Although clinical research is evolving alongside new technological advances, the inclusion of diverse populations within clinical trials has been slow. Regulatory professionals are essential stakeholders in the quest for ensuring inclusivity of these groups. It is increasingly obvious that regulatory functions cannot work in isolation to improve clinical research. Recent COVID-19 clinical trials and vaccine roll outs have highlighted stark problems that have existed within the industry for years, specifically the treatment of patients from historically marginalised communities. Awareness of this problem has emphasised the need for improvements within the clinical trial industry as a whole and a deeper understanding of the importance of increased diversity of populations participating in clinical research.
It is increasingly important to focus on the relatively neglected area of inclusivity of diverse populations within clinical trials. It is now an area that affects not just clinical research, but also the availability of new medicines and therapies to all patients. Diversity in clinical research is in a new era. It is imperative, not just in a business sense but also in a moral and social justice sense, to focus on inclusivity. For many years, diversity has not been a priority in clinical research. Historically, there have been multiple priorities and facets within the industry that have coalesced to enable successful clinical research. However, more comprehensive research will have to embrace diverse populations. Now that there is a long-awaited spotlight on this area, there is motivation from all members of the clinical research industry to do better. While this realisation is long overdue, there is still serious attention that needs to be paid to the methodology employed to accelerate diversity initiatives. Regulatory affairs must challenge the clinical research community to renew its focus on diversity and inclusion.
Diversity – why a regulatory perspective?
Regulatory agency guidance
In November 2020, the US FDA released its final guidance ‘Enhancing the diversity of clinical trial populations – eligibility criteria, enrolment practices, and trial designs guidance for industry’. There is an expectation that other regulatory agencies will follow suit, with specific guidance offered to sponsor companies, to encourage or even mandate recruiting and retaining clinical trial participants from diverse populations. Questions on diversity, asked by regulatory agencies, are put to sponsor companies not only when an application for approval is submitted, but as early as engagement meetings with the agencies. The FDA final guidance describes how the study population should be more representative of the population that will use the drug if it is approved, such as: broadening the eligibility criteria and adopting more inclusive enrolment practices during development; facilitating the discovery of important safety information about the use of investigational drugs in patients who will take the drug after approval; and increasing the ability to understand the therapy’s benefit–risk profile in the later stages of drug development across the patient population who are likely to use the drug. The FDA encourages sponsors to consider the approaches outlined in the guidance and develop other approaches as appropriate.
ICH E6 (R3) Good Clinical Practice
Good guidance is an enabler. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 (Revision 3) Good Clinical Practice (GCP) revision draft principles published in March 2021 states: “Clinical trial designs that bring the trial to participants and their communities may improve the representativeness of the participant population and enable wider participation. The process of building quality into the design of the trial may be supported by the participation of those directly involved”. Regulatory authorities should implement stricter reviews of clinical trial applications and protocols and challenge any pharmaceutical companies that are excluding relevant populations. There are specific populations to consider, as outlined below.
It is well-documented that women are under-represented in clinical trials, and that medications may aff ect males and females in diff erent ways. According to the FDA’s drug trials snapshot, females accounted for 56% of participants in clinical trials that lead to drug approvals in 2020. Although this number is encouraging, the FDA’s Center for Drug Evaluation and Research approved 53 novel drugs where, upon a deeper examination, some drugs had been approved where female participation was low. Such under-representation can result in females having more incidences of adverse side effects to approved drugs, owing to biological differences or incorrect dosages that were not explored deeply enough when the drug was being developed. One study investigated how sex differences in pharmacokinetics could predict adverse drug reactions in females. It delved deep into how sex differences in pharmacokinetics can predict adverse drug reactions in women. The lack of females in drug dose trials often leads to overmedicated women, with females experiencing adverse drug reactions nearly twice as often as males.
|Title of guidance||Date of issuance||Status|
|Considerations for the inclusion of adolescent patients in adult oncology clinical trials||March 2019||Final|
|Inclusion of older adults in cancer clinical trials||March 2020||Draft|
|Cancer clinical trial eligibility criteria: patients with HIV, hepatitis B virus, or hepatitis C virus infections||July 2020||Final|
|Cancer clinical trial eligibility criteria: patients with organ dysfunction or prior or concurrent malignancies||July 2020||Final|
|Cancer clinical trial eligibility criteria: brain metastases||July 2020||Final|
|Cancer clinical trial eligibility criteria: minimum age considerations for inclusion of paediatric patients||July 2020||Final|
|Male breast cancer: developing drugs for treatment||August 2020||Final|
|Premenopausal women with breast cancer: developing drugs for treatment||June 2021||Final|
|Cancer clinical trial eligibility criteria: available therapy in non-curative settings||June 2021||Draft|
|Evaluating cancer drugs in patients with central nervous system me||July 2021||Final|
The exclusion of older populations in clinical trials remains a significant problem, especially as the global population is ageing. This is surprising based on the guidance available, including the 1993 ICH-E7 guideline: ‘Studies in support of special populations: geriatrics’. This guideline defi nes the geriatric population as patients aged 65 years or over, which was implemented widely as a general principle: “Drugs should be studied in all age groups, including the elderly, for which they will have significant utility. Patients entering clinical trials should be reasonably representative of the population that will be later treated by the drug”. It also highlights the importance of “not to exclude unnecessarily patients with concomitant illnesses; it is only by observing such patients that drug-disease interactions can be detected” and “for drugs used in diseases not unique to, but present in, the elderly, a minimum of 100 patients would usually allow detection of clinically important differences”
A published analysis reviewed all COVID-19 trials on (clinicaltrials. gov/) to evaluate the risk for exclusion of older adults ≥65. Findings show that although older adults are at greatest risk of severe disease and death from COVID-19, they are likely to be excluded from more than 50% of Phase 3 COVID-19 trials on (Clinicaltrials.gov)., Such exclusion will limit the potential to evaluate the efficacy, dosage and adverse effects of the intended treatments.
The National Cancer Institute (NCI) highlights that advancing age is the most important risk factor for cancer overall, with more than 1,000 per 100,000 people in age groups 60 years and older. A study into older adult participation in cancer clinical trials highlights the complex, burdensome and structural impediments that effectively exclude older and frail patients with cancer from clinical trials. To address this, the NCI says that the current research infrastructure must be modified to accommodate the needs of older patients. If their inclusion cannot be operationalised, we must determine new ways to meet older adults where they are, rather than where they should be, to fit the current structure.
Racial and ethnic minorities
Racial and ethnic minority groups are frequently under-represented in clinical research. This is an important consideration as there may be genetic and pharmacokinetic differences for racial or ethnic minority populations. A review of the literature on the influence of race or ethnicity on the pharmacokinetics of analgesics found that there may be diff erences in bioavailability, hepatic metabolism, renal secretion, protein binding and distribution.For this reason: “A patient’s genetic makeup should be considered when prescribing medications that are known to be aff ected by genetic factors. Research in the area is limited, but pharmacokinetic studies of codeine have demonstrated that 10% of the white population and 0.5% of the African American and Asian populations obtain no pain relief from codeine due to the lack of an enzyme needed for the metabolism of codeine to morphine. However, although pharmacogenomics has the potential to identify a particular analgesic that may not work in certain populations, more research is needed”. These differences should not be ignored. For the influenza virus, there are significant variations in genetic factors that affect vaccine response, with one important human gene having 14 different forms that vary greatly between black people, Asian people and white people. As the different polymorphic forms of the antibody produced bind to different targets on the viral surface, there could be potentially significant variation in vaccine effectiveness.
In the same way as other populations, research has demonstrated that LGBTQ individuals experience numerous health disparities and barriers linked with sexual orientation and gender identity. As a result, many members of the community choose either to avoid healthcare altogether or receive substandard care, owing to societal stigma and discrimination by healthcare providers and organisations. It is difficult to ascertain to what extent LGBTQ patients are under-represented in clinical trials because a large majority of studies do not collect data on sexual orientation or gender identity, which leads to a lack of knowledge regarding this population. Each subgroup within the LGBTQ community has unique health needs and experiences unique health disparities. Emerging evidence suggests that cancer in the LGBTQ population is a growing epidemic and this population experiences increased risk and poorer outcomes for some cancers. The National Institutes of Health recently designated cancer in LGBTQ populations as a priority research area because they are a medically underserved and disparate population. A survey in the US of oncologists at the NCI–Designated Comprehensive Cancer Centers was completed to measure attitudes, knowledge, institutional practice behaviours, and interest in education on the care of LGBTQ patients with cancer. Overall, there was limited knowledge about LGBTQ health and cancer needs but a high interest for education.
|Areas to consider||Steps required to build a diversity plan|
|Overview of the disease/condition||
Summarise available information on the incidence and prevalence of the disease/condition in both the overall population and in the Racial Ethnic Minority (REM) subgroups
|Target enrolment of REM subjects||
Define and provide justification for the planned accrual of subjects from REM subgroups.
|Scope of drug development programme||
Describe the planned studies that will support the safety, efficacy and dosage of the medical product in a future marketing application. Outline the following:
|Measures to enrol diverse population||
Describe in detail the measures that will be implemented to enrol and retain REM subjects in the planned trial(s), and the planned use of data from trials to characterise safety, efficacy and dosage in these subjects. Describe trial accrual and retention strategy in terms of:
|Justification for deferral to post-approval||
Describe factors precluding obtaining data in pivotal trial(s).
People with disabilities
Patients with disabilities have a similar problem to LGBTQ patients as they are largely absent from mainstream health research. Exclusion of people with disabilities may be explicit (attributable to poorly justified exclusion criteria) or implicit (attributable to inaccessible study documents, interventions or research measures). Meanwhile, people with disabilities experience poorer health, greater incidence of chronic conditions and higher healthcare expenditure than people without disabilities. Patients with disabilities may be asked to sign informed consent forms that they do not understand without assistance, and visits to clinics may be restricted owing to lack of driving ability or wheelchair access.
Cancer patients In a paper, the FDA reflected on diversity in the oncology space: “Members of racial and ethnic minority groups in the US are frequently under-represented in clinical trials submitted to the US Food and Drug Administration (FDA) to support the approval of anticancer therapeutics. The FDA has long held the view that trials should represent the populations for which the therapeutic is intended, to ensure the external validity of results. The FDA recommendations to improve trial diversity address the collection and analysis of data on racial and ethnic minority groups, describe considerations for broadening eligibility and encourage discussions with the appropriate division at the FDA regarding enrolment plans. External stakeholders have also recommended that pharmaceutical companies develop a plan that outlines measures to ensure diverse clinical trial participation. In oncology, a greater reliance on small studies, intermediate and early endpoints and innovative trial designs to expedite drug development and approval underscore the need to prospectively define such a plan”. 
The FDA has been consistently stipulating that studies ensure racial and ethnic minority subjects are enrolled. As an example, in May 2021, it approved [accelerated approval] Truseltiq (infigratinib) capsules for oral use, for treatment of adult patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with fi broblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangement as detected by an FDA-approved test.
There was a post-marketing requirement to: “Submit the final progression-free survival (as assessed by blinded independent review) analysis and interim overall survival analysis at the time of final progression-free survival analysis, including datasets from a randomised clinical trial comparing infigratinib to chemotherapy to verify and describe the clinical benefit of infigratinib in patients with advanced or metastatic cholangiocarcinoma harbouring an FGFR2 gene fusion or other rearrangement. Ensure that racial and ethnic minority subjects are adequately represented in the trial population, at a minimum, proportional to the prevalence of FGFR2 alterations in these subgroups in the US population”.
Earlier in 2021, Pfizer conducted a vigorous and industry-first transparent analysis of its US clinical trials initiated between 2011 and 2020. The review included 213 clinical trials studying cancer, rare diseases, vaccines, inflammatory and autoimmune diseases and neurological conditions. Making this data transparent is a call to action for industry to follow suit. Research findings showed that more than half of Pfizer trials included black participants at rates approximately equal to their representation in the overall population. However, black people were under-represented in cancer-related studies. Around 16% of oncology studies included proportional representation of black people. Hispanic or Latino individuals are under-represented in clinical trials, particularly in cancer-related studies. Just 6.5% of oncology trials included proportional representation of Hispanic or Latino people. It will take time to achieve equitable representation in clinical trials.
Consideration is being given to the idea of having a plan that outlines measures to ensure diverse clinical trial participation from racial and ethnic minority (REM) groups. Table 2 shows the information that could be in such a plan.
Another approach: decentralised trials
There has been discussion in industry about decentralised clinical trials (DCTs) and how use of these could solve the diversity problem in clinical research. We must understand that the use of pure technological advancements and reliance on DCT solutions rather than a hybrid approach may have the opposite effect and amplify the problems by not making technology accessible to marginalised groups. There is an assumption that patients have access to smartphones, computers, internet access, data plans or even want to have access to the aforementioned. The pandemic demonstrated many barriers to digital health access. The ICH E6 (R3) GCP revision addresses flexibility whenever appropriate to facilitate the use of technological innovations in clinical trials. The draft principles, published in March 2021, highlight that the use of innovative technologies may help enable those designing and conducting a trial to include relevant patient populations. Clinical trials designs that bring the trial to participants and their communities may improve the representativeness of the participant population and enable wider participation.
There have been many initiatives within industry to encourage an increase in diversity in clinical research. For example, in November 2020, PhRMA, which represents the leading biopharmaceutical research companies, published the first ever industry-wide principles that took effect in April 2021. At the core of these principles is a need for industry to better serve historically underserved populations.
The five principles focus on:
- enhancing education throughout the medical community and diversity among clinical investigators
- highlighting eff orts to increase clinical trial awareness and participant diversity by improving individual health literacy and community outreach, such as partnering with health and community advocacy groups
- working to identify and reduce barriers to clinical trial access and participation
- the use of real-world data to enhance information on diverse populations beyond product approval
- enhancing information and promoting transparency about diversity and inclusion in clinical trials.
Regulatory professionals are essential stakeholders in the quest for ensuring that diverse populations and regulation do not work in isolation from other stakeholders. A diversity plan could be incorporated into the clinical development plan or regulatory strategic plan, or a standalone document could be created that is a living document throughout the asset’s journey of development
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