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  1. Oncology Center of Excellence

OCE Scientific Collaborative

The OCE Scientific Collaborative supports FDA oncology staff who participate in regulatory science research, including internal research projects and collaborations with external experts. OCE research focuses on applied (rather than basic) research questions to address specific challenges encountered during the IND and NDA/BLA review process.

OCE engages with external scientists using several approaches including informal collaborations, research collaboration agreements, memoranda of understanding, and sometimes provides research funding using mechanisms such as the FDA Broad Agency Announcement.

Scientific Interest Areas

OCE identified nine scientific priority areas for its applied research efforts:

I. Cell/gene and personalized neo-antigen-based therapies for cancer

Cell therapy is a promising new form of cancer treatment as demonstrated by recent CAR T-cell therapy approvals. New technologies are enabling rapid manufacturing of cells with tumor-killing capacity, necessitating more efficient clinical evaluation and innovative regulatory approaches.

The science of neo-antigen-based therapies for cancer is also developing rapidly, particularly since advances in genomics and proteomics allow identification of somatic mutations unique to individual cancers. Recent studies have demonstrated that high levels of somatic tumor mutations are correlated with response to immunotherapies such as checkpoint inhibitors, suggesting that individual tumor mutations (neoantigens) could be harnessed for immune targeting to develop personalized therapies such as cancer vaccines and cell therapies that target these neoantigens.

OCE is interested to support research related to clinical development, safety, manufacturing and quality control for cell therapy and neo-antigen-based therapies for cancer. Example OCE research interests in this scientific priority area include:

1. Support research to develop / improve a consensus grading system for cytokine release syndrome and neurotoxicities that can be used for patient management, clinical trials and labeling.              

2. Facilitate regulatory review of neoantigen-based cancer therapies by supporting research to

  • Develop, optimize and standardize algorithms for neoantigen identification. These are important to ensure the efficacy and safety of these products in the treatment of patients with cancer
  • Create novel technologies and approaches to evaluate both efficacy and safety for neoantigen-based therapies that incorporate unique features of individual cancers, neoantigen and immune responses.

3. Implement innovative clinical trial designs for a group of cell or neoantigen-based therapies that were developed using a common platform (but target distinct antigens) to compare safety and clinical activity among products to identify the most promising candidates for further development.

II. Health equity and special populations in oncology clinical trials

OCE is interested to improve understanding factors affecting prognosis, treatment response and safety of racial/ethnic minorities, gender minorities, and older adults in oncology trials. For example, populations such as the elderly and certain racial and ethnic groups have a higher incidence of co-morbidities and it is unknown how these will impact the biology of certain symptoms and toxicities or whether the duration and severity of toxicities vary in these populations. Information about special populations is critical to ensure that the evidence for drugs deemed safe and effective in clinical trials submitted to FDA is generalizable to the larger patient population.

Example OCE research interests in this scientific priority area include:

4. Conduct qualitative research to understand barriers to including older adults in oncology clinical trials 

5. Improve data collection in oncology clinical trials relevant to older populations

6. Identify best practices for enrolling racial/ethnic minorities, gender minorities and older adults in oncology clinical trials, including patient-, physician-, and community-focused approaches

7. Understand the prevalence of biomarkers in racial/ethnic minorities used in oncology trial enrollment and design and implications for oncology drug development.

III. Immuno-oncology

Immune checkpoint inhibitors (ICI) have become the standard of care for multiple types of cancer and offer long-term disease control often with fewer (albeit unique) side effects compared to those encountered with chemotherapy. As the number of clinical trials evaluating ICIs either as single agents or in combination for the treatment of patients with cancer continues to increase, standardized approaches for predicting, identifying, and reporting side effects of ICIs becomes increasingly important.

Additionally, a large proportion of patients do not respond or become resistant to these treatments. There is a high unmet need to develop therapeutics for ICI-refractory or resistant patients, yet the field lacks a consistent definition of response for these drugs. Response is well defined for cytotoxic drugs and targeted therapies using images analyzed by Response evaluation criteria in solid tumors (RECIST) criteria v 1.1; however, RECIST analyses reveal that a considerable proportion of patients treated with ICI demonstrate late response or may show initial-- potential accelerated--tumor growth that can be followed by tumor shrinkage. These atypical response patterns complicate FDA’s ability to provide advice to sponsors about clinical trial design.

Example OCE research interests in this scientific priority area include:

8. Perform analyses of clinical data to develop a better understanding of the proportion of patients with atypical response and explore the development of predictive analytic approaches to identify patients who will eventually respond to ICI treatment from those who will not respond. Develop approaches to distinguish among patients who have become resistant to ICI on an ongoing basis from those who may respond again upon re-challenge.

9. Develop technologies and approaches that better predict or characterize atypical response patterns to immune checkpoint inhibitors. Promising technologies for consideration include:

  • Radiomic analysis of tumor images. This approach can capture features of the tumor that are not addressed by RECIST measurements and may incorporate information about changes in the tumor microenvironment in addition to information about tumor size.
  • Circulating tumor DNA to monitor response to treatment by measuring cancer-associated somatic mutations at multiple time points during a patient's treatment.
  • Novel approaches for immune cell profiling of the tumor microenvironment

10. Develop clinical trial endpoints that account for atypical response patterns and more fully characterize the clinical benefit of immune checkpoint inhibitors

11. Develop of technologies that better identify patients at risk for serious adverse reactions with ICIs

12. Develop standardized approaches for identifying and reporting side effects in clinical trials evaluating ICIs.

IV. Oncology patient-focused drug development

Cancer patients experience disease symptoms and symptomatic treatment side effects that can impact their ability to function and other aspects of their health-related quality of life. OCE is interested in supporting research focused on developing approaches to assess the patient experience that will complement existing survival and tumor information.

Symptomatic adverse events and overall side effect impact are critically important to patients and improved analysis and visualization of symptomatic adverse events is a priority. In addition, the OCE is interested in exploring the utility of a single overall side effect global impact question that can be used to summarize overall side effect burden.

Physical function is another important patient-centered outcome that is a focus area of OCE research efforts. In particular, OCE is interested to learn more about the impact of different technologies, recall periods and different data collection platforms for gathering physical function data in oncology clinical trials.

FDA has identified the use of electronically captured patient-reported outcome (ePRO) physical function scales and wearable technologies as promising drug development tools to inform future development of oncology clinical trial endpoints. OCE is interested to understand the impact of using different measurement techniques on assessing physical function in a prospective natural history study of advanced cancer, particularly (1) wearable technologies (e.g., MIT E4 watch, actigraph accelerometer); (2) electronically captured patient-reported approaches (e.g., PROMIS ® physical function item bank) and (3) traditional clinician-based assessments (e.g., ECOG or Karnofsky performance status) and performance outcomes (e.g. 6-minute walk test or other PerfO). The research would analyze these data sources and their association with global anchor questions and other important clinical events such as hospitalizations, treatment changes, concomitant/supportive medication use and palliative procedures and survival.

Example OCE research interests in this scientific priority area include:

13. Investigate measurement characteristics for new and existing patient-reported global items assessing overall side effect impact such as the FACIT GP5 item for patients undergoing anti-cancer therapy.

14. Evaluate differences in clinical outcome measures of physical function in an advanced cancer patient cohort undergoing treatment by prospectively capturing data from (a) electronic PRO, (b) wearable technologies, (c) performance outcomes and (d) clinician assessment (e.g. ECOG/Karnofsky).

15. Conduct a prospective study to compare the sensitivity and measurement characteristics of patient-reported physical function using a 7-day recall period versus no recall period using a well-defined PRO physical function scale such as the PROMIS physical function bank.

16. Implement PRO symptom and functional measures using ePRO in advanced cancer patients using the FDA MyStudies application to test feasibility, accuracy and ease of use.

V. Oncology safety

Many advances have been made in the treatment of cancer with an increasing number of treatment options available to oncology patients. With the introduction of newer treatment approaches, little is known about the differential rate and severity of side effects and toxicities. Many cancer patients are living longer but at the same time they are experiencing an increase in symptom burden due to exposure to multiple lines of cancer therapy.

Some toxicities are acute while others become chronic. Often, the extent of the toxicity burden is unknown until the drug is administered to a large population of 'real-world' patients with comorbidities that were not included in a clinical trial, or until long-term follow-up uncovers late-onset toxicities.  The natural trajectory, as well as the underlying mechanisms of many toxicities, is not well understood. There are no clear predictors of who may experience these symptoms and toxicities and why they vary in severity and duration from one individual to another.

For most of the toxicities caused by cancer treatment, no approved mitigating therapies or evidence-based management strategies are in place. There is a lack of mechanistic insight into these adverse events, difficulties in objectively measuring treatment-related toxic effects and insufficient studies validating pre-clinical biomarkers in the clinical setting.

Example OCE research interests in this scientific priority area include:

17. Develop approaches for collecting safety data from electronic health records to obtain a better understanding of the safety profile of approved oncology drugs in clinical practice. Pilot a study using this approach in a specific disease area and analyze the results.

18. Analyze clinical data collected in real world settings to understand which patients are most likely to experience cardiotoxicity (or other types of severe toxicity) during cancer treatment

19. Conduct studies that investigate underlying causes of recent safety alerts issued by FDA oncology. Recent examples in oncology include: safety alerts for multiple myeloma clinical trials that showed an increased risk of death in patients receiving venetoclax in combination with bortezomib and dexamethosone and the use of immune checkpoint inhibitors and immunomodulatory agents as compared to control groups

Oncology trial designs, endpoints and statistical methodologies

OCE provides detailed advice to sponsors about appropriate clinical trial designs, including statistical analysis methods. Rapid technological developments in electronic capture of medical record and claims data has increased sponsors’ interest in using data sources other than information collected during traditional clinical trials to support regulatory submissions.

OCE is also interested in research to define and validate real world endpoints that can be collected from Electronic Health Records (EHR) and how real world endpoints perform relative to traditional endpoints used in clinical trials to support regulatory approval oncology products, such as Overall Response Rate, Progression Free Survival, and Overall Survival. Collecting traditional oncology endpoints is labor-intensive and normally only performed in the context of a clinical trial, so it is unclear whether data collected during the course of clinical care will provide comparable information.

Example OCE research interests in this scientific priority area include:

20. Develop novel statistical approaches for using external controls in oncology trials, which could supplement, augment, or replace concurrent control arm data. External controls have the potential to reduce patient enrollment and clinical trial costs, but new methods are needed to mitigate challenges including (1) population differences such as mismatched eligibility criteria between external control and clinical trial patients; (2) differences in exposure (e.g., use of prior therapies) and outcomes (e.g., endpoint assessments) between external control and clinical trial patients; and (3) different sources of bias (i.e., measurement, selection and confounding). Use of external data is further complicated by rapidly evolving standards of care and the approval of new drugs and biologics.

OCE is particularly interested to support research addressing how external control data can be used to isolate the treatment effect of experimental combination therapies. In this situation, external data for each component of the combination may be used to estimate the efficacy of a monotherapy or supplement existing control data collected in a clinical trial. High priority research areas relating to external controls include exploration of design (e.g., sample size calculations, borrowing from external data if applicable, operational characteristics) and methodology considerations (balancing arms, endpoints and analysis).

21. Develop, define and test real world oncology endpoints (e.g., from mining information available in electronic health records) that could be used to generate evidence to complement traditional clinical trial data submitted to FDA.

Pediatric oncology

The development of drugs for children with cancer involves unique biological, clinical, societal and economic challenges. Pediatric drug development usually leverages efforts in adult drug discovery and development. Recent observations made possible through large scale pan-cancer genomic profiling across multiple pediatric cancers suggest that more than 50% of childhood cancers express druggable  (approved, targeted drugs available) molecular aberrations. However, some targeted agents developed for adults are not effective in children. For example, immune checkpoint inhibitors have transformed treatment for several adult cancers; however, these drugs are less effective in pediatric cancers because of diminished neoantigen expression due to low mutational burdens. The lack of pre-clinical testing in pediatric tumors is also a major obstacle to advancing the field and is critical to identify promising molecular targets for pediatric cancers.

Example OCE research interests in this scientific priority area include:

22. Support the development of preclinical models (patient-derived xenograft models, orthotopic mouse models, organoids) of pediatric tumors, most of which are embryonal in origin to facilitate decision-making regarding the evaluation of emerging novel agents potentially applicable to tumors which predominantly occur in the pediatric population.

23. Support studies that can elucidate the relevance of specific molecular targets to the growth and/or progression of pediatric tumors to understand and assess target actionability using text mining and artificial intelligence to analyze, assess and interpret the scientific literature. This information can be used to identify promising candidates for further research and development.

24. Support translational research to develop combination regimens for pediatric patients that include ICIs and other treatments (e.g., chemotherapy, vaccines, radiation) based on a strong scientific rationale, such as understanding how the non-ICI treatment in the combination regimen can make immunologically “cold” tumors (those that have few infiltrating T cells and do not provoke a strong immune response) into tumors that are responsive to ICI.

Precision oncology

Implementation of precision oncology has grown rapidly in recent years, with dozens of gene- and protein-based markers used to define enrollment criteria for oncology clinical trials and included in drug labels as companion or complementary diagnostics, pharmacogenomic or safety markers. There is a continued need to further understand the role of different biomarkers in oncology including identifying groups of patients who respond or do not respond to different treatment, better understand disease progression and resistance mechanisms, and identify high risk populations.

Several exciting technologies are advancing precision oncology, including measuring molecular changes in circulating tumor DNA isolated from plasma, and radiomics, an emerging science that uses algorithms to extract features from medical images that are invisible to the human eye. Combined with advanced machine learning algorithms, radiomics can improve disease detection, characterization, staging, as well as assessment and prediction of treatment response.  A related field, radiogenomics, assesses the relationship between imaging features and gene expression. Work in this area is advancing rapidly since extensive imaging and genomic information are routinely collected in oncology clinical trials.

Example OCE research interests in this scientific priority area include:

25. Identify biomarkers/algorithms that predict an individual patient’s genotype and/or response (in terms of both efficacy and safety) to cancer therapy using machine learning of medical imaging data, potentially in combination with other types of data (for example, demographics, genetics, and laboratory test results) to help advance precision medicine.  In addition to radiology imaging data, histopathology imaging data can also be used in this research.

26. Identify biomarkers (including liquid biopsy biomarkers) to gain information related to oncology diagnosis, monitoring, response, or resistance.

Rare cancers

Identifying candidate drugs and testing their effects in rare populations can be challenging and time consuming. Investigating approved drugs potentially offers a more efficient pathway for drug development for rare cancers. Telemedicine is also an area of interest for OCE, as it has been a successful tool for clinical trials and patient care in other disease areas (e.g., stroke, Parkinson’s disease), but has not been widely implemented in oncology.

27. Explore mechanisms to support and expedite development of approved drugs for rare cancer indications (i.e., repurposing) such as analyzing real world data (e.g. registries) to inform screening and evaluation of drugs in rare populations.

28. Pilot a study in rare cancers to implement a clinical trial protocol incorporating use of telemedicine approaches for patient assessments.  Proposed studies should focus on evaluating feasibility and implementation, including an analysis of the risks and benefits of different technologies, impact on clinical trial participation and the quality of data collected.

For any questions regarding the OCE Scientific Collaborative, contact FDAOncology@fda.hhs.gov.

 

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