
==== Front
Contemp Clin Trials Commun
Contemp Clin Trials Commun
Contemporary Clinical Trials Communications
2451-8654
Elsevier

S2451-8654(24)00078-4
10.1016/j.conctc.2024.101331
101331
Article
Regulatory landscape with U.S. patient requirements and Clinical Trial Diversity expectations
George Elizabeth a⁎
Baker McDowell Alicia b
Vozza Melissa c
Mitchell Talley d
Quartley Ben e
Kennedy Cassandra S. f
Hanlon Bill g
a Patient Diversity, Labcorp, USA
b Regulatory Strategy, Fortrea, USA
c CDCS Regulatory Compliance & Quality Assurance, Fortrea, USA
d Patient Recruitment Services, Labcorp, USA
e Patient Recruitment & Engagement, Labcorp, USA
f Quality, Regulatory Affairs & Sustainability, Fortrea, USA
g Real-World Data Product Strategy, Labcorp, USA
⁎ Corresponding author.
06 7 2024
12 2024
06 7 2024
42 1013311 8 2023
14 6 2024
5 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
The Food and Drug Administration (FDA) has an expectation that products filed for marketing authorization have to include data that are representative of the US patient population. Any foreign clinical data that is submitted has to represent an ethnically diverse population that is generated utilizing qualified Principal Investigators (PIs) and conducted according to Good Clinical Practices (GCP) requirements outlined in 21 CFR 312.120, Foreign clinical studies not conducted under an IND. With the recent passing of the Omnibus Legislation, FDA now also has the authority to require Diversity Plans for all Phase 3 clinical trials of new drugs or “as appropriate, another pivotal study of a new drug.” The FDA has released a guidance document, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials” (April 2022), for the industry with expectations to update the document in 2023 now that legislation is passed. This whitepaper discusses the FDA guidance and expectations of sponsors with regards to foreign clinical data and the intersection with enrolling ethnically diverse populations in clinical studies.
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pmc1 Introduction

Over the years, the FDA has issued multiple guidance for the industry to focus on increasing the diversity and participation of underrepresented populations in clinical trials. However, trials continue to enroll very homogenous populations that do not represent the real-world populations with disease. The most recent FDA guidance “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials” in April 2022, has clear expectations for sponsors to adhere to specific guidelines for appropriately diverse populations in studies of medical products (i.e., drugs and medical devices) planned for marketing authorization submission. This paper reviews FDA expectations for clinical trial data collected outside the US and diversity in clinical trials.

2 Current regulatory landscape

Image 1

Sponsors submitting clinical trial data to support marketing authorizations and/or label changes to the FDA need to comply with FDA guidance on foreign clinical data and FDA guidance on the expectation for representation of under-represented racial and ethnic minorities in the trials.

Acceptance of foreign clinical data in submissions has to be applicable to the US patient population. The study must be performed by Principal Investigators (PIs) of recognized competence internationally and has to follow GCP requirements. Regulators look at the PIs and sites and routinely inspect sites conducting clinical trials to verify GCP requirements are being followed.

3 FDA guidance on applicability of foreign clinical data to the U.S. Population

FDA has issued guidance for the industry on FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND [1].

3.1 Per guidance in 21 CFR 314.106 (b)

As sole basis for marketing approval. An application based solely on foreign clinical data meeting U.S. criteria for marketing approval may be approved if: (1) The foreign data are applicable to the U.S. population and U.S. medical practice; (2) the studies have been performed by clinical investigators of recognized competence; and (3) the data may be considered valid without the need for an on-site inspection by FDA or, if FDA considers such an inspection to be necessary, FDA is able to validate the data through an on-site inspection or other appropriate means. Failure of an application to meet any of these criteria will result in the application not being approvable based on the foreign data alone. FDA will apply this policy in a flexible manner according to the nature of the drug and the data being considered.

Recent instances where the FDA did not approve applications submitted on entirely limited foreign data from a single country include surufatinib [2], toripalimab [3] and sintilimab [4] applications filed with the FDA based on clinical data from China only. The FDA indicated that the data submitted in the application was not generalizable to the U.S. population. Furthermore, the FDA cited a need for multi-regional clinical trials in order to gain approval in the U.S. These applications were too heavily weighted towards a single ethnicity, which was not representative of the US patient population and, additionally in these cases, there wasn't an unmet medical need. While US patients are not required for a clinical program, sponsors have to pay attention to the diversity of the entire clinical development program. It is important for sponsors to engage with the FDA early and often through the clinical milestone meetings to ensure alignment.

4 ICH guidelines

ICH E5 (R1) Ethnic Factors in the Acceptability of Foreign Clinical Data [5] and ICH E17 General Principles for Planning and Design of Multi-Regional Clinical Trials [6], address the international expectations for diversity in trials and have been adopted by global regulatory agencies. The ICH guidelines have informed the basis for the US patient requirements. ICH E5 (R1) provides a framework for evaluating the impact of ethnic factors on the safety and efficacy of a medicine in order to facilitate the registration of medicines among ICH regions (Europe, Japan, United States).

Multi-regional clinical trials (MRCTs) can be accepted by regulatory authorities across different regions to support the marketing approval of drugs. ICH E17 provides general principles for the planning and design of MRCTs with the goal of increasing the acceptability of MRCTs in global regulatory submissions. Sponsors often submit data from MRCTs to multiple regulatory authorities simultaneously without a harmonized regulatory view on the clinical development programme. MRCTs that are properly designed and executed according to ICH E17 could facilitate more effective drug development and reduce the time to bring new drugs to market worldwide. MRCTs have been recognized as an efficient way to enable recruitment of the planned number of relevant participants (e.g. rare, pediatric, elderly, etc.). MRCTs may enhance scientific knowledge about variation of treatment effects across regions and populations under a single study protocol and whether the variation can be explained by intrinsic and extrinsic factors [6].

5 FDA guidance on Diversity Plans and legislation

In April 2022, the FDA issued draft guidance for the industry with Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials [7]. The guidance provides clear expectations for sponsors to provide Diversity Plans for all studies, not just pivotal ones. The guidance specifies that the FDA recommends that the Diversity Plan be submitted with the investigational new drug (IND) application, for a drug or biologic, or the investigational device exemption (IDE) application, for a device. Sponsors are expected to work on Diversity Plans as early as practicable in development and to discuss the Plan with the FDA early and often. For drugs, this should occur no later than the End of Phase 2 (EOP2) meeting, when sponsors are seeking feedback for the applicable pivotal trial(s) for the drug.

Within the Diversity Plans, sponsors are expected to provide enrollment goals based on the target patient population for an indication and the epidemiology of the disease. Understanding the limitations of datasets, sponsors may need to consider multiple sources to establish realistic goals leveraging real-world data and published literature. Sponsors will need to develop a plan of action to engage, enroll and retain diverse participants, as well as establish metrics to ensure that the enrollment goals are achieved. The Diversity Plan should be updated in an ongoing manner and the metrics should be reported to the FDA as agreed upon in the Diversity Plan. However, a sponsor should consider more frequent monitoring of the metrics internally to take necessary mitigation steps to support meeting enrollment goals. In the event the enrollment goals are not met, a plan and justification to collect the data in a post marketing setting will be needed.

In December 2022, the U.S. Congress passed the Food and Drug Omnibus Act (FDORA), and among the many provisions in the legislation there is a requirement for drug and device sponsors to submit diversity action plans articulating goals for enrollment of participants that represent the intended patient population for the product. Barriers to inclusion of historically underrepresented populations will need to be identified with proposed mitigations. With the legislation, Congress has endorsed and strengthened FDA's ability to require that sponsors enroll and retain participants from underrepresented populations.

6 Recommendations for sponsors

Given the draft guidance issued by the FDA on Diversity Plans and the legislation that was passed, it is imperative for sponsors to prioritize diversity in clinical trials to meet regulatory expectations.

We recommend sponsors consider diversity as early as the Phase 1 studies to gather valuable insights on potential safety, PK/PD differences in populations early on that can be taken forward within the clinical development program. In the Draft Guidance on Diversity Plans, the FDA has recommended sponsors request FDA feedback on Diversity Plans by including specific questions in a formal milestone meeting request (line 153–154). Our recommendation is for sponsors to develop the Diversity Plan and get FDA input at the pre-IND meeting to facilitate development of an acceptable diversity plan and to allow for operational planning to recruit studies. The End of Phase 2 meeting may be too late, as it is prudent to have negotiated the Diversity Plan with the FDA ahead of launching the Phase 3/pivotal study since the negotiation can take time. Having the earlier discussion will avoid unnecessary delays and additional costs to the Phase 3 study.

While the FDA guidance to the industry on Diversity Plans is still Draft at this time, the expectation of sponsors is unlikely to change with the final guidance, and therefore it is advisable for the industry to start building in appropriate strategies to increase the diversity of the enrolled participants in clinical trials. Sponsors are expected to provide Diversity Plans before filing for a Phase 3 or pivotal clinical trial and are required to provide such a plan for all trials whose enrollment will begin at least 180 days from the issuance of the FDA's final guidance on Diversity Plans.

Although a Refusal to File (RTF) decision from the FDA for lack of diversity in clinical trials is not known to have been issued to date, there is the potential that the FDA could issue an RTF if sponsors do not provide relevant diversity data or submit a Diversity Plan. A call to action to sponsors is to proactively consider prioritizing the collection of diversity data in clinical trials to mitigate future RTFs.

7 Post marketing studies

The FDA has issued Post Marketing Commitment (PMC) and Post Marketing Requirement (PMR) studies before the Draft Guidance on Diversity Plans was issued in April 2022 and passing of the FDORA legislation. Examples of PMC/PMR studies issued by the FDA include:• Sotorasib (PMC) [8] – The patient population enrolled in Study 20170543 included a small proportion of African American patients (2 %). This is not reflective of the incidence of the KRAS G12C mutation in African American patients with advanced NSCLC in the U.S. (10 %); therefore, the Applicant will provide the results of clinical trials enrolling a sufficient number of African American patients as a post-marketing commitment in order to further characterize the safety and efficacy of sotorasib in these patients. A total of 15 % of the study population was Asian, which is sufficiently representative of the overall population of Asian patients with NSCLC with KRAS G12C mutations. KRAS mutations are generally more prevalent in the Western population than in Asia, and in the U.S., the KRAS mutation is found in a higher proportion of White and Black patients than in Asian patients (Nassar 2021).

• Amivantamab (PMC) [9] – Information submitted by the Applicant utilizing data from Flatiron Health reported 9.4 % of patients with NSCLC with EGFR exon 2insertion mutations were Black or African American. In the primary efficacy population of the CHRYSALIS study, 2.3 % of patients were Black or African American. Based on the demographic and baseline disease characteristics of the patients in the primary analysis population for this application, this population is comparable to the overall U.S. target population, with the exception that Black or African American patients were underrepresented. The benefit demonstrated in the CHRYSALIS study is expected to extend to the post-market setting. A PMC was agreed to for the Applicant to submit clinical trial data to further characterize the safety and efficacy of amivantamab in Black or African American patients with EGFR exon 20 insertion mutated NSCLC.

• Melphalan flufenamide (PMR) [10] – Submit an integrated final report containing data from clinical trials including trial OP-108 to further characterize the exposure of melphalan flufenamide, the increased risk of serious adverse events including hematologic toxicities, and efficacy among U.S. racial and ethnic minorities including Black patients with relapsed or refractory multiple myeloma. Provide the pharmacokinetic analysis in the interim report.

Having reviewed the various FDA and ICH guidance that have been issued to the industry, it is time to look at what the industry must focus on to have a direct and positive impact on clinical trial diversity.

8 Increase diverse participation in clinical trials

Although the new FDA guidance helps to shine a spotlight on the need for change, numerous barriers still exist that result in inadequate diversity within clinical trial populations. Some of these barriers include lack of awareness, access, transportation and financial challenges. These challenges negatively impact more diverse communities as well as those living in rural areas. Spreading awareness of clinical trials for both patients and providers and destigmatizing the clinical trial experience are pivotal to increase trial participation. Utilizing direct to patient communications such as emails and social media can help educate people directly where they typically consume information and provide linkages to actual study opportunities. However, it is also important to raise awareness with physicians, and to enable physicians to discuss clinical research with their patients as part of routine care visits. These physician-patient discussions build trust in clinical trials and empower patients to choose clinical research as a care option. Additional approaches need to be considered such as engaging community health care centers, Federally Qualified Health Centers (FQHCs) and diverse investigators to broaden the geographic scope of clinical trials in order to reach patients where they are located, thereby easing the burden of participating in trials.

Moving beyond simply increasing awareness, it is important for the industry to focus on innovative solutions to address the spectrum of barriers faced by patients in clinical trial participation. Support services such as a concierge to plan and guide patients and caregivers through the events of a long study visit day or having a transportation service that provide rides for patients to and from the clinical site should be considered.

Adding decentralized trial elements such as having a mobile nursing unit come to a patient's home or place of work, shipping the study drug directly to patient's home, telemedicine visits, and/or allowing the patient to receive a study blood draw at a lab location closer to home, can make study participation more appealing and accessible. Many of these decentralized trial options were made available to patients during the COVID-19 pandemic and should continue to be made available and expanded. However, these conveniences ultimately need to be balanced against a patient's preferences and comfort levels, while still maintaining compliance with all regulatory and GCP elements of a trial.

Although there have been strides towards addressing the convenience of study participation, the industry needs to continue to listen to patients and care givers, innovate and to evolve the way in which clinical trials are both designed and conducted. Clinical research must change to truly keep the patient at the center of the overall process and to bring the patient voice and insight into all aspects of the clinical trial. Patient and care giver feedback should be incorporated beginning with protocol design, continuing with enrollment and conduct of the trial, and through the end of the clinical trial to apply the learnings to subsequent trials.

CRediT authorship contribution statement

Elizabeth George: Conceptualization, Writing – original draft, Writing – review & editing. Alicia Baker McDowell: Writing – original draft, Writing – review & editing. Melissa Vozza: Writing – review & editing. Talley Mitchell: Writing – original draft, Writing – review & editing. Ben Quartley: Writing – review & editing. Cassandra S. Kennedy: Resources, Writing – review & editing. Bill Hanlon: Conceptualization, Resources, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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References

1 Guidance for Industry and FDA Staff FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND Frequently Asked Questions.
2 Hutchmed press release. https://www.hutch-med.com/suru-fda-nda/.
3 Coherus press release https://investors.coherus.com/news-releases/news-release-details/coherus-and-junshi-biosciences-receive-complete-response-letter.
4 Lilly press release https://investor.lilly.com/news-releases/news-release-details/lilly-announces-complete-response-letter-sintilimab-combination.
5 ICH E5 (R1) Ethnic Factors in the Acceptability of Foreign Clinical Data.
6 ICH E17 General Principles for Planning and Design of Multi-Regional Clinical Trials.
7 Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, Draft Guidance for Industry.
8 “Sotorasib.” FDA. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214665Orig1s000MultidisciplineR.pdf. Accessed April 2023.
9 “Amivantamab-vmjw.” FDA, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761210Orig1s000MultidisciplineR.pdf. Accessed April 2023.
10 Melphalan flufenamide.” https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214383Orig1s000MultidisciplineR.pdf. Accessed April 2023.
