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Guidance will compel sponsors to consider new enrollment strategies and to be more diverse.
On May 2 of this year, FDA issued a complete response letter for surufatinib, an oral angio-immunokinase inhibitor developed for the treatment of pancreatic and extra-pancreatic neuroendocrine tumors.1 The NDA for surufatinib was supported by two Phase III studies conducted in China, and a bridging trial conducted in the US. Per the complete response letter, a multi-regional clinical trial that includes patients representative of the US population and medical practice consistent with current US standards will be required for FDA approval.
This is the second such rejection of a cancer drug by FDA this year: on March 24, a complete response letter was issued for sintilimab, a PD-1 inhibitor developed in combination with pemetrexed and platinum chemotherapy for the first-line treatment of nonsquamous non-small cell lung cancer.2 The BLA for sintilimab was supported by a Phase III trial conducted exclusively in China. At a February 10, 2022, Oncologic Drugs Advisory Committee meeting, the committee voted 14 to 1 that FDA should require additional studies demonstrating applicability to patients in the US and to US medical practice before approval. The complete response letter reiterated the requirement for a multi-regional clinical trial.
Although FDA has previously published guidance encouraging diversity in clinical trials,3 little progress has been made in improving the representation of racial/ethnic subgroups in trials of cancer therapies: in the trials supporting the 15 novel drug approvals for cancer indications in 2021, the majority of patients (72-95%) were White.4 Inadequate representation of the patient population limits the generalizability of cancer clinical trial results and contributes to the efficacy-effectiveness gap, whereby real-world patients may experience lower median survival outcomes and greater toxicity relative to trial participants.5 Cancer drugs represent the largest share of new therapies currently in development,6 therefore it is critical to change this pattern and ensure that future trials generate data relevant to the patients who will eventually receive the drug. FDA’s recent actions, including the two complete response letters referenced above, indicate an awareness of the urgency and a shift towards a tougher stance.
With the April issuance of a new draft guidance, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials”,7 the Agency sends a clear message: racial and ethnic diversity in clinical trials cannot be an afterthought. The guidance recommends the prospective development of a plan to address the inclusion of representative numbers of patients from racial and ethnic subgroups in clinical trials. In this article, several key points in the guidance as they relate to cancer drug development are reviewed.
FDA recommends that the sponsor discuss the plan with the Agency no later than when seeking feedback on pivotal trials, which would be the End of Phase II meeting for many drug development programs. However, cancer drugs frequently follow an expedited path, and utilize trials with designs and endpoints intended to streamline the development program. First-in-human Phase I studies that utilize expansion cohorts and transition into Phase II may end up being the sole pivotal trial supporting the marketing application. For example, sotorasib8 received accelerated approval on May 28, 2021 for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer who have received at least one prior systemic therapy, based on the safety and objective response rate outcomes of 124 patients in the CodeBreaK 100 trial, a first-in-human Phase I/II study initiated less than three years prior. Thus, sponsors developing cancer drugs may need to be prepared to discuss their plan with the Agency much earlier, potentially from the outset of their program. Indeed, as the guidance underscores the importance of capturing pharmacokinetic, pharmacodynamic and pharmacogenomic data from a diverse population, Phase I would be the optimal time to begin.
As the guidance notes, limited data may be available regarding the racial/ethnic incidence or prevalence of the specific disease in question. For cancer in particular, it is well established that significant disparities exist in access to cancer screening and treatment among racial/ethnic subgroups, hence even where data exists, it may under-report the actual numbers.9 In addition, a growing segment of new cancer drugs in development are targeted therapies which are mutation-specific: 66 such targeted therapies were approved by FDA between 2001-2021.10 Disparities in access to next generation sequencing and other testing to identify the presence of genetic aberrations may further complicate assessment of the true incidence of the mutation by racial/ethnic population.11 For these reasons, defining the enrollment goals for under-represented racial and ethnic participants in cancer clinical trials may be problematic.
Another factor to consider is the increasing proportion of cancer drug approvals for orphan or rare indications in recent years. Between 2017 and 2020, more than half (63.5%) of cancer drugs receiving original or supplementary approvals were granted orphan drug designation for the indication.12 With few patients available to participate in clinical trials, enrollment can be challenging, and studies may employ a single arm design and small sample size. In these cases, where patients are already, by definition, hard to come by, the added stipulation of needing to meet certain enrollment goals for racial or ethnic participants builds in another layer of complexity.
FDA acknowledges in the guidance document that even with best efforts, a sponsor may not be able to achieve their enrollment goals as outlined in their plan. When this occurs, sponsors may be able to fulfill their diversity plan obligations by collecting the data in the post-marketing setting. The Agency has already made use of this mechanism in the past few years to require data on a more diverse patient population for approved cancer drugs.12 For example, umbralisib received accelerated approval on February 5, 2021 for the treatment of adult patients with relapsed or refractory marginal zone lymphoma who have received at least one prior anti-CD20-based regimen, and for the treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least three prior lines of systemic therapy.13 The supporting UNITY-NHL trial enrolled 69 patients with marginal zone lymphoma and 117 with follicular lymphoma:14 in total, 89% of enrolled patients were White, 6% were Black, 3% were Asian, and 5% were Hispanic.4 In the approval letter, FDA issued a post-marketing commitment for a “…final report containing data from clinical trials, post-marketing reports, compassionate use/expanded access program, real-world evidence, and other sources to further characterize the safety and efficacy of umbralisib monotherapy and in combination with immunotherapy among U.S. racial and ethnic minority patients with follicular lymphoma or marginal zone lymphoma.”13 While real-world data has limitations, its use in this context is appropriate to complement clinical trial findings and characterize a drug’s safety and effectiveness in a broader patient population.
Despite the challenges that will inevitably arise in implementing the new guidance, its issuance represents a significant step forward. Importantly, it creates the impetus for sponsors to prospectively think about and devise a concrete operational plan to recruit and retain diverse patients in their clinical trials. In the race to drug approval, especially for therapies to treat serious or life-threatening conditions such as cancer, sponsors are focused on efficiency. This often translates into repeating what worked in the past for previous trials, e.g. using similar protocol inclusion/exclusion criteria, or returning to sites that were good enrollers. The new guidance compels the sponsor to consider whether these same tactics will help them accomplish their enrollment goals for under-represented racial/ethnic populations, or whether a change is needed. The application of new strategies and different approaches to meet these goals can improve the evidence generated in cancer clinical trials15—and it is the right thing to do for patients.
Marjorie E. Zettler, PhD, MPH, Executive Director of Clinical Science, Regor Pharmaceuticals, Inc.