The FDA Oncology Center of Excellence Scientific Collaborative: Charting a Course for Applied Regulatory Science Research in Oncology

Abstract

The FDA Oncology Center of Excellence (OCE) is a leader within the agency in scientific outreach activities and regulatory science research. Based on analysis of scientific workshops, internal meetings and publications, the OCE identified nine scientific priority areas and one cross-cutting area of high interest for collaboration with external researchers. This paper describes the process for identifying these scientific interest areas and highlights funded and unfunded opportunities for external researchers to work with FDA staff on critical regulatory science challenges.

Introduction

The Oncology Center of Excellence was established in 2017 as authorized by the 21^st Century Cures Act. The OCE leverages the combined skills of regulatory scientists and reviewers with expertise in drugs, biologics, devices, and diagnostics to support an integrated approach to the clinical evaluation of medical products addressing cancer. For products that are selected for expedited review, OCE forms an interdisciplinary medical oncology review and evaluation team with representatives from the appropriate FDA centers, including CDER, CBER, and CDRH. The clinical review is sent to the product center to incorporate reviews of quality, toxicology, statistics, manufacturing, and facilities inspection to make the final approval determination (1).

In addition to review activities, OCE oversees a robust regulatory science effort focusing on scientific questions that arise during regulatory review. The OCE emphasizes applied research, rather than the basic and translational science supported by organizations such as the National Cancer Institute. Applied research focuses on solving a specific, practical problem rather than expanding general knowledge. This work is consistent with FDA’s recent efforts to support regulatory science research, defined as the “science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of certain FDA-regulated products” in the 2011 FDA Strategic Plan for Regulatory Science (2) and the recently published FDA focus areas of regulatory science (3). FDA subsequently developed new mechanisms such as the FDA Broad Agency Announcement (BAA) (4) and the Centers for Regulatory Science and Innovation (CERSI) (5) to provide funding to external scientists to address high-priority regulatory science questions (described below).

Drug development is costly and time consuming, and there is a great need for novel, scientifically sound approaches that can improve efficiencies, deepen our understanding of safety and efficacy, and expand access to investigational therapies through facilitating trial participation (6). Development of novel endpoints (7, 8, 9, 10, 11) and statistical approaches (12, 13, 14) are examples of applied research, but there are many others. The OCE has contributed to research across drug development including clinical pharmacology and dose optimization (15), use of real-world data (16), effects of expanded eligibility criteria (17) clinical outcome measures (18), clinical trial diversity (19), novel data analysis and visualization methods (20), and many other key aspects of cancer product development. The majority of this work has been completed by FDA medical officers and scientific staff in addition to their review responsibilities without the need for additional dedicated research funding.

In this paper, we summarize scientific activities led by the OCE from 2017–2019 to identify nine scientific interest areas. This methodology is consistent with OCE’s grassroots approach for initiating scientific outreach and research, where members of FDA’s multidisciplinary scientific staff have the autonomy to pursue topics encountered during regulatory review. As OCE’s research portfolio matures, future work will focus on developing and implementing a forward-looking strategic planning process with the overarching goal to generate science that can inform regulatory review and decision making.

Summary of Recent OCE Scientific Activities

We catalogued technology transfer agreements, public workshops, scientific presentations delivered at regular internal meetings, internal scientific educational events, and publications by FDA oncology staff from 2017–2019. We identified 27 active technology transfer agreements for research projects, 28 public workshops (Supplementary Table S1), 48 educational mini-symposia and 101 individual scientific presentations at internal FDA meetings. We also analyzed 236 scientific papers published by FDA oncology staff between 2017 and 2019. Lists of scientific papers published by FDA staff in 2018 and 2019 are available in the OCE annual reports (21, 22). The OCE published its first annual report in 2018.

Public Workshops, Mini-symposia and Other Scientific Presentations

As shown in Supplementary Table S1, the OCE frequently works with external partners to organize public workshops. Mini-symposia are internal educational meetings where FDA oncology staff invite approximately 3–5 academic experts to discuss specific scientific topics. The OCE also frequently invites internal and external experts to deliver individual presentations during regular meetings such as OCE Clinical Rounds and OCE Research Rounds.

Scientific Publications

FDA oncology staff actively contribute to the scientific literature, publishing an average of 75 articles per year. About 21% of papers published in 2017, 2018, and 2019 are summaries of individual regulatory approvals, but approximately 50% of the remaining papers address the scientific priority areas described below.

A recent analysis of FDA oncology publications revealed that these papers are cited in the scientific literature about two times more frequently than the average NIH-funded publication (23). Furthermore, 12% of FDA oncology publications were among the top 1% most cited papers in the field to which they were assigned based on journal of publication.

Technology Transfer Agreements

The OCE’s technology transfer agreements are established with private companies, academic institutions, and non-profit organizations when data, material (e.g., human biospecimens) and/or financial resources are transferred to the agency to support a research collaboration. Research Collaboration Agreements (RCA) and Material Transfer Agreements (MTA) are established for some unfunded research collaborations. The OCE generally uses MTAs when the external partner provides data or biological materials and RCA when the external partner also contributes substantial intellectual/scientific expertise, for example to co-author a scientific paper with FDA staff. OCE develops Cooperative Research and Development Agreements (CRADAs) when funding is provided to FDA to support the research. Additional information about these agreements is available on the FDA Technology Transfer website (24). The titles and partner institutions of selected OCE RCAs can be found in Supplementary Table S2.

OCE Scientific Interest Areas

Based on analysis of the scientific outreach (Figures 1 and 2), publications, the program areas included in the 2018 and 2019 OCE Annual Reports (21, 22) and extensive input from OCE and Office of Oncologic Diseases experts, we identified nine scientific priority areas of high interest for collaboration with the external scientific research community (Table 1 and OCE Scientific Collaborative web page [25]). We also identified Oncology Real World Evidence (RWE) Utilization as an important cross-cutting theme that relates to several of the scientific interest areas. These scientific interest areas involve research areas relevant to drugs, biologics and devices and are consistent with OCE’s mission to serve as a focal point for oncology products at FDA.

Figure 1:

OCE Public workshop topics from 2017–2019 organized by Scientific Priority Area

Figure 2:

OCE Mini-symposium topics from 2017–2019 organized by Scientific Priority Area

Table 1:

OCE Scientific Interest Areas

Scientific Interest Area	Description
Cell /Gene and Personalized Neo-antigen-based Therapies for Cancer	Support clinical development, safety evaluation, manufacturing and quality control of innovative approaches such as gene editing-based technology (e.g., CRISPR-Cas9), cell therapy (e.g., TIL, TCR-T, CAR-T) for solid and hematologic malignancies, and neo-antigen-based cancer therapy.
Health Equity and Special Populations in Oncology Clinical Trials	Support research to ensure that oncology therapeutics are safe and effective for the greatest number of cancer patients.
Immuno-oncology	Analyze clinical and scientific issues unique to regulatory submissions of immuno-oncology products such as understanding unique side effects and atypical responses (e.g., delayed progression, pseudoprogression) to immune checkpoint inhibitors.
Oncology Patient-Focused Drug Development	Support scientifically rigorous use of clinical outcome measures to quantify symptoms and function. Develop and create standard clinical endpoints, analytic and visualization methods, and use of digital health technology to further characterize a product’s safety and efficacy.
Oncology Therapeutic Safety	Develop innovative approaches to allow for consistent and rigorous analysis of safety signals throughout the lifecycle of oncology therapeutics and to improve understanding of toxicity from oncology therapeutics in the patient population. Explore use of “real-world data” to inform post-marketing safety.
Pediatric Oncology	Accelerate the development of oncology therapeutics for children building on incentives created by the Research to Accelerate Cures and Equity (RACE) for Children Act as part of the FDA Reauthorization Act (FDARA).
Precision Oncology	Develop and deploy biomarkers (e.g., molecular, imaging) to accelerate and improve regulatory review of oncology therapeutics
Rare Cancers	Pilot novel approaches to support drug development in rare cancers such as drug repurposing, telemedicine and innovative trial designs and real-world data.
Oncology Trial Designs, End points and Statistical Methodologies	Develop innovative approaches for statistical analyses of oncology clinical trials. Identify and refine real world endpoints (e.g., defined and extracted using EHR data) that could be used in clinical studies to inform regulatory submissions.

OCE added the scientific interest areas in Table 1 to the FDA BAA (3) funding mechanism and also has presented them to CERSI program leadership to encourage new research collaborations in these areas. The BAA is an FDA-wide funding mechanism that solicits research proposals from external institutions. BAA proposals are reviewed by FDA experts, and may result in a research contract. BAA contracts are awarded for a maximum of five years. Investigators should develop budgets suitable to complete the proposed work, but OCE prefers to support focused pilot projects. Applications are reviewed on a rolling basis.

The CERSI program consists of cooperative agreements with six institutions: Johns Hopkins, University of Maryland, UCSF-Stanford, and Yale-Mayo Clinic. These institutions were selected through a competitive process. There are CERSI Principal Investigators designated for each institution, but FDA staff may propose projects with any assistant, associate or full professor employed by the participating universities. The primary focus of the CERSIs is to support regulatory science research in collaboration with FDA staff, but also supports a limited number of training opportunities, including workshops, lectures and courses.

Funded OCE projects

As a new center, OCE began funding regulatory science research in the past 18 months and has supported a small number of projects through the BAA and CERSI mechanisms. (Supplementary Table S3) These projects address some of the nine scientific interest areas described below. OCE is interested in continuing to fund regulatory science research as its budget allows, and seeks to develop a balanced portfolio across these interest areas in the coming years.

Discussion

The OCE is actively engaged in a variety of scientific outreach and research activities, and focuses its efforts on practical issues that can facilitate FDA’s mission to expedite the delivery of cancer products to patients. As such, the topics for most activities are identified by individual FDA scientific review staff guided by their regulatory review work. The analysis described in this paper organizes this work into topic areas to help communicate the OCE’s scientific efforts to the external oncology community, and establish priority areas for future investigation. Future work will focus on implementing strategic planning processes to identify additional research interest areas. FDA oncology staff are actively engaged in each of the areas described in Table 1, and detailed information about example areas of interest for future research for each topic is available on the OCE Scientific Collaborative website.

Cell and gene therapies

FDA recently supported a research study in this area focused on developing a novel approach for preparing T cells for oncology cell therapy. (Supplementary Table S3) Example interest areas for future research include: studies that facilitate regulatory review of neoantigen-based therapies such as developing, optimizing and standardizing algorithms for neoantigen identification; and implementing innovative clinical trial designs to identify the most promising candidates among neo-antigen based therapies developed using a common platform.

Health equity and special populations in oncology clinical trials

OCE staff have led several initiatives related to this topic including organizing a public workshop in November 2017 to explore opportunities and challenges in enrolling older patients on oncology trials (26). FDA staff also contributed to a multi-stakeholder paper about how US cancer centers can increase racial and ethnic minority enrollment on clinical trials (27). OCE continues to lead important scientific workshops in this area including a 2020 meeting co-organized with the American Association for Cancer Research on African Americans in Multiple Myeloma Clinical Trials (28).

OCE has identified several example research interests relating to health equity, such as: understanding factors that affect the safety and treatment response in demographic subgroups that have been historically underrepresented in oncology trials (e.g., racial/ethnic minorities, sexual and gender minorities, older adults) including qualitative research to understand barriers; improving clinical trial data collection for underrepresented subgroups; understanding the impact of remote assessments and decentralized trial procedures; characterizing the prevalence of currently druggable biomarkers in racial/ethnic minorities to understand implications for trial enrollment; and RWD studies to improve understanding of safety and efficacy of approved drugs in underrepresented subgroups.

Immuno-oncology

Past OCE activities in this area include co-organizing a workshop with the Society of Immunotherapy and Cancer in November 2018 that featured a multi-stakeholder discussion on the state of immune-modified response criteria in cancer immunotherapy clinical trials (e.g., iRECIST). This meeting explored the challenges of using traditional oncology trial endpoints designed to evaluate cytotoxic treatments (e.g., radiographic progression evaluated by RECIST 1.1) in clinical trials of immuno-oncology agents. FDA oncology staff have published several papers in this area, such as a pooled analysis of urothelial carcinoma patients treated with immune checkpoint inhibitors, which showed a relationship between immune-mediated AEs and response to therapy (29), and publications investigating atypical response to immune checkpoint inhibitors (30, 31)

Example research interests for future immuno-oncology studies include: performing analyses of clinical data to improve understanding of patients with atypical response to immune checkpoint inhibitors (ICI) and developing new technologies to improve characterization of atypical response such as radiomic analyses of tumor images, ctDNA, and novel approaches for immune cell profiling of the tumor microenvironment. Other areas of interest include studies to develop pharmocodynamic endpoints to isolate the contribution of individual components of cancer immunotherapy combination regimens; developing biomarkers of response to immunotherapy; and research to improve understanding of side effects of ICI. OCE is also interested in real world data (RWD) studies to understand the utilization of complementary in vitro diagnostics for ICIs.

Oncology patient-focused drug development

OCE has a sustained effort to improve rigorous measurement of symptoms and function in cancer clinical trials using electronic patient-reported outcomes (ePRO), wearable devices and other digital health technologies. OCE actively collaborates with the outcomes research community, hosting annual workshops on clinical outcome assessments in oncology trials (32). An example publication in this area reviewed statistical analyses of patient-reported outcomes (PRO) in lung cancer clinical trials between January 2008 and December 2017 (33). OCE recently funded two research projects related to patient-focused drug development (Supplementary Table S3). One project focuses on understanding the measurement characteristics of multiple types of physical function measures, and the other is conducting qualitative research into patients’ interpretation of the concept of physical function.

Additional research interest areas not yet addressed by ongoing projects include: investigating measurement characteristics of new and existing patient-reported global items quantifying overall side effect impact; implementing PRO symptom and functional measures using electronic PROs in advanced cancer patients with the FDA MyStudies application; analyzing the sensitivity and measurement characteristics of existing patient reported physical function measures in patients with rare and ultra-rare cancers; developing longitudinal analysis and visualization methods to communicate changes in physical function over time; and investigating individual-level change and meaningful change thresholds for PRO symptom measures using qualitative research methods.

Oncology Therapeutic Safety

OCE organized a December 2017 workshop on cardiovascular toxicity assessment in immuno-oncology trials (34). Recent publications include a paper that investigated 1137 commercial INDs over a three-year period and found that only about 10% of INDs were placed on hold, and most of these were first-in-human studies with a clinical concern (35). OCE is working in collaboration with the FDA Office of Medical Policy to support research conducted by the Alliance NCTN foundation that is piloting approaches for collecting adverse event data using the electronic health record for use in clinical studies (Supplementary Table S3).

Example research interest areas include: developing approaches for collecting data from RWD sources to expand understanding of the safety profile of approved oncology drugs in clinical practice; using RWD as a method to provide emerging evidence to understand the natural history, outcomes and safety profile of approved drugs in patients with cancer and a history of or active COVID-19 infection; developing standardized methods to collect and analyze cardiotoxicity data in clinical trials and clinical practice; analyzing clinical data collected in real world settings to understand which patients are most likely to experience cardiotoxicity during cancer treatment; conducting basic, translational or clinical studies that investigate underlying causes for cardiac toxicity associated with oncology agents; and conducting translational studies to investigate underlying causes of recent safety alerts issued by FDA oncology.

Pediatric Oncology

FDA has prioritized pediatric oncology activities for several years, but recent notable initiatives include an April 2018 workshop to inform a list of molecular targets relevant to drug development in pediatric oncology. This was an important milestone in implementing the Research to Accelerate Cures and Equity (RACE) for Children Act as part of the FDA Reauthorization Act (FDARA) (36). FDA Oncology staff have published several pediatric oncology papers, including an analysis of pediatric development of molecularly targeted oncology drugs which analyzed 98 drug and biologic oncology products where sponsors intended to request waivers from FDA for pediatric development (37).

Example areas of interest for future applied research include: developing preclinical models for pediatric tumors; studies about the relevance of specific molecular targets to the growth and/or progression of pediatric tumors to understand target actionability, for example by using AI and text mining to refine the evidence base of specific molecular targets to pediatric cancers supported by peer-reviewed published literature and to identify potential new targets for inclusion on the legislatively mandated list to guide decision making for early pediatric assessment of new drugs and biologics; translational research to develop combination regimens for pediatric patients based on strong scientific evidence; and investigations to explore the development of external control arms from RWD to accelerate pediatric drug development.

Precision Oncology

Precision oncology is relevant to many recent drug approvals and OCE leads several activities in this area. For example, OCE organized two important workshops in precision oncology in January 2018 (38) and April 2019 (39). The first meeting explored how to interpret the clinical relevance of the large numbers of genetic variants typically presented in oncology pathology reports. The second workshop focused on recent experiences with tumor agnostic approvals, where indications are based on biomarkers status rather than tumor location. OCE continues to participate in organizing impactful scientific workshops in this area, including a public workshop on detecting circulating tumor DNA for cancer screening (40).

OCE outlined several example research interest areas related to precision oncology on the OCE Scientific Collaborative website, including: developing algorithms that predict an individual’s response to therapy using different types of medical images (e.g., radiology or histopathology); identifying biomarkers to inform oncology diagnosis, monitoring, response or resistance; developing methodologies to inform clinical trial design of liquid biopsy studies that assess multiple cancer types simultaneously for early detection indications; conducting studies to compare the performance of local and centralized molecular tests used for trial enrollment; research to understand why tumors located in different organ sites with molecular alterations in the same target respond differently to therapies directed at that target; studies to understand potential differences in response to targeted cancer treatment based on somatic vs. germline alterations of the targeted gene, including the effect of germline mutations on pharmacogenetics including both efficacy and toxicity.

Rare Cancers

FDA oncology is interested in promoting therapeutic development for rare cancers, and participates in the Cures Drug Repurposing Collaboratory, a platform for health care professionals to share case reports and discuss potential off-label uses of drugs to support possible future repurposing (41). Example research areas of interest include: studies to investigate the natural history of rare cancers to provide clinical and scientific context to inform the design and interpretation of clinical trials; research to develop and characterize symptom function measures for rare cancers, particularly studies that focus on establishing clinical benefit with potential practical use in clinical trial settings; innovative approaches to identify opportunities for clinical development of previously approved drugs (or drugs for which development has discontinued) for rare cancers based on strong scientific evidence; and studies in rare cancers that implement a clinical trial protocol incorporating telemedicine or other decentralized approaches.

Oncology trial designs, endpoints, and statistical methodologies

OCE organized a workshop on this topic in February 2018 to discuss analytical approaches for addressing non-proportional hazards observed in clinical trials of immune checkpoint inhibitors (42). OCE is supporting two research studies in this scientific interest area. The first study is developing novel statistical approaches to estimate treatment effect when patients receive subsequent therapies, and the second study is investigating methods for using Bayesian adaptive designs to investigate borrowing information across subpopulations within clinical trials and external controls (Supplementary Table S3). OCE also recently established Project SignifiCanT (Statistics in Cancer Trials), which is organizing open forum discussions to foster collaboration among regulators, professional organizations, industry, academicians and patients leading to advance drug development with improved design of cancer clinical trials

OCE is interested to support several types of research in this area, including: developing, defining and testing real world oncology endpoints from RWD; understanding and defining RWD quality; and exploring how RWD can be used to enhance understanding of treatment effects and safety in populations under-represented in clinical trials; and developing flexible clinical trial designs to account for unexpected events such as those occurring during the COVID-19 pandemic.

Utilization of Oncology RWE is a related cross-cutting topic, which focuses on evaluation of FDA approved drugs in “real world” clinical practice. The 21^st century cures act includes a section on modern trial design and evidence development which addresses the potential use of RWE to inform regulatory decisions (43).

RWD sources include electronic health records, administrative health claims, drug or disease registries, patient reported or generated health data. Further research is needed to develop an understanding of the strengths and limitations of these types of RWD, and the potential utility to inform the safety and efficacy of FDA-approved drugs outside of randomized controlled clinical trials. This work will focus on methodologically rigorous studies which evaluate study designs, data quality, statistical approaches and real world endpoints. As shown in Supplementary Table S2, OCE has established research collaboration agreements with various RWD providers, and is supporting an applied research study with the Alliance NCTN Foundation on this topic.

A key strength of real-world data is the ability to access patients from important populations that may be under-represented in controlled clinical trials, including racial and ethnic minorities, children, and older adults. For example, an FDA study in this area analyzed outcomes of NSCLC patients treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval. One of the interesting findings of this study is that older patients did not experience poorer outcomes (44).

OCE is also exploring the potential for using RWD in hypothesis development for emerging public health concerns. Given the recent emergence of the global pandemic, OCE is prioritizing research related to the impact of COVID-19 on cancer clinical trials. OCE’s research interests are primarily focused on three areas: understanding of how SARS-CoV-2 infection may affect future patient eligibility for cancer clinical trials, managing new infections of patients on study, and evaluating the safety profile of approved drugs in cancer patients post COVID-19 infection to identify increases in known drug adverse reactions or new toxicities, longitudinal sequelae and outcomes.

The launch of the Oncology Center of Excellence provides new opportunities for multidisciplinary participation and support of oncology regulatory science research, particularly initiatives that involve product areas relevant to multiple FDA Centers. This research work is complementary to basic and translational science, and supports valuable improvements to the regulatory review process.

We encourage the scientific community to provide feedback on these scientific areas and share ideas for potential research collaborations by engaging with our staff at FDA workshops and other scientific conferences, via Twitter (@FDAOncology) or email (FDAOncology@fda.hhs.gov).