a line in the guidance that gives me hope:
Inclusion of racial and ethnic minorities in clinical trials and the analysis of clinical trial data by race and ethnicity. Differences in response to medical products (e.g., pharmacokinetics, efficacy, or safety) have been observed in racially and ethnically distinct subgroups of the US popoulation. These differences may be attributable to intrinsic factors (e.g. genetics, metabolism, eliminations), extrinsic factors (e.g., diet, environmental exposure, sociocultural issues), or interactions between these factors. Analyzing data on race and ethnicity may assist in identifying population-specific signals. Therefore, the FDA recommends that for drugs and biologics, sponsors include a plan for the inclusion of clinically relevant populations no later than the end of the Phase 2 meeting.
For emphasis, let me repeat that last sentence:
Therefore, the FDA recommends that for drugs and biologics, sponsors include a plan for the inclusion of clinically relevant populations no later than the end of the Phase 2 meeting.
If you are not aware, the sponsors routinely meet with the FDA during the course of a clinical trial. At these meetings there are discussions around FDA questions and concerns as well as those of the sponsor. All along the way the FDA can question the make-up of a population, the prevalence of the disease being studied. Now, the question can be asked “What is your plan to ensure the study population reflects the demographics of the eventual users?”. This is a BIG deal. As much as the FDA only recommends and there are no “shoulds”, sponsors work hard to comply with each and every guidance. With this recommendation I am hopeful that we will finally see change. As COVID has made plain, this change is not only the right thing to do, this change can positively effect the ROI. I look forward to supporting the life sciences industry as it complies with this guidance.
Just my thoughts,