Total Diversity Clinical Trial Management (TOTAL, Dallas Texas) supports efforts to bring all aspects of Diversity into the management of clinical research trials and appreciates the opportunity to provide comments on the Food and Drug Administration (USA FDA) Draft Guidance on recommendations to sponsors about the development and submission of Race and Ethnicity Diversity Plans for clinical trials.
In general, TOTAL supports planned approaches to recruitment, enrollment, and retention of diverse subject populations for clinical research trials that will augment evidence-based understanding of safety and efficacy of new therapeutics.
Specifically in relation to the agency’s Draft Guidance:
- We support FDA’s proposed evidence-based approach to determining whether a detailed Race and Ethnicity Diversity Plan is needed for a clinical research study;
- We have comments relating to the importance of Clinical Sites as key implementers for achieving operational effectiveness of Diversity Plans in clinical study populations.
1.0 TOTAL Diversity Clinical Trial Management.
TOTAL Diversity Clinical Trial Management (TOTAL) is a full-service clinical research and Diversity organization, providing industry services for drug and device Sponsors. TOTAL has teams for clinical site management and global patient recruitment, enrollment, and retention services, all of which emphasize Diversity across the clinical study lifecycle.
2.0 Comments on the Draft Guidance
2.1 FDA’s Evidence-Driven Approach to Race and Ethnicity Diversity Plans.
TOTAL supports with the approach expressed in the Draft Guidance for the need for evidence that indicates a particular investigational medical product may perform differently across a target population.
- 176-178: “…the Plan should begin with an assessment of any data that may indicate the potential for a medical product to have differential safety or effectiveness associated with race or ethnicity.”
- 196-199: “When there are data that indicate that the medical product may perform differentially across the population based on factors associated with race or ethnicity, the Plan should specify the study design features that will support analyses that will inform the safety and effectiveness of the medical product in the relevant racial and ethnic populations.
- 201-203: When there are no data that indicate that race or ethnicity will impact safety or effectiveness, it is nonetheless appropriate that enrollment reflects the epidemiology of the disease.
2.2 Clinical Sites as Key Implementers for Study Plans.
Observation: The Draft Guidance on Diversity Plans does not identify Clinical Sites as essential partners of the Clinical Research Team to implementing diversity programs relating to recruitment, enrollment, and retention of research patients.
We also reviewed the “Final Guidance” on Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs which was referenced in the “Draft Guidance” on Diversity Plans. However, in our assessment neither the Final Guidance nor the Draft Guidance recognize the importance of operational effectiveness of Clinical Sites to ensure the success of clinical trial Study Plans. In the context of FDA’s Diversity Guidances, clinical trial Study Plans would expand to include a Diversity Plan.
Request: TOTAL asks that FDA consider the following provisions for the Draft Guidance that identify the importance of Clinical Site qualification and training for implementing site-level Diversity Plans and activities relating to recruitment, enrollment, and retention.
- First Proposed Insert in the Guidance: “FDA recognizes that the detailed content of Diversity Plans may be complex. In order to help ensure operational effectiveness of the Plan, Sponsors and CRO’s should consider extending site qualification to include assessments of experience and capability of Sites to effectively implement Diversity Plans relating, for example, to: achievement of racial and ethnicity targets; recruitment, enrollment, and retention processes; previous site diversity training; and patient tracking and risk mitigation strategies to monitor diversity metrics across the lifecycle of the study.”
- We suggest that this insert (as drafted or in similar intent) logically fits in Section IV. “Timelines and Process for Submitting Race and Ethnicity Diversity Plans” after the single sentence in Item D which reads: “Sponsors should include the Plan in the marketing application for the medical product as well as a description of the successes and challenges in implementing it.”
- Second Proposed Insert for the Guidance. “… the planned diversity training program of site personnel, …”.
We suggest FDA insert the phrase in Section V Content of the Race and Ethnicity Diversity Plan of the April 2022 Draft Guidance in the Table at Category 4 (page 12) entitled Specific Plan of Action to Enroll and Retain Diverse Participants. The phrase is in bold italics only for purposes of this document.
- We propose the following inclusion of the phrase as highlighted here in boldface type in the following guidance paragraph: “A. Describe in detail the operational measures that will be implemented to enroll and retain underrepresented racial and ethnic participants in the planned trial(s) or studies, the planned diversity training program of site personnel, and the planned use of data to characterize safety, efficacy, and optimal dosage in these participants, when applicable.”
In the 2020 final guidance on enrollment, FDA encourages diversity training of site personnel, as follows:
“Providing cultural competency and proficiency training for clinical investigators and research staff may help facilitate the building of a trusting relationship with participants, provide a helpful resource for investigators and research staff on how to engage with participants with different backgrounds, help decrease biased communication and behavioral practices, and help avoid the use of cultural generalizations and stereotypes in interactions with participants. Understanding how participants choose whether to participate in a clinical trial allows sponsors to more effectively recruit participants who may be reluctant to enroll.”
In the 2022 Draft Guidance, FDA makes no mention of diversity training. Diversity competency through training is the catalyst to ensure clinical research investigators and staff can engage with study participants so that those participants feel respected, have emotional comfort, feel physically secure, and are more willing to engage in study procedures through information sharing and communication. These are important attributes to facilitate enrollment and retention of diverse populations. To achieve this, diversity training of clinical personnel is essential to help ensure the provisions of the diversity plan can be realized.
Executive Overview: The Statement that TOTAL proposes for FDA’s consideration supports FDA’s intention to have Sponsors and/or CROs create and manage Diversity Plans for clinical trials. Furthermore, our proposal enhances the importance of operational effectiveness of the Diversity Plan at the Site level by expanding site qualifications to include diversity assessments of the Site’s experience and capability to fulfill provisions of the Diversity Plan. Study Plans and site qualifications are routinely used as planning and operational tools in clinical research studies. Enhancing these tools with a Diversity Plan and site diversity qualification can be reasonably implemented within the existing system of clinical trial management.
FDA Opened the Door to Considering the Real-World Scope of Diversity Plans and their Potential Complexity. In its Introduction to the Draft Guidance, FDA makes the following statement.
- 33-36, “However, FDA advises sponsors to seek Diversity in clinical trial enrollment beyond populations defined by race and ethnicity, including other underrepresented populations defined by demographics such as sex, gender identity, age, socioeconomic status, disability, pregnancy status, lactation status, and co-morbidity.”
- 36-38: “FDA encourages sponsors to also submit plans that help ensure the adequate participation of relevant and underrepresented populations…”
This suggests that when FDA receives a Diversity Plan per the Draft Guidance for review, the agency’s expectations will extend beyond race and ethnicity. This extension would most likely be based on both the Draft Guidance on Diversity Plans and the Final Guidance on “Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs.” Hence, Diversity Plans may be complex, requiring substantial effort by CRO’s and Sites to deliver on provisions of the Plan.
Study Plans with the Study Protocol Create the Core Scaffolding for Operational Effectiveness. Operational effectiveness of a clinical research team is Critical-To-Quality for a successful clinical study. Here it is defined as ready-for-use (i.e., operational) to the degree to which a clinical research study is expected to be successful in producing its desired results. The clinical research team includes Sponsors, CROs, and Clinical Sites. Operational effectiveness for Clinical Sites is realized through contracts, SOPs, training, protocols, and Study Plans used routinely by the Clinical Team.
Most if not all clinical trials are associated with Study Plans pertaining to project management, site selection and feasibility, recruitment plan, data management plan, communication plan, monitoring plan, medical monitoring plan, quality assurance plan, risk management plan, statistical analysis plan, among others. A Diversity Plan would be one among other essential and routinely used Study Plans.
Site Qualifications Are Routinely Done During Site Selection, such that the Addition of Diversity Assessments Would Be Easily Incorporated into Existing Activities. The projected feasibility of engaging a site for a clinical study is achieved with a formal site qualification by the Sponsors and/or CROs. These site qualifications assess site experience with the subject disease or condition, recent past FDA inspections, PI and staff experience and training, clinic capacity in terms of staff and facilities, policies, and procedures, among other details. Adding diversity queries related to site training on diversity (which if absent can be introduced at the Site Initiation Visit), recruitment and retention strategies for the target diverse population and subpopulations, and Patient Focused Services (e.g., availability of phone prompts for frequently used languages; operation hours outside of normal business hours; transportation services etc.) – all of which can be appropriately aligned within the provisions of the Diversity Plan and used effectively by Sponsors, CROs and Sites.
For these reasons, we ask that FDA consider (a.) the addition of our proposed statement that emphasizes the importance of Clinical Sites for implementing Diversity Plans (b.) the associated need for diversity qualification of Clinical Sites to help predict their effectiveness in implementing the Diversity Plans, and (c) the second proposed insertion of the phrase for inclusion in the Section V Content of Race and Ethnicity Plans in Content Table at Category 4 on page 12 which is stated above as “… the planned diversity training program of site personnel …”.
In conclusion, TOTAL supports FDA’s approach that will broaden the application of Diversity in clinical research. We ask for FDA’s consideration of the importance of Study Plans (such as Diversity Plans) for achieving operational effectiveness of Clinical Sites and of the need for diversity site qualifications as Critical-To-Quality factors in clinical research.