Stakeholder comments on FDA’s Diversity Action Plan guidance show tension on scope — and question enforceability

Life Sciences | By Rachel Coe, MSC

Oct. 10, 2024

At the end of 2022, Congress passed legislation mandating the FDA to require sponsors to submit “Diversity Action Plans” (DAPs) for certain clinical studies. However, questions lingered about the scope of these plans and how sponsors should submit them to the FDA. In June, a revised draft guidance spelled out the details, but was light on enforcement strategies. AgencyIQ reviewed the hundred-plus comments on this document, finding tension among stakeholder groups that the FDA may find difficult to reconcile when it does finalize its DAP guidance – though the agency is already achieving some diversity goals by other means.

A quick 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  • In April 2022, the FDA issued a draft guidance document on diversity in clinical research programs.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 [ Read AgencyIQ’s extensive analysis of the draft guidance here.]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.”
  • 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. [See AgencyIQ’s full analysis of the draft guidance, discussion of questions raised by the draft, and peek into how the FDA is already putting the draft into action.]
  • FDA requested feedback on the draft be submitted by September 26, 2024.

The comment period on the DAP guidance just closed. Here’s what groups are asking the FDA to change about it

The importance of commitments, reporting and transparency

  • “A plan is only as good as its implementation,” wrote the Muscular Dystrophy Association (MDA). “We do not want to see sponsors submit an excellent Diversity Action Plan that then fails to recognize and address these participation barriers, and consequently does not succeed in enrolling individuals from underrepresented populations.” The association explained further: “We have heard from many within the neuromuscular field that the barrier to representative enrollment in clinical studies is often logistical and financial. Whole families have to travel hundreds of miles to visit one of only a handful of trial sites, and if the trial is for a gene therapy, they have considered moving to the location for several months. Parents cannot take time off from work to take their children to study visits, and sponsors do not always cover the costs of travel, lodging, food, and forgone wages.” The group also conveyed profound disappointment that the guidance did not include a requirement for sponsors to include patients with disabilities, “the largest minority in the United States (it is estimated that one-in-four Americans lives with a disability).”
  • The American Medical Association (AMA) agreed and advocated for the FDA to ensure plans are not just written, but put into action. For example, AMA suggested that “formal structures such as advisory boards or regular consultations with community representatives” should be created and leveraged throughout the study’s lifecycle to ensure process is being made. AMA also questioned whether the “FDA (and potentially Congress) should consider if new mandates, authorities, or sponsor incentives would further promote commitments to diversity and inclusion.”
  • PhRMA took a different approach, contending that FDA simply does not possess the authority to prescribe the use of prevalence or incidence data to set them goals, period. The statute, the trade group argued, “does not prescribe any specific source of data for these goals or authorize FDA to fix these goals in a binding, numbers-based fashion” but instead simply requires that a DAP include the sponsor’s goals for enrollment in such clinical study. PhRMA made the case that the statute says sponsors may include the estimated prevalence or incidence in the United States of the disease or condition, meaning: “It does not prescribe that U.S. prevalence be the only or main factor in setting the sponsor’s enrollment goals.” Later on, PhRMA brought up the same argument in regard to the FDA’s instructions for sponsors to include (among other information), “an overview of the natural history of the disease or condition and risk factors, as well as prevalence and incidence estimates, if available” as rationale for DAP enrollment targets. Again, PhRMA argued that “FDORA’s provision on rationales is more flexible,” giving sponsors the option — not a mandate — to use prevalence and incidence data.
  • To check in on sponsors’ progress, a clever suggestion was put forth by the National Health Council. First, NHC stated that tracking and assessing the progress of sponsors in meeting their DAP goals is essential to improving clinical trial diversity and to this end, the FDA should require regular reporting by sponsors, including any revisions or other updates to their DAPs. Next, the council pointed out that the FDA is required by FDORA to “submit an annual summary report to Congress, which must also be made publicly available, detailing the progress made toward increasing diversity in clinical studies,” and that to “optimize this statutorily required reporting process,” the FDA should provide details to sponsors on how and when to submit regular reports, so that the process offers “the FDA, Congress, and the public with valuable insights into the efforts to meet diversity targets, while enhancing transparency and allowing for a clear assessment of overall industry progress.” Other organizations, like Women of Color in Pharma (WOCIP), agreed, requesting that sponsors be required to submit disaggregated data in annual reports that will be made public by the FDA.
  • But industry offered a defense of its efforts to meet enrollment goals. BIO stated that “Despite sponsor efforts, enrollment will continue to be affected by factors outside the control of sponsors, including systemic racism, historical mistrust in clinical research, healthcare inequities, and differences in health literacy.” Most patient and clinician groups (e.g., the American Kidney Fund and the Cystic Fibrosis Foundation) took a completely opposite stance on this issue, squarely placing the onus on sponsors to meet underrepresented patients where they are by making long-term investments in underserved communities, building relationships with community groups and leaders early-on to build trust in the healthcare system, and to adapt clinical trial materials to accommodate different levels of health literacy.
  • A broader theme across comments—with the exception of those submitted by the life sciences industry—was that transparency is key. The National Alliance for Hispanic Health (NAHH) requested FDA make all DAPs submitted by sponsors publicly available along with all waiver requests. The American Society of Hematology (ASH) agreed that not only would sharing DAPs publicly offer accountability, but could also aid sponsors by showcasing successful strategies, sharing cases where things went wrong, and fostering an open research environment where inclusive research practices are seen as an authentic commitment. The Rare Disease Diversity Coalition (RDDC) even suggested that sponsors should disclose staff demographics at clinical trial sites to the FDA, in order to determine whether clinical trial teams reflect the diversity of the patient populations they aim to serve, a factor known to influence the participation of diverse patient groups.
  • What about sponsors who don’t meet their goals? Clinician and patient groups requested the FDA hold sponsors accountable to the goals set out in their DAPs, not just during trial enrollment but all the way through trial completion as well. “Previous failures to incentivize diversity in clinical trials clearly demonstrates the need for robust enforcement of compliance with Diversity Action Plans (DAP),” stated Doctors for America, “We find merely the inclusion of sponsor updates on DAP progress in the annual IND report to be insufficient and strongly urge the FDA to detail how they will respond in cases where a study is failing to meet enrollment deadlines. Additionally, the FDA should clearly state how this failure will impact approval decisions.” Other groups went further, with the American Geriatrics Society advocating for FDA to utilize enforcement mechanisms such as “penalties, including financial, labeling changes, removal from the market, or initial time-limited marketing approvals that would expire unless data is generated that supports the initial approval and the post-marketing requirements are judiciously applied.”
  • Another suggestion, offered by the Tigerlily Foundation—a national women’s health and oncology organization—was for the FDA to cite sponsors who failed to provide transparent documents on their DAPs and to recognize those who do. Furthermore, the foundation proposed that sponsors cited for lack of transparency should be subject to monetary penalties, which should be used to fund public sector programs that “better engage and educate diverse populations about equitable biomarker driven care and the hope and opportunity that clinical trials bring to the community.”

When should requirements be allowed to be waived?

  • When should waivers be allowed? Hardly ever, was the consensus of most non-industry stakeholders. One of the few academic institutions to weigh in, Yale’s Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT), suggested that “Posting waiver requests in the Federal Register for public comment may encourage sponsors to seek waivers only when absolutely necessary, as public scrutiny could deter unnecessary requests. Additionally, it allows the public including patients to provide input, offering perspectives that may differ from the sponsor and FDA, which the agency can consider in its decision-making process.”
  • PhRMA took a sharply different stance, writing that “The language used in the Draft Guidance—that DAPs ‘will be possible in most cases’ and that waivers ‘will only be granted in rare instances’—appears to prejudge the ability to develop meaningful DAPs and the legitimacy and validity of waiver requests.” In response, the trade group requested that “FDA delete the discussion stating that DAPs ‘will be possible in most cases’ and that waivers will be granted only in ‘rare instances’ thus ensuring that the Draft Guidance aligns with the statute.” The group also stated that in scenarios where a study is not originally planned as a pivotal trial, but is only later deemed a pivotal study, the “absence of a DAP should not prevent such a study from being considered a pivotal study nor should it delay approval of an application.”
  • As for the public disclosure of DAPs and waivers, suffice it to say industry was strongly opposed. “Neither FDORA nor section 505(z) of the Federal Food, Drug, and Cosmetic Act require that FDA publicly post information about the granting of DAP waivers on its website. Although we recognize that FDA states it will consider releasing information only ‘to the extent permitted under applicable disclosure law,’ we believe that this information may reveal sensitive information about sponsors’ development programs that often may constitute confidential commercial information,” wrote PhRMA.
  • The group also requested that FDA “delete its proposal to post information on waiver decisions on its website or revise this recommendation to provide that FDA will only post summary statistics.” Lastly, though FDA encouraged sponsors to independently disclose information included or related to their DAPs in the guidance, PhRMA requested that the final guidance “expressly state that the public posting of strategies and other key information on DAPs is optional, consistent with the statute and the fact that DAPs might contain or constitute confidential commercial information about in development products or regulatory strategy.”
  • Perhaps the most meaningful comment on this subject was an anonymous letter submitted by a scientist working in clinical development at a pharmaceutical company. Diverging from most industry feedback, the letter requested that FDA require sponsors to develop diversity action plans for every program, without exception. In explaining their request for anonymity, the letter says, “In my experience, when I have advocated for the implementation of Diversity Action Plans, I have often been ignored or told that requesting a waiver would be an easier path. This is precisely why I believe a more stringent approach to DAPs is necessary to ensure that underrepresented populations are not overlooked in clinical research.” Another anonymous health professional cited similar apprehensions: “My primary concern is that this will create quotas and much lip service about ‘equity’ without substantively changing the way we enroll patients in trials.”
  • While companies are likely to request waivers for rare diseases with a known genetic component, the author of the preceding point emphasized that this is exactly when they are most important. “Given the historical disparities in access to genetic testing and healthcare, relying solely on general prevalence estimates could lead to inaccurate assumptions of rarity in certain populations. By requiring more comprehensive studies that take into account genetic factors and utilizing modern tools like AI and real-world data, sponsors can provide a more accurate and inclusive assessment of disease prevalence.”
  • Another frank assessment came from Elevate Advocacy, a patient advocacy organization which wrote that sponsors it has engaged with often attempt to “justify the least amount of effort or investment in a Diversity Action Plan.” While disappointing, the group stated it’s no longer a surprise and that even now, “There is a large contingen[cy] of sponsors who believe that they will get waivers despite the Guidance stating that waivers will be difficult to secure.”

What about gender identify and sexual orientation?

  • The National LGBTQI+ Cancer Network, along with a list of allied partner organizations, stated that while they understand most of the guidance was written according to the language used in the FDORA legislation, FDA should consider adding stronger language about the inclusion of sexual orientation and gender identity. The organizations stated that some sponsors have “already taken the initiative of working with Clinical Data Interchange Standards Consortium (CDISC) to add sexual orientation, gender identity, and intersex status measures.” However, the group stated that from their collective experience in engaging with sponsors on this topic, one point has been made clear: FDA’s inclusion of LGBTQI+ persons in diversity action plans would have a “pronounced effect on how many trial sponsors move to address this gap.”
  • Likewise, the Federal AIDS Policy Partnership (FAPP) Research Working Group strongly urged the FDA to mandate the inclusion of other underrepresented patient populations in clinical trials, including “populations that have been historically disenfranchised or neglected such as LGBTQ+ communities, people living with HIV and the aging population.” The group stressed that patients particularly vulnerable to HIV, such as black cisgender women in the U.S., require “as many prevention options and choices as possible,” and that including key vulnerable populations in clinical trial research also has significant downstream implications when it comes to market access and subsequent research on “the unique challenges and needs of underserved populations in accessing prevention and treatment options.” Like other groups focused on health equity, the group urged FDA to limit the waiver process for fear that sponsors could take advantage of this loophole. One member of the research working group, the AIDS Vaccine Advocacy Coalition (AVAC) submitted a near-identical comment letter reasserting these requests.
  • But PhRMA’s comments propose that such arguments – and FDA’s guidance – likely exceed the agency’s statutory authority. The group pushed back on FDA’s request for sponsors to consider factors “including but not limited to geographic location, gender identity, sexual orientation, socioeconomic status (SES), physical and mental disabilities, pregnancy status, lactation status, and co-morbidity.” PhRMA stated, simply: “Although these recommendations are not binding, they appear to exceed FDA’s express statutory mandate [emphasis added] to develop guidance on enrollment goals disaggregated by age group, sex, race, and ethnicity for purposes of a DAP.”
  • One of the very few points that both industry, researchers, and patients aligned on was recognition that members of the LGBTQ+ community are also underrepresented in clinical research. However, patients and researchers advocated for the FDA to recommend sponsors engage with these communities at the minimum, with some urging the agency to mandate their inclusion in DAPs and in clinical trials. Sponsors took a different angle on this issue, stating that capturing sexual orientation and gender identity could actually undermine efforts for clinical trials to be more inclusive given that patients may be unwilling to share this information. PhRMA made the case that these patients (and others belonging to multiple underrepresented demographic groups) can be especially challenging to reach and enroll in clinical trials. Regarding sexual orientation and gender identity, BIO requested that FDA work with sponsors and trial sites to “explore considerations for the collection of Sexual Orientation and Gender Identity (SOGI) data.”
  • On the topic of intersectionality, BIO also stated that the “multiplicity of factors to account for will make it challenging to meet all the goals at the same time.” In addition to setting enrollment goals by race, ethnicity, sex, and age, BIO noted that sponsors are also expected to enroll a “patient population based on global disease burden and demographics, according to already existing applicable guidelines on this topic (ICHE17 and ICHE5),” and that adding in the “other population-level or individual characteristics that available data suggest have an impact on the clinical outcomes (e.g., SES, geographic location, comorbidities)” would make trial enrollment difficult. To account for this challenge, BIO requested FDA allow sponsors to primarily “focus on the dimensions of diversity based on strengths of evidence and magnitude of the differences in sub populations [emphasis added] . This prioritization should guide setting the goals, their monitoring and any resulting corrective actions (with a focus on high priority dimensions of diversity for monitoring and corrective actions).”
  • A potential loophole? As noted by the National LGBTQI+ Cancer Network, the Department of Health and Human Services (DHHS) has already promulgated regulations that interpret and enforce the nondiscrimination requirements contained in Section 1557 of the Affordable Care Act (42 U.S.C. 18116) and Title IX of the Education Amendments of 1972 (20 U.S.C. 1684). Per the final rule issued by DHHS and CMS in May, forms of discrimination on the basis of sex include factors such as pregnancy, sexual orientation, gender identity, and sex characteristics. If the FDA formally adopts this definition finalized by DHHS and CMS, the mandate for sex to be included in DAPs by FDORA would thus require—by default—sponsors to include sex-based characteristics such as pregnancy, sexual orientation, gender identity, and sex characteristics, etc. in DAPs.

What about body composition?

  • Generally, the FDA does not require the enrollment of patients with varied body compositions, including patients with obesity, in clinical trials. Obesity is broadly defined using a crude metric referred to as body mass index (BMI). BMI is calculated using only height and weight, and does not factor in biological sex, muscle mass, age, or various other factors that can have major effects on total weight and total body fat. There is currently a strong push in the medical field to move beyond the use of BMI to define obesity and instead utilize measures like waist-to-hip ratio, which are more likely to predict body fat percentage and thus more likely to predict long-term health risks. Regardless, weight classes for adults in the U.S. are currently defined using the following BMIs, expressed as kg/m ^2: 1) Normal weight: 18.5-24.9, 2) Overweight: 25-29.9, 3) Obese: 30-39.9, 4) Severe obesity: 40+. [See AgencyIQ’s detailed analysis of obesity and drug dosing here]
  • Yet, this topic was not included in FDA’s 2022 draft guidance on enhancing diversity in clinical trials, nor the June 2024 guidance rewrite. In fact, FDA’s only general guidance on clinical trial conduct that alludes to obesity is its 2020 guidance, which refers to patients “at the extremes of the weight range” as a certain population that has been commonly excluded in clinical trials.
  • The Obesity Action Coalition (OAC) pointed out this flaw in the DAP guidance, noting that “excluding individuals with obesity in clinical trials leads to a lack of data on how medications perform in the majority of the population.” How so? Per OAC’s comment letter, not only do people living with obesity make up 42% of adults in the U.S.,” but “Another 31% of people live with pre-obesity or overweight, representing 73% of the general population [emphasis added].” As AgencyIQ has previously noted, the prevalence of obesity in adults and children living in the U.S. continues to increase each year.
  • Secondly, OAC stated that “exclusion of persons with obesity from clinical trials leads to incomplete drug labeling, leaving healthcare providers without necessary information to properly prescribe medications to patients with obesity.” Borrowing from the FDA’s own statements in the guidance about the importance of clinical trials accurately representing the patients that a product is intended to treat, the organization stated, it is thus “imperative to include people living with obesity because they represent a significant proportion of the intended use population.” Lastly, the comment letter states that obesity is a complex chronic disease that disproportionately impacts communities of color, “For example, “58% of Black women are living with obesity. If clinical trials only include lean Black women, the trial is not representative of the population.” The organization Emerald Lake Safety shared similar concerns about the lack of information on obesity included in current labeling.
  • While most of the comments submitted to the DAP guidance were put forth by organizations, of the 20+ comments submitted by individuals, most of them interestingly cited this same concern. One individual noted that continuing to exclude persons with obesity in clinical trials perpetuates the marginalization of obese patients in medical care as a whole. Another scolded FDA, stating “Everyone deserves to know how a medication will impact them or be dosed correctly based on their actual size and not from a study that only includes thin people. Excluding larger people is wrong at best, and harmfully neglectful at worst.”

What about age?

  • Where are the requirements for clinical trials to accurately reflect patient age? The guidance states that certain populations, defined by demographic factors like age, have been underrepresented in medical product development and that inclusion of these patients in clinical trials is a priority of the FDA. However, as was raised by the American College of Cardiology, the guidance does not require age-proportionate clinical trial enrollment, the use of evidence-based, clinically relevant cutoffs between different age groups, nor acknowledge that “older persons of similar ages can exhibit differences in health characteristics, including comorbidity, functional impairment, frailty, and polypharmacy, among other geriatric syndromes.” Cardiovascular disease (CVD) is the leading cause of morbidity and mortality for patients over the age of 65, both in the U.S. and globally. The risk of CVD increases with age and researchers estimate that approximately 70% of people aged 70 and older will develop CVD—making this issue uniquely important to the cardiologists who work with, and medicate, this patient group frequently.
  • Still, the letter states that “simply categorizing age as above or below 65 or 75 years is inadequate,” since prognosis, drug response, adverse effect profiles, and metabolism vary greatly with age, especially for patients between 65-75 years of age. Beyond enrollment, the ACC also underscored the need to design trials with older patients in mind. For example, sponsors should account for the extent to which decline in cognitive function could impact “the collection of self-reported outcomes and the use of questionnaire,” and assess both physical and cognitive function—at a minimum—at the time of study entry.

What about global trials?

  • Sponsors have good reason to question the implications of the guidance on their clinical development programs. According to the National Library of Medicine’s database, out of the 511,843 studies currently registered by sponsors and investigators (as of October 10, 2024), nearly 60% (304,977) of trials are conducted either partially or fully at trial sites located outside the United States.
  • In the draft guidance, FDA advised that study enrollment should ultimately reflect the U.S. intended use population, but that DAPs should account for participants outside the U.S. as well. BIO suggested that this “would be impracticable for sponsors for many reasons, including, as noted by FDA, the lack of uniformity in language for population descriptors across the globe.” Not only did other industry and research-oriented groups agree with BIO’s point on inconsistencies in definitions and characterization of demographic data around the world but contended that different countries’ regulatory and legal frameworks could also prevent sponsors from accessing or using this information, even if collected in a way consistent with U.S. practices.
  • Of note, this is one of the issues that the 2024 guidance framed differently from its 2022 predecessor. While the previous draft recommended that sponsors use existing knowledge about potential differences in product performance to adjust and rationalize subgroup enrollment goals, the new draft is broader. The Institute for Clinical and Economic Review (ICER) pointed out that the draft could be interpreted this way, leading sponsors and other stakeholders to view FDA’s goal of “increasing the enrollment of patients from historically underrepresented populations to help improve the strength and generalizability of the evidence for the intended population,” as equating the need for diversity with the need for generalizability.
  • ICER argued that “In fact, in many cases, there is no heterogeneity in treatment effects based on factors such as race, ethnicity, and sex, that are evaluated in clinical trial diversity,” writing that, to “make real progress in clinical trial diversity without compromising on evaluating the generalizability of studies, we recommend that clinical trial diversity be considered distinctly from generalizability. We believe that the key goals of the diversity action plan should be to build public trust in medical research and promote fairness.” From one perspective, the FDA actually aligns with ICER’s view and makes almost the exact same points early on in the guidance. However, the document does later recommend that if data indicates a product may perform differently in certain patient subgroups based on factors associated with race or ethnicity, DAPs 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 population.” Thus, to both BIO and ICER’s points, FDA’s messaging is a bit mixed.

How did we get here and what comes next?

  • As evidenced by the comments, there is a considerable divergence among what various stakeholders are asking FDA to do. Some (mostly public health stakeholders) are asking to FDA to expand the scope of the guidance further. Others (mostly industry stakeholders) are asking FDA to further explain or expand upon the limits of the guidance, including waivers. And some stakeholders (like PhRMA) claim the guidance is not consistent with federal law in some meaningful ways and should therefore be curtailed. Unlike some guidance comment periods, where most feedback provided to the FDA is generally consistent, the FDA may find it challenging to make any changes to its guidance to satisfy one group of stakeholders without irritating another. And based on PhRMA’s comments, even keeping the guidance as-is may invite future litigation from negatively affected drug companies.
  • We expect FDA to tread carefully when assessing changes to the guidance. While the agency isn’t required to finalize the guidance until June 2025, the upcoming Presidential and Congressional elections may result in a new administration or oversight bodies that are less friendly to FDA’s interpretation of its statutory authority for Diversity Action Plans. In particular, any changes made to the guidance to strengthen or expand FDA’s authority with respect to data collection categories or to clarify the manner in which the agency might use the data could invite criticism from conservative-leaning legislators or regulators. And as one senior FDA official told AgencyIQ earlier this year, it seems unlikely that this guidance would be implemented in a meaningful way under a second Trump administration.
  • A key question for both stakeholders and the FDA to answer is: What impact will the guidance actually have? There’s a case to be made for skepticism. Without the explicit authority for the FDA to take specified actions on Diversity Action Plans that do not achieve their stated goals, most of the impact of the guidance will be to increase the amount of information that FDA has at its disposal. What it does with that information is another story.
  • There are historical examples where increased information about diversity hasn’t resulted in meaningful improvements. For example: The FDA’s 1998 Demographics Rule required sponsors to tabulate subjects by age group, gender, and race in Investigational New Drug (IND) annual reports, and to present available safety and efficacy data by sex, age, and race in two documents submitted to FDA as part of the product review process: the Integrated Summary of Safety and the Integrated Summary of Efficacy. However, the rule did not “require any change in the number of studies a drug sponsor needs to conduct, nor does it impose any new requirements on the conduct of those studies. The rule refers only to the presentation of data that already have been collected.”
  • Likewise, the FDA clarified that New Drug Applications needed only to provide descriptive statistics for demographic subgroups, and that the subgroup data “need not be analyzed further and would not ordinarily appear in labeling,” unless clinically meaningful differences were identified. At the same time, the agency acknowledged that demographic subgroups may not be large enough to detect differences in product safety and efficacy. Thus, in practice, this created a bit of a circular dilemma where a lack of evidence on potential differences between demographic subgroups meant that potential differences weren’t being looked for. Since then, numerous research studies have confirmed that these FDA reporting requirements failed to produce meaningful change.
  • But there’s a case to be made that FDA already has – and is already using – authority to make sponsors comply with significant parts of their Diversity Action Plans. According to a recent analysis by AgencyIQ, some FDA divisions are increasingly using its authority to impose certain postmarketing requirements (PMRs) and commitments (PMCs) on companies as a condition of approval. As of the end of July 2024, AgencyIQ found that there were 55 outstanding PMRs and PMCs related to racial and ethnic diversity or representativeness of the population to be studied. Across these instances, the FDA requested that sponsors address these concerns by performing additional data analyses, an integrated assessment, a prospective observational study, or even an entirely new clinical trial. While the oldest still-open requirement included in the database was issued in 2018, the FDA has been making similar requests for sponsors to assess approved products in more diverse patient populations via PMC/PMRs for more than a decade now. However, FDA went from assigning just one of these requirements in 2018 to 14 in 2023 – a significant increase. While the previous version of the DAP guidance (issued in 2022) indicated that sponsors who do not meet their recruitment goals may work with FDA to come up with a plan to collect this data in the postmarketing setting, the new draft does not.
  • Notably, the legislation mandating submission of DAPs did not provide the FDA with any new enforcement tools. This point was driven home forcefully in comments from TOUCH, the Black Breast Cancer Alliance. The group emphasized that since the FDA’s 2022 guidance, their organization hasn’t seen any indication that things have improved, questioning FDA: “Who is managing the farm? How will the guidance be enforced? Whose job will it be to measure the impact of these diversity plans and mandate action for pharma to comply?”
  • In the absence of such tools, if the FDA is interested in enforcing diversity action plans in any meaningful way, it would need to do so on a case-by-case basis leveraging its existing authorities. The agency could, for example, impose certain postmarketing requirements, issue Complete Response Letters if it believes a sponsor has not collected representative data (which does occasionally happen, such as in the case of Eli Lilly’s sintilimab), or refuse to file applications. But this approach takes considerable effort, and past cases indicate that without the threat of meaningful enforcement, companies may not reliably comply. For example, sponsors still do not always adhere to the agency’s 1998 demographics rule, and sponsors also do not always complete their required PMRs.
  • The next critical date to watch: June 26, 2025. The FDORA legislation directed the FDA to finalize the guidance no later than nine months following the close of the comment period on the draft guidance. The comment period ended on September 26, 2024, meaning FDA has until June 26, 2025 to consider the 150+ comments submitted. After the guidance is finalized, sponsors will then have 180 days to comply with its requirements.

Featuring previous research by Laura DiAngelo.

To contact the author of this item, please email Rachel Coe ( rcoe@agencyiq.com).
To contact the editors of this item, please email Kari Oakes ( koakes@agencyiq.com) / Alexander Gaffney ( agaffney@agencyiq.com

Key documents

Get an insider’s view on regulatory movements.

Sign up for AgencyIQ’s newsletters to receive exclusive regulatory updates and analysis impacting the life sciences or chemical industry.

Copy link
Powered by Social Snap