FDA’s Diversity Action Plan: Questions, answers, and what we (don’t) know so far

Last month, the FDA published a new draft guidance document on diversity action plans. While the new version of the guidance is greatly expanded as compared to an earlier version from 2022, it has left plenty of important questions unanswered. In this piece, AgencyIQ answers some of the most common questions we’ve received about the guidance – and raise a few of our own.

By Laura DiAngelo, MPH | Aug 2, 2024 6:30 PM CDT

A refresher on FDA’s Diversity Action Plan (DAP) guidance:

  • In April 2022, the FDA issued a draft guidance document on diversity in clinical research programs. At a high level, the guidance laid out a policy whereby sponsors of certain products would voluntarily submit a Race and Ethnicity Diversity Plan as part of their development program that would outline and justify their approach to recruiting and retaining a “representative” research population. [ Read AgencyIQ’s extensive analysis of the draft guidance here.]
  • In December 2022, as part of the Consolidated Appropriations Act, 2023, Congress provided the FDA with new authority to require what the law referred to as Diversity Action Plans (DAPs) for certain clinical studies. Section 3601 of the law amended the Federal Food, Drug and Cosmetic (FD&C) Act to expressly grant the FDA the statutory authority to require DAPs for 1) Drugs: for “a new drug that is in a phase 3 study” or “as appropriate, another pivotal study of a new drug (other than bioavailability or bioequivalence studies)”; 2) Medical devices: As part of an Investigational Device Exemption (IDE) submission or “for any clinical study.”
  • DAPs are a plan, developed by the product sponsor, that would need to include specific enrollment goals, the rationale by which these goals were developed, and “an explanation of how the sponsor intends to meet such goals.” The statutory provision also allows for certain research programs to be exempted from the DAP requirement through a waiver system, which could be initiated by the FDA or “at the request of a sponsor.”
  • The law also directed the FDA to “update or issue guidance” on DAPs. Per Section 3602 of the Consolidated Appropriations Act, this guidance should include information about the specific format and content of the plans, such as the rationale for enrollment goals (e.g., estimated prevalence of the condition of interest, any relevant pharmacokinetic or pharmacogenomic data, demographic factors) and how they intend to meet those goals, as well as operational and process factors such as how they should be submitted and how the “action plan” may be updated over time.
  • The agency issued a new draft guidance on DAPs in June 2024, several months after the Congressional deadline had passed. While the new draft guidance document and FDA’s original 2022 draft guidance document share a federal docket – meaning that the comments submitted on the original 2022 draft guidance are in the same online folder that comments on the new draft will be submitted to – the new draft is essentially a complete rewrite of the 2022 version, and not a simple revision.
  • A quick recap of the draft guidance: The new June 2024 draft guidance describes the various elements of a DAP (enrollment targets, rationale to justify those targets), the basics of their formatting, and how to submit a DAP to the FDA – including both the information they expect and when/how those documents should be sent in. The guidance also includes a section describing the process for sponsors to seek a waiver from the DAP requirements. Notably, FDA continues to maintain that DAP waivers should be “rare” – previewing its expectations that it will receive just five waiver requests for drugs/biological products and five waiver requests for medical devices each year. [Read AgencyIQ’s full analysis of the July 2024 DAP draft guidance here.]

Answering key questions about the Diversity Action Plan guidance document

  • Although the 2024 draft guidance on DAPs includes significantly more detail than the 2022 version, there are still significant outstanding questions that it leaves unanswered.
  • Following a recent AgencyIQ webinar, we collected dozens of questions from our subscribers and webinar attendees to put together this list of commonly-asked questions, as well as our attempts to answer them using available information. We’ve also collected additional questions that we have about the guidance.

What programs or products need a DAP?

  • According to the guidance, the following drug studies need a DAP: Clinical investigations of a new drug “that is a phase 3 study” or “another pivotal” clinical study except for bioavailability or bioequivalence (BA/BE) studies will need a DAP. For these studies, the DAP should be submitted to the relevant Investigational New Drug (IND) “as soon as practicable but no later than the date on which the sponsor submits the protocol to FDA for the phase 3 study” or “another” pivotal study.
  • What does that mean: “Phase 3”? The actual legal definition of a Phase 3 study can be found at 21 CFR 312.21, and the DAP authority references this specific definition: “Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects.” The agency may also require a DAP for an “other pivotal clinical study” of any kind (besides a BA/BE). However, it doesn’t go into depth about what studies, exactly, they mean here – beyond its function as either a Phase 3 or “another pivotal study.”
  • What does that mean: a “new drug”? As defined in statute, the DAP requirement for drug products applies to clinical studies for a “new drug.” The statute does not offer a specific definition for new drug, although the FDA has its own extensive definitions of the term (21 CFR 310) that have been set by previous legislation. Per those regulations, the “newness of a drug may arise by any reason (among other reasons) of: (1) the newness for drug use of any substance which composes such drug, in whole or in part, whether it be an active substance or a menstruum, excipient, carrier, coating, or other component. (2) The newness for a drug use of a combination of two or more substances, none of which is a new drug. (3) The newness for drug use of the proportion of a substance in a combination, even though such combination containing such substance in other proportion is not a new drug. (4) The newness of use of such drug in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body. (5) The newness of a dosage, or method or duration of administration or application, or other condition of use prescribed, recommended, or suggested in the labeling of such drug, even though such drug when used in other dosage, or other method or duration of administration or application, or different condition, is not a new drug.”
  • In guidance, FDA has noted that it has “recognized, and courts have accepted, that drug can be interpreted, among other possible meanings, to mean ither drug product or drug substance” and that because the definition is broad, the statute “delegates to FDA the task of determining how to apply the definition in particular statutory provisions.” However, it’s possible that its interpretations may be on shakier ground following the landmark Supreme Court decision in Loper Bright earlier this year, which determined that courts are not obligated to defer to FDA judgments. In other words, it’s possible that companies may disagree with FDA regarding the “newness” of their drug products – for example, whether certain studies intended to inform new indications, formulations, or other adjustments to an approved drug product may cross the line into being a “new” drug and therefore need a DAP.
  • Per the guidance, the following device studies need a DAP: Investigations for products under an Investigational Device Exemption (IDE), as well as studies that are not under an IDE but are intended to be the primary basis of evaluation by the FDA; no IDE-exempt study is required to submit a DAP. For products under an IDE, DAP information must be submitted with the IDE. For products not under an IDE but that are not IDE exempt and are intended to serve as the primary basis of FDA’s review, the DAP must be submitted with a marketing application for the product.
  • What about combination products? Combination products are defined by the FDA as: “A product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic” that are either combined/mixed into a single entity or are co-packed or cross labeled. In general, combination products generally do not need separate regulatory authorizations for each constituent part, but are authorized under a marketing application for the part that provides the primary mode of action (PMOA) of the combination product; the part that provides the PMOA is considered to “lead” the combination product. The DAP guidance does not include any information about combination products – this will likely need to be addressed by the FDA in future clarifications. From regulatory precedent, it seems likely that the way that a DAP would be submitted for a combination product would follow the rules of the “lead” part; in effect, a DAP would be submitted under the IND for a drug-led combination product, or the IDE or in the marketing application of a device-led combination product. However, it’s not entirely clear at this point how that would affect enrollment target setting or rationale.
  • What about companion diagnostics (CDx)? CDx are diagnostic products that are “essential for the safe and effective use of a corresponding therapeutic product” and are authorized to reference that/those therapeutics. Unlike combination products, CDx are authorized separately from the associated drug product, and need their own marketing application. However, depending on study design, the investigations into a CDx might not need their own investigational submission. While investigations of CDx typically do require an IDE application to the FDA (and therefore require a DAP per statutory requirements), a sponsor “may seek to submit an IND alone, or both an IND and an IDE.” In the case that a CDx is included in the IND (rather than getting its own IDE), it’s not clear if the DAP requirement for the CDx as a standalone product would be waived out, or whether the sponsor would need to submit a DAP for the CDx to the IND. Notably, there are significant developments on CDx policy expected in the next few years, and it’s not clear if clarification needed in this are will come in a DAP guidance or in a CDx-specific guidance (or if it’s something the agency has thought through just yet).

Global trials, enrollment targets, and how to account for a DAP population

  • Quick definition: What are the enrollment goals? The DAP is comprised of three basic content elements: Enrollment goals, the rationale for the enrollment goals, and the measures to meet enrollment goals. FDA’s 2024 draft DAP guidance includes an Appendix summarizing these three elements. The section of the guidance on enrollment goals begins on page 11 of the document. The enrollment goals are the baseline framework underlying a DAP; in effect, they’re intended to break down the sponsor’s “goals” in enrolling a participant population by demographic subgroups.
  • How to set enrollment goals: the U.S. population should be the baseline. “Generally, enrollment goals should be informed by the estimated prevalence or incidence of the disease or condition in the U.S. intended use population for which the medical product is being studied” (lines 232-234). More specifically: “The estimated prevalence or incidence of the disease or condition by demographic characteristics in the U.S. population for which the medical product is being investigated should generally inform enrollment goals” (lines 267-269). In effect: The enrollment goals should be focused solely on the intended use population in the U.S.
  • What does this mean for global, or multinational, trials? The agency acknowledges “the importance of global medical product development and supports the use of well-designed and conducted multi-regional clinical studies, when appropriate.” However, the DAP requirements still apply for multinational trials.
  • The guidance offers some information on what DAPs for multinational trials will look like: These recommendations can be found at lines 295 to 318 of the guidance. While the setting of enrollment goals should be based on the U.S. intended use population, the DAP’s enrollment goals “must describe participant enrollment goals for the entire study and should not be limited to U.S.-enrolled participants” – in effect, the enrollment goals themselves should be set using U.S.-specific data to inform the goals themselves, and then should incorporate the participation enrollment for the entire study, including multi-national geographies. Or, as the FDA explains at line 243, “the sponsor’s enrollment goals specified in the Diversity Action Plan for each study should consider how individual clinical studies may fit into an overall clinical development program for the medical product (i.e., for a particular indication or intended use), and how such individual studies should help generate data representing the clinically relevant population’s demographic characteristics consistent with the incidence or prevalence in the disease population for the program.”
  • How should sponsors of global trials collect data on patient demographics? As the guidance acknowledges, sponsors are expected to collect DAP data using U.S.-specific categorizations of race and ethnicity (as defined by OMB Directive 15). However, this is likely to be challenging – something noted in the guidance. “FDA recognizes that the lack of uniformity across the globe in the use of population descriptors across the globe in the use of population descriptors such as race and ethnicity may pose challenges when setting enrollment goals for international sites” the guidance states (lines 305-307). In other words: The challenge is that sponsors need to describe the enrollment of non-U.S. participants using demographic descriptors that may not be available (or used, or legally permitted to be collected) in the data in that region.
  • What data can be – or shouldn’t be – used to set enrollment targets? As mentioned above, demographic information must be in the U.S. formatting for racial and ethnic categories (a subject on which more clarity would be welcome). Further, the agency urges sponsors to use “appropriate available sources” – such as certain registries, “publicly available” epidemiological surveys or published literatures – but notes that “non-publicly available sources” can also be used. In these cases, sponsors should “provide the rationale for the approach, a synopsis of the analysis used, and citations for the source(s) for these data.” So far, it’s not yet clear what level of granularity the agency will be looking for in information about non-public sources.

Enforcement and post-market implications:

  • A key point of the statutory authority: FDA has the authority to require the submission of DAPs, but it’s less descriptive about what happens after that. The statutory authority to FDA that was granted under FDORA to require DAPs is limited to their submission – not their completion or FDA’s enforcement of specific provisions.
  • How might FDA enforce DAPs? One option: Refuse to accept, refuse to file. The first consideration is that, upon the implementation of this policy, DAPs will be a required component of certain submissions and therefore, will be necessary for the FDA to accept or file the submission. In effect, missing a DAP would be missing a required element of the submission, and therefore the application would theoretically not pass (appropriate, by submission) technical review and not be accepted or filed by the FDA.
  • What happens if you don’t meet your goals? That is a significant question, and not addressed in the guidance. As AgencyIQ has previously discussed, the 2022 version of the draft guidance (which was not backed up by statutory authority) included the following footnote, which was the subject of much discussion in comments on the document: “In the event that recruitment goals are not met despite best efforts, sponsors should discuss with FDA a plan to collect this data in the post-marketing setting” (footnote 24). The new 2024 version of the document, notably, does not include any information on the subject, and does not address the question of what happens if studies under DAPs are unable to reach their goals in the pre-market setting.
  • There is one place where “postmarketing clinical studies” are mentioned: Medical device Post-Approval Studies (PAS) and section 522 studies. In footnote 31 of the new draft guidance, the agency states that “although medical device postmarketing clinical studies are outside the scope of this guidance, FDA considers diversity and representative patient enrollment to be important in postmarketing clinical studies of devices.” As AgencyIQ noted in analysis of the 2022 version of the diversity plan guidance, the framework for the diversity plans in these guidance documents aligns operationally with agency guidance on these two study types that were drafted just a year before the original diversity plan guidance (PAS guidance, 522 guidance), and were finalized in October 2022. These include similar elements like the establishment of pre-study enrollment goals, the requirement that sponsors/manufacturers provide rationale on how they intend to meet those goals, and time-based milestone check-ins.
  • However, those two guidance documents go further than the DAP guidance does (even the 2024 version), recommending specific enrollment milestones (e.g., first subject enrolled within 6 months of the date that the study protocol is approved, 20% enrolled by 12 months). The new DAP draft guidance does not include any such specific expectations, but could preview work in future years should the agency raise similar concerns with DAPs as it did with PAS/522 studies not being sufficiently enrolled. Further, it’s not entirely clear what impact, if any, a DAP will have on enrollment goals under a PAS/522.
  • For devices, will this be an eSTAR module? In the U.S., most medical device submissions are now either required to be submitted, or can be voluntarily submitted, via the electronic submission template and resource (eSTAR). If and when DAPs become required for certain medical device submissions, the content would either need to be built into the template or the FDA would need to provide more information on where it goes. For example, the guidance states that DAPs for drugs under an IND would need to be submitted in eCTD module 2.5 (Clinical Overview).

Timeline, analysis, and what’s next

  • When should we expect the guidance to be finalized? For now, the guidance comment period runs through September 2024; it’s not yet clear if the FDA will extend the comment period. If it doesn’t, there’s a quick turnaround on getting the guidance finalized. Under FDORA (and notwithstanding that the agency blew past the 12-month timeline for a draft guidance), the final guidance would theoretically be due in June 2025.
  • When would the guidance go into effect? Under the statute, the DAP requirement would go into effect for studies “for which enrollment commences after 180 days from the publication of the final guidance” – assuming the final guidance is issued on time, this would be December 2025.
  • Are there any exemptions? The agency says “It does not expect” a DAP for certain projects in three specific scenarios: 1) when a drug product’s protocol is submitted “within 180 days” after a final guidance is published and in which enrollment will begin in the 180 days (i.e., during the implementation period); (2) device studies for which an Investigational Device Exemption (IDE) is received within 180 days of the publication of the final guidance; and (3) device studies for which an IDE is not required but which are approved by an institutional review board (IRB) or independent ethics committee (IEC) within 180 days of the final guidance publication.
  • There are significant remaining operational questions, such as who at FDA will be reviewing DAPs (and whether reviews will differ by review division), what FDA enforcement will involve, the mechanics of these submissions, and implications for combination products and CDx. Overall, it’s likely that this new draft guidance will garner significant feedback from industry, particularly on how to interpret some of the more ambiguous sections.
  • Can sponsors submit a diversity plan in advance of final guidance? Yes, although these would presumably count as voluntary diversity plans (per the 2022 draft guidance), rather than DAPs (which are statutorily required under a provision of the law that has not yet been implemented). This might give sponsors a little bit more time to get a feel for how the FDA will be interpreting key provisions in advance of when submission would be required.

To contact the author of this item, please email Laura DiAngelo ( ldiangelo@agencyiq.com)
To contact the editor of this item, please email Alexander Gaffney ( agaffney@agencyiq.com)

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