FDABAA-20-00123 - Amendment 1.pdf

FDABAA-20-00123 – Amendment 1

FDABAA-20-00123

Overview Information

Agency Name: Department of Health and Human Services, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993

Issuing Office: Department of Health and Human Services, Food and Drug Administration, Office of Acquisitions & Grants Service, 4041 Powder Mill Rd. Beltsville, MD 20705

Research Opportunity Title: Food and Drug Administration Broad Agency Announcement for the Advanced Research and Development of Regulatory Science

Announcement Type: Broad Agency Announcement

Eligible Applicants: This BAA is open to ALL responsible sources. Offerors may include single entities or teams from private sector organizations, Federally Funded Research and Development Centers (FFRDCs) (see page 4 for FFRDC eligibility requirements) and academic institutions.

Research Opportunity Description: The Food and Drug Administration (FDA) solicits for advanced research and development proposals to support regulatory science and innovation. The FDA anticipates that research and development activities awarded under this BAA will serve to advance scientific knowledge to accomplish its mission to protect and promote the health of our nation.

Types of instruments that may be awarded: Procurement Contracts

Notes: Regarding Funding

In order to ensure enough time to conduct the two-tiered evaluation described in Section IV and still be considered for an award within the current fiscal year, prospective Offerors are encouraged to submit white papers no later than 5:00 pm, Eastern Standard Time, March 2, 2020, and earlier if possible. White papers submitted after that date will still be accepted, but due to a lack of lead time, will not be considered for award in FY20.

TABLE OF CONTENTS

INTRODUCTION

Part I: Research Areas of Interest ....................................... Error! Bookmark not defined.

Part II: Reporting Requirements and Deliverables Part III: Proposal Preparation and Submission

Section 1: The Application Process Section 2: Stage 1 Quad Chart and White Paper Section 3: Quad Chart and White Paper Submission Section 4: Stage 2 Full Proposal Preparation Section 5: Full Proposal Submission Section 6: General Information

Part IV: Proposal Evaluation Award Decision Part V: Attachments

Attachment 1: Summary of Related Activities Attachment 2: Government Notice for Handling Proposals Attachment 3: Quad Chart and White Paper Format Template Attachment 4: Research and Development Justification

INTRODUCTION

Advancing Regulatory Science and Innovation

This Broad Agency Announcement (BAA), which sets forth research areas of interest for Food and Drug Administration, is issued under the Federal Acquisition Regulation (FAR) part 35.016(c). The purpose of this BAA is to provide a mechanism by which FDA can utilize industry’s and academia’s capabilities to advance the state of the art and achieve improvements in technology, materials, processes, methods, devices, or techniques in specific topics as described in this document. Proposals selected for award are the result of full and open competition and in full compliance with the provision of Public Law 98-369, "The Competition in Contracting Act of 1984" and subsequent amendments.

The FDA protects and promotes the health and safety of all Americans through enhancing the availability of safe medical products and foods and promoting innovation that addresses unmet medical and public health needs. FDA also protects and promotes the health and safety of animals through assuring the availability of safe animal drug products and food. Since 2009, FDA has worked to reduce the harm from all regulated tobacco products. FDA is a science-based regulatory agency and a critical component to the success of the nation’s public health, health care systems, and economy. FDA was created in 1906 as one of our nation’s principal consumer product protection agencies, and is now responsible for assuring the safety of biologics, such as blood products and vaccines, drugs, medical devices, foods, cosmetics, and many other consumer goods.

In the US, FDA-regulated products account for about 25 cents of every dollar spent by American consumers each year — products that touch the lives of every American daily. FDA is responsible for advancing the public health by helping to speed innovations that make foods safer and make medicines and devices safer and more effective. At the same time, FDA helps consumers and health care providers get the accurate and science-based information they need to make the best possible decisions about their use of medical products and foods. FDA is working to protect Americans from tobacco-related death and disease. FDA must make decisions based on the best available scientific data and using the best tools and methods available to ensure products meet the highest quality standards for consumers, while at the same time fostering and advancing innovation in the products it regulates.

The core responsibility of FDA is to protect consumers by applying the best possible science to its regulatory activities — from pre-market review of efficacy and safety of many of its regulated-products; to post-market product surveillance to review of product quality; to regulation of the manufacture, distribution and marketing of tobacco products. In the last few years, rapid advances in innovative science have provided new technologies to discover, manufacture and assess novel medical products, and to improve food safety and quality; FDA must keep pace with and utilize these new scientific advances to accomplish its mission to protect and promote the health of our nation.

The BAA is open to all responsible sources. Offerors may include single entities or teams from private sector organizations, Federally Funded Research and Development Centers (FFRDCs), and academic institutions. Non-U.S. organizations and/or individuals may participate to the extent that such participants comply with any necessary nondisclosure agreements, security regulations, export control laws, and other governing statutes applicable under the circumstances.

Federally Funded Research and Development Centers (FFRDCs) and Government entities (e.g., Government/National laboratories, military educational institutions) are subject to applicable direct competition limitations and cannot propose to this BAA in any capacity unless they meet the following conditions:

1. Clearly demonstrate that the proposed work is not otherwise available from the private sector.

2. Provide a letter on official letterhead from their sponsoring organization citing the specific authority establishing their eligibility to propose to Government solicitations and compete with industry, and their compliance with the associated sponsoring agreement and terms and conditions.

Historically Black Colleges and Universities (HBCU), Minority Institutions (MI), Small Business concerns, Small Disadvantaged Business concerns, Women-Owned Small Business concerns, Veteran-Owned Small Business concerns, Service-Disabled Veteran-Owned Small Business concerns, and HUB Zone Small Business concerns are encouraged to submit proposals and to join other entities as team members in submitting proposals.

The purpose of this BAA is to solicit proposals that focus on one or more of the following areas of interest as listed here and further described in Part I of this announcement.

1. Modernize Toxicology to Enhance Product Safety

2. Stimulate Innovation in Clinical Evaluations and Personalized Medicine to Improve

Product Development and Patient Outcomes

3. Support New Approaches to Improve Product Manufacturing and Quality

4. Ensure FDA Readiness to Evaluate Innovative Emerging Technologies

5. Harness Diverse Data through Information Sciences to Improve Health Outcomes

6. Implement a New Prevention-Focused Food Safety System to Protect Public Health

7. Facilitate Development of Medical Countermeasures to Protect Against Threats to U.S.

and Global Health and Security

8. Strengthening Social and Behavioral Science at FDA by Enhancing Audience

Understanding

9. Strengthening the Global Product Safety Net

Multiple awards are anticipated. The amount of resources made available for individual contract awards under this BAA will depend on the quality of the proposals received and the availability of funds. All funding is subject to government discretion and availability.

The Government reserves the right to select for negotiation all, some, one, or none of the proposals received in response to this solicitation, and to make awards without discussions with proposers. The Government also reserves the right to conduct discussions if it is later determined to be necessary. If warranted, portions of resulting awards may be segregated into pre-priced/severable options. Additionally, FDA reserves the right to accept proposals in their entirety or to select only portions of proposals for award. In the event FDA desires to award only portions of a proposal, negotiations may be opened with that proposer. The Government reserves the right to fund proposals in phases with options for continued work at the end of one or more of the phases.

To be eligible for award, a prospective recipient must meet certain minimum standards pertaining to financial resources, ability to comply with the performance schedule, prior record of performance, integrity, organization, experience, operational controls, technical controls, technical skills, facilities, and equipment.

This BAA is available on the following websites:

https://beta.sam.gov/opp/2313b4c8ab7a967d880cf16dee4ec116/view?keywords=FDABAA-20- 00123&sort=-relevance&index=&is_active=true&page=1

This BAA is a continuously open announcement valid throughout the period from the date of issuance through the closing date specified in fbo.gov. Amendments to this BAA will be posted to https://beta.sam.gov/opp/2313b4c8ab7a967d880cf16dee4ec116/view?keywords=FDABAA-20- 00123&sort=-relevance&index=&is_active=true&page=1 when they occur. Interested parties are encouraged to periodically check these websites for updates and amendments.

Part I: Research Areas of Interest

Through this BAA, FDA seeks to support advanced research and development strategies with potential for regulatory application in the following research areas of interest. This section presents the technical objectives that FDA seeks to achieve through this BAA. Because resources are limited, preference will be given to projects geared towards developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products.

Offerors should propose a Statement of Work (SOW) that is consistent with research and development work as defined in FAR 35.001. Proposal preparation and submission instructions are contained in Part III.

1. Modernize Toxicology to Enhance Product Safety

FDA seeks to improve the toxicologic and pharmacologic tools used to minimize risk and evaluate product safety and efficacy by conducting internal and collaborative research and development. Areas of interest include:

1.1. Develop better models of human and animal (where applicable) adverse response:

1.1.1. Evaluate and promote the use of cell- and tissue-based assays that more accurately represent human susceptibility than animal models to adverse reactions (e.g.

primary cells growth at the air liquid interface);

1.1.2. Develop new animal models that better mimic diseases to better understand the potential influence of disease progression and risk factors, including disease co-morbidities on the emergence of adverse events;

1.1.3. Promote a better understanding of toxicity mechanisms by evaluating safety assessment data at multiple levels of biological organization including genes, proteins, pathways, and cell/organ function;

1.1.4. Assess and characterize molecular targets, host genetic and inflammatory factors that may be associated with rare and unexpected adverse events (“off-target” drug effects);

https://beta.sam.gov/opp/2313b4c8ab7a967d880cf16dee4ec116/view?keywords=FDABAA-20-00123&sort=-relevance&index=&is_active=true&page=1 https://beta.sam.gov/opp/2313b4c8ab7a967d880cf16dee4ec116/view?keywords=FDABAA-20-00123&sort=-relevance&index=&is_active=true&page=1 https://beta.sam.gov/opp/2313b4c8ab7a967d880cf16dee4ec116/view?keywords=FDABAA-20-00123&sort=-relevance&index=&is_active=true&page=1 https://beta.sam.gov/opp/2313b4c8ab7a967d880cf16dee4ec116/view?keywords=FDABAA-20-00123&sort=-relevance&index=&is_active=true&page=1

1.1.5. Initiate in vitro and in vivo studies to identify potential biomarkers of harm associated with exposure to tobacco products or tobacco product constituents;

1.1.6. Using in vitro and in vivo methods, assess toxicological implications of electronic nicotine delivery systems (ENDS) products considering aerosol chemistry (e.g., HPHCs), e-liquid composition (e.g., flavors, PG/VG ratio), and aerosolization methods (e.g., wicking systems and voltage delivery)

1.1.7. Develop in vitro methods that can more accurately predict in vivo responses resulting from exposure to ENDS and other tobacco products or their constituents

1.1.8. Develop new methods that can assess toxicokinetics and toxicodynamics of nicotine across different routes of exposure and its contribution to cancer and non-cancer toxicological risk

1.1.9. Develop models for the prediction of respiratory tract deposition of smoke/aerosol particulates, their retention, sites of deposition in relation to respiratory and cardiovascular outcomes

1.1.10. Develop methods for biocompatibility and toxicological risk assessments for new device materials In line with 21st Century Cures Least Burdensome measures and the reduction in the use of animals.

1.1.11. Develop methods that facilitate the use of cell- and tissue-based assays that more accurately assess human adverse response to ingredients in dietary supplements

1.1.12. Develop computational modeling and simulation methods to promote the use of in silico assessment of devices and materials

1.1.13. Develop computational tools and models to predict immunogenicity for biologic products including modified sequences for mitigation of immunogenicity risk.

1.2. Identify and evaluate biomarkers and endpoints that can be used in non- clinical and clinical evaluations:

1.2.1. Evaluate the accuracy (specificity and sensitivity) with which animal models and in vitro assays better predict potential human and animal risk, both overall and/or in subpopulations;

1.2.2. Assess concordance between animal and human biomarkers of toxicity and determine how the performance of these biomarkers and their interpretation may vary across different organ systems and human populations;

1.2.3. Evaluate quantitative imaging (e.g., positron emission tomography, magnetic resonance imaging, computed tomography) and other advanced approaches (e.g., metabolomics) for identifying new biomarkers and predictors of efficacy and adverse responses of novel materials and chemicals.

1.2.4. Investigate precision medicine and biomarkers for predicting medical device performance, disease diagnosis and progression.

1.2.5. Evaluate the biomarkers and the role of the microbiome in contributing to adverse responses through alterations in metabolism or other mechanisms

1.2.6. Evaluate critical toxicity mechanisms and modes of action for key constituents of ENDS and other tobacco products, including HPHCs that drive cancer and non-cancer toxicological risk

1.2.7. Identify and assess characteristics, design features, ingredients and topography of a wide variety of ENDS products that could affect HPHC production and potential risk to users

1.3. Develop and Use computational methods and in silico modeling:

1.3.1. Develop clinical trial simulation models that can reveal interactions between drug or device effects, patient characteristics, and disease variables influencing outcomes;

1.3.2. Develop computer models of cells, organs, and systems (including the impact of hormones) to predict product risk, safety and efficacy;

1.3.3. Develop computational models to evaluate regulated-product toxicity or the safety and efficacy during pregnancy;

1.3.4. Develop computer models that integrate pharmacokinetic, pharmacodynamic, materials science, or mechanistic safety data to predict clinical risk and corroborate post-market findings in different patient populations; and

1.3.5. Develop and apply data mining, knowledge building, and data visualization tools to inform computer model development, clinical risk prediction, and regulatory decision-making.

1.3.6. Develop computer models for assessing the risk of new tobacco products that will potentially enter the market by considering potential risks to users of the products and users’ demographic attributes and usage patterns.

1.3.7. Develop innovative models for effectively correlating in vitro data to in vivo findings for the assessment of human health risk resulting from exposure to ENDS and other tobacco products or their constituents.

1.3.8. Develop predictive toxicology tools that can integrate multiple types of data from in vitro and in vivo studies regarding ENDS and other tobacco products into a unified risk assessment paradigm.

1.3.9. Develop computer models of cells, organs, and systems to predict risk and safety of ingredients in dietary supplements, including potential interactions with drugs and other dietary supplements.

1.3.10. Develop rare-disease clinical trial simulation models that can reveal interactions between drug or device effects, patient characteristics, and disease variables influencing outcomes, with attention to the challenges of small population and heterogeneity of patients with rare conditions.

2. Stimulate Innovation in Clinical Evaluations and Personalized Medicine to Improve Product Development and Patient Outcomes

FDA seeks to develop new tools and approaches needed to catalyze the development of personalized medicine and to modernize and advance the science and conduct of clinical trials.

Areas of interest include:

2.1. Develop and refine clinical trial designs, endpoints and analysis methods:

2.1.1. Refine clinical trial design and statistical methods of analysis;

2.1.1.1. Refine or develop statistical clinical trial designs and data analyses methods for leveraging data from external sources such as historical studies, registries, patient-generated health data, insurance claims, electronic health records and pre-clinical studies;

2.1.1.2. Develop and validate statistical program packages for innovative clinical trial designs and data analyses;

2.1.2. Identify and evaluate improved clinical endpoints and related biomarkers for trials in areas where optimal endpoints are lacking (e.g., efficacy and safety endpoints for osteoarthritis in humans and animals, for gene therapy, for transplant-related studies (endpoints and duration), for tumor vaccines, and for stem cell-derived therapies);

2.1.3. Develop novel trial designs and endpoints for special needs (e.g., small trials for orphan indications, designs and endpoints for pediatric trials including neonatal trials);

Pilot research to assess the impact of Accelerated approval (AA), and Fast track (FT), priority review (PR), and Breakthrough (BT) designations to help assess adequacy of pre-market efficacy and safety assessments and the generalizability of the findings from smaller clinical trial populations to larger more diverse populations.

The impact of incentives for the respective programs such as marketing exclusivity, priority review vouchers and the application of flexibility and scientific judgment available under existing regulations needs to be assessed. The intent is to identify factors or metrics that may further enhance drug development and safe and effective use post-approval. Approaches include:

A. Assessing the adequacy of currently available data sources to conduct appropriate analyses and tracking and

B. Identifying appropriate comparators for assessing impacts.

C. Identifying factors either common for all or particular to each expedited program that can assess:

• Safety of the drugs in the post-approval period (e.g., higher numbers/rates of withdrawals, adverse events reported, or serious labeling changes for safety, such as a boxed warning or restricted indication)

• Timelines, achievement of milestones or costs during drug development

• Application of novel or innovative clinical trial designs and data analyses

• Clinical trial population sizes and diversity; drug, disease, or program attributes (such as available natural history studies or registries, patient-advocacy involvement, funding sources, drug class or disease precedent)

• Pricing and accessibility post-approval; and effectiveness post-approval

• In particular for orphan drugs, effectiveness of programs and incentives to address unmet medical needs in the rare disease population and FDA's use of flexibility for rare disease drug development and approvals

2.1.4. Refine the use of modeling and simulation in clinical trial design to enhance the effectiveness of clinical studies; and

2.1.5. Develop practical methods to determine the absolute or comparative effectiveness of patient-matched medical products

2.1.6. Develop educational materials to enhance FDA’s capacities to conduct review of clinical outcome assessments (and their resulting endpoints), including patient-reported outcomes, clinician-reported outcomes, observer-reported outcomes, and performance outcomes.

2.1.7. Identify and evaluate good practices of patient involvement in clinical study design and conduct.

2.1.8. Improve clinical study design and conduct to better identify and evaluate possible sex and gender differences related to FDA-regulated products

2.1.9. Improve clinical study design and conduct to examine diseases and conditions primarily affecting women across the lifespan (e.g., pregnant, lactating, pre- and post-menopausal and elderly women);

2.2. Leverage existing and future data:

2.2.1. Develop quantitative models and measures of disease progression;

2.2.2. Develop natural history studies on both prevalent and rare diseases to identify disease subsets/phenotypes amenable to differential approaches for therapy or management, and possibly with novel biomarkers for their identification.

2.2.3. Utilize large, pooled clinical trial datasets to identify potential trial endpoints, explore differences in specific populations and subpopulations (e.g., stage of disease, chronic disease states, sex, gender, race and ethnicity, pediatrics and age groups) and different subsets of diseases, improve understanding of relationships between clinical parameters and outcomes, and evaluate clinical utility of potential biomarkers.

2.2.4. Develop new tools and methodologies to harness big data and real-world data (e.g.

data derived from electronic health records (EHRs); medical claims ad billing data;

data from product and disease registries; patient-generated data, including from in-home-use settings; and data gathered from other sources that can inform on health status, such as mobile devices) to support regulatory decision-making.

2.2.5. Survey existing and develop new statistical methods for synthesizing data from various sources such as outside of US studies, historical studies, and registries.

2.2.6. Advance methodologies to generate clinical evidence from real-world data sufficient to support regulatory use:

• Incorporate real world data sources in innovative clinical trial designs

• Develop and validate tools and models that assess fitness of real-world data to support regulatory decision making

• Develop and validate methods to predict device performance using real-world data

• Using a collaborative approach, identify high-priority areas for development of real-world data source methodology that meet stakeholder needs

• Explore methodological reasons for discordant findings among randomized and observational analyses addressing the same clinical topic involving FDA-regulated products

2.2.7. Develop core data elements and data sets for device categories to support regulatory decision making

2.2.8. Develop standards for data quality and data sources that increase the quality, interoperability, and usability of real-world data.

2.2.9. Design and optimize data infrastructure to facilitate information exchange and data extraction.

2.2.10. Identify, develop, and evaluate data sources and efficient techniques for data mining, data linkage, and large data set analysis that can be used to assess the safety and effectiveness of FDA-regulated products, to specifically identify women’s health issues.

2.2.11. Develop and validate a tool that uses natural language processing, machine learning and artificial intelligence to semi-automate review of medical charts to improve, expedite and lower chart review costs.

2.2.12. Develop and improve the efficiency of computable phenotype generation in support of future postmarket active surveillance systems for CBER-regulated biologics and drugs

2.2.13. Identify and develop new, large medical databases such as EHR, claims, registries and others to improve safety and effectiveness evaluations of patient subpopulations such as pediatric, elderly, rare diseases, and others.

2.2.14. Identify and develop new regulatory quality EHR data sources that use ISBT-128 coding for use in studying safety or effectiveness of blood, blood products, cellular products and others.

2.2.15. Develop methods and conduct studies that replicate findings of randomized controlled trials of CBER-regulated biologic products using regulatory quality observational data for specific studies of biologic products.

2.3. Identify and qualify biomarkers and study endpoints:

2.3.1. Facilitate identification and qualification of new and improved biomarkers for safety and efficacy. Develop and evaluate novel approaches for biomarker identification, including -omics, systems biology, and high throughput methods. Other approaches may include pharmacodynamic response - dose selection, disease severity, progression and prognosis, and pharmacogenomics (to predict safety and efficacy or guide dosing).

2.3.2. Identify and evaluate biomarkers to be used in the assessment of products related to conditions that affect women and identify sex differences in biomarkers related to the performance of medical products

2.4. Facilitate Antibacterial Drug Development and Address Antibacterial Drug Resistance

Antibacterial drug resistance is a major threat to public health. FDA’s roles in combatting antibacterial drug resistance are to: (1) facilitate the development of new antibacterial drugs to treat patients and (2) advance the science of clinical trial design. FDA is interested in the following topic areas:

2.4.1. Evaluate potential innovations in clinical trial design for new antibacterial drugs such as enrollment strategies, data collection streamlining, drug development tools, clinical endpoints, and new statistical analytic approaches

2.4.2. Advance the science of in-vitro, animal model, and/or pharmacokinetic studies to facilitate antibacterial drug development, including studies focused on drug development for special populations such as patients with unmet need, children and patients with renal or hepatic dysfunction (for more background, see link:

https://www.fda.gov/media/133767/download)

2.4.3. Evaluate strategies to enrich enrollment in clinical trials for new antibacterial drugs such as the use of rapid diagnostic tests

2.4.4. Advance the science of antibacterial drug susceptibility testing to ensure that up to date susceptibility testing criteria (breakpoints) are available for patient care and antimicrobial stewardship. For example, provide updated data from microbiologic surveillance studies, pharmacokinetic studies, including modeling, and/or clinical outcome data to support updating susceptibility test interpretive criteria for certain antibacterial drugs that are a high public health priority. (for more background, see link: https://www.fda.gov/media/133769/download)

2.5. Facilitate Drug Development and Appropriate Use for Patients with Serious Mental Illness.

Serious Mental Illness (SMI) is a major threat to public health. FDA’s roles in addressing SMI include: (1) facilitating the development of new therapies to treat patients, (2) advancing the science of clinical trial design, including identification of biomarkers, and (3) developing a better understanding of the performance of available therapies, including the specific risks and benefits in specific populations, including those with comorbid diagnoses, such as substance abuse and dependence. FDA is interested in the following topic areas:

2.5.1. The development and refinement of clinical trial designs, endpoints, and analysis methods that could be used for SMI drug development. This includes the topics listed above in Section 2.1 but should consider and specifically be tailored to SMI drug development. Of interest also are specific approaches that could be used to support the development of treatment options for pediatric patients with SMI.

2.5.2. The development or enhancement of clinical trial networks, platforms, and/or registries to study new or existing drugs for SMI for patients of all ages. This includes the conduct of randomized trials, including pragmatic design trials, or observational or natural history studies within these networks, platforms, and/or registries to inform patients and prescribers about the appropriate use of medications for SMI and to facilitate new drug development.

2.5.3. The identification and qualification of biomarkers or other study endpoints that could be used for SMI drug development. This includes the topics listed above in Section

2.3 but should consider and specifically be tailored to SMI drug development, including pediatric patients.

2.5.4. The development of approaches to better identify patients who would benefit from treatment with drugs intended for SMI or to encourage increased compliance with SMI drug treatment, including pediatric patients.

2.6. Facilitate Development of Drug Therapies for Youth Tobacco Cessation

In addition to the prevention of initiation, which will be the cornerstone of any successful effort to curb youth tobacco use, FDA is also exploring additional approaches to address this public health issue. One such approach may be the development of drug therapies, as part of multimodal treatment strategies including behavioral interventions, to support youth tobacco cessation. To date, research on youth tobacco cessation has been limited and https://www.fda.gov/media/133767/download https://www.fda.gov/media/133769/download focused primarily on cigarette smoking cessation. FDA is interested in the topic areas described below. Of note, we believe that many of these issues will need to be addressed uniquely based on the type of tobacco product being used (e.g., combustible cigarette, e-cigarette, smokeless tobacco). Submissions should indicate what type of tobacco products will be addressed by the research and include justification for any evaluation that combines multiple type of tobacco products.

2.6.1. The development of data or methods to quantify the range of factors that contribute to initiation and continuation of specific tobacco products among youth, as well as youth attitudes towards tobacco cessation.

2.6.2. The development of data or methods to identify youth tobacco users who may benefit from treatment with drugs intended for cessation, either alone or in combination with behavioral interventions. Factors to consider include age (older vs.

younger adolescent), patterns of use (duration and frequency of use), clinical features (level of addiction, presence/absence of comorbidities including psychiatric disease), and type of tobacco product.

2.6.3. Identification and analysis of scientific, clinical, and societal factors that could either encourage or impede the conduct of clinical studies designed to evaluate drugs intended for various youth tobacco product cessation. Evaluation of approaches that could be used to overcome identified barriers and encourage research.

2.6.4. The development of methods, measures and study designs appropriate for the evaluation of drug therapies for youth tobacco cessation. Factors to consider include the identification of informative endpoints and the development of assessment tools to evaluate these endpoints.

2.6.5. The development of data or approaches to support the ability to extrapolate data from approved smoking cessation drug therapies for adults to youth tobacco cessation.

2.7. Immuno-oncology

FDA is interested in supporting research in two areas to improve understanding of atypical response patterns observed in patients treated with immune checkpoint inhibitors (additional background information relating to these areas of interests may be found here https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative):

2.7.1. 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. FDA is also interested in understanding how to distinguish among patients who have become resistant to ICI on an ongoing basis from those who may respond again upon re-challenge.

2.7.2. Supporting research for the development of 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 https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative 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

2.7.3. FDA is also interested in the development of clinical trial endpoints that account for atypical response patterns and more fully characterize the clinical benefit of immune checkpoint inhibitors.

2.7.4. FDA has an interest in supporting research in two areas to improve understanding of the side effects of ICIs:

(1) Support the development of technologies that better identify patients at risk for development of serious adverse reactions with ICIs.

(2) Support the development of standardized approaches for identifying and reporting side effects in clinical trials evaluating ICIs.

2.8. Cell /Gene and Personalized Neo-antigen-based Therapies for Cancer

OCE is interested in supporting research related to clinical development, safety, manufacturing and quality control for cell therapy and neo-antigen-based therapies for cancer, specifically to: (additional background information relating to these areas of interests may be found here https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative)

2.8.1. 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.

2.8.2. 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.

2.8.3. 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.

2.9. Health equity and special populations in oncology clinical trials (additional background information relating to these areas of interests may be found here https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative)

2.9.1 Conduct qualitative research to understand barriers to including older adults in https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative oncology clinical trials

2.9.2 Improve data collection in oncology clinical trials relevant to older populations

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

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

2.10. Oncology trial designs, end points and statistical methodologies (additional background information relating to these areas of interests may be found here https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative)

2.10.1 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.

2.10.2 OCE is particularly interested in supporting 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).

2.10.3 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.

2.11. Pediatric Oncology (additional background information relating to these areas of interests may be found here https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative)

2.11.1 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.

2.11.2 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.

2.11.3 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 https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative 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. This is particularly important in pediatric cancers which often have diminished neoantigen expression due to low mutational burdens.

2.12. Precision Oncology (additional background information relating to these areas of interests may be found here https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative)

2.12.1 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.

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

3. Support New Approaches to Improve Product Manufacturing and Quality

FDA seeks to support the application of novel technologies to product development and innovative analytical approaches to improve product manufacturing and quality through active research. Areas of interest include:

3.1. Enable development and evaluation of novel and improved materials and manufacturing methods:

3.1.1. Investigate the effects of advanced manufacturing on product quality.

Proposals could include research on technologies and materials that:

• Result in manufacturing technology, tools, or approaches that enhance control of critical quality attributes for drug substances or products, or

• Improve manufacturing capabilities for complex drugs as defined within the GDUFA II Commitment Letter, or

• Outcome can include, but is not limited to, trainings on the methods.

• Round robin validation of modeling and simulation approaches for the on-line product quality analysis.

3.1.2. Examine specific novel material and manufacturing technologies to determine how they impact product failure rates; and

3.1.3. Evaluate complex drug substances and complex drug product dosage forms, especially potential regulatory questions related to drug quality. Some specific areas of research could include: (1) appropriate analytical methods for complex drug substances or products, (2) in-process controls during manufacturing processes to ensure product quality, and (3) raw material quality control.

Proposals should clearly describe the potential impacts of the proposed enabling technology on readiness for broad implementation in pharmaceutical industry, control strategy, and/or regulatory evaluation for complex drug substances and complex drug product dosage forms, including natural products.

Develop improved methods and tools to detect and measure the physical structure, chemical properties, and biological behavior of engineered nanomaterials, additively manufactured pharmaceuticals (pharmacoprinted products), and complex dosage forms (e.g., transdermal patches, inhalation delivery systems, and targeted drug delivery systems) in FDA-regulated products.

3.1.4. Develop and evaluate practical in-process monitoring systems, methods, and metrics for additive manufacturing processes.

3.1.5. Explore novel application of large-scale continuous manufacturing processes for more complex biologic products, such as vaccines, and cell and gene therapies.

Proposals should clearly describe the potential impacts of the proposed enabling technology on readiness for broad implementation in pharmaceutical industry, control strategy, and/or regulatory evaluation of CM, and should clearly quantify the improvement metric for implementation of CM at a commercial scale as compared to batch or pilot production if relevant:

• Closed and automated manufacturing technologies

• Modular platforms for complex biologics manufacturing and testing

• Process modeling and simulation

• Novel in-line and real time monitoring technologies

• Improved cell lines for continuous viral vector production and improved vector purification technologies

• Advanced manufacturing technologies for cell cultures used to manufacture vaccines

3.1.6. Refine or enhance existing technologies to improve the sensitivity, specificity, and robustness of testing methods used to measure medical countermeasure (MCM) potency, in-process characteristics, and final drug substance characteristics (for example, in-line sensors and process analytical technologies)

3.1.7. Advance broadly-applicable, commercially-ready (manufacturing readiness level {MRL} 4-61) tools, technologies, and platforms that improve manufacturing efficiency, consistency, quality, and speed of medical countermeasures (MCMs) to bolster the MCM supply chain; for example, “plug-and-play” modular unit operations applicable for downstream processing, or continuous manufacturing.

3.2. Develop new analytical methods:

3.2.1. Investigate feasibility and value of using improved analytical technologies for evaluating product quality of pharmaceutical agents and other regulated products, and evaluate whether these improved technologies should be incorporated into product assessments;

3.2.2. Evaluate applicability of various analytic technologies for determination of the “similarity” of biosimilars to their reference products;

3.2.3. Perform statistical research to support development and evaluation of new assays and tests needed to assure analytical methods give consistent reproducible results.

3.2.4. Genetically modified animals: Investigate new analytical methods to identify unintended genomic modifications introduced using genome editing or other modern molecular biology techniques and to differentiate these changes from naturally

1 Manufacturing Readiness Levels as defined by Department of Defense: http://www.dodmrl.com/ And further explained at: https://www.nextflex.us/wp-content/uploads/NextFlex_PC3.0_MRL-TRL_Definitions.pdf and http://www.niimbl.us/Downloads/MRLGuidance.pdf http://www.dodmrl.com/ https://www.nextflex.us/wp-content/uploads/NextFlex_PC3.0_MRL-TRL_Definitions.pdf http://www.niimbl.us/Downloads/MRLGuidance.pdf occurring mutations.

3.2.5. Genetically modified animals: Develop new analytical methods to screen for the occurrence of unintentional genomic modifications during commercial production in which intentional genomic alterations are introduced.

3.3. Develop assessment tools to support facility and product surveillance and monitoring of quality systems and processes:

3.3.1. Advance the study of quality metrics and quality culture, including pharmaceutical quality systems, manufacturing operations, continuous improvement, and overall quality culture in domestic and international establishments, including to inform consistent assessment of robustness of a manufacturer’s Quality Management System. Develop methods for data collection, validation, and assessment of such metrics.

3.3.2. Advance statistical methodology for assessing disparate data types and sources in the evaluation of products, manufacturing facilities and quality systems and processes

3.4. Reduce risk of microbial contamination of products:

3.4.1. Develop sensitive, rapid, high-throughput methods to detect, identify, and enumerate microbial and chemical contaminants and validate their utility in assessing product sterility; and

3.4.2. Develop and evaluate methods for microbial inactivation/removal from medical products that are not amenable to conventional methods of sterilization.

3.4.3. Enhance safety and performance of reusable devices by improving the quality and effectiveness of antimicrobials, sterilization and reprocessing of medical devices.

3.4.4. Develop sensitive, rapid methods to detect, identify, and enumerate communicable disease contaminants (i.e., viral, prion protein) and validate their utility in assessing product contamination

3.5. Improve scientific approaches to evaluate generic drugs

In July 2012, Congress passed the Generic Drug User Fee Amendments (Title III of the Food and Drug Administration Safety and Innovation Act (Public Law 112-144)). The Generic Drug User Fee Amendments (GDUFA) is designed to enhance public access to safe, high-quality generic drugs, and to reduce costs to industry. To support this goal, FDA agreed in the GDUFA commitment letter to consult with industry and the public in order to create an annual list of regulatory science initiatives specific to research on generic drugs for each year covered by GDUFA. This commitment continues in the Generic Drug User Fee Amendments of 2017 (GDUFA II). The research activities related to the FY 2020 topic areas are as follows:

3.5.1. Post-market Evaluation of Generic Drugs

3.5.1.1. Develop surveillance and monitoring methods for generic drug substitutions.

3.5.1.2. Understand patient perceptions of generic drug quality and effectiveness.

3.5.2. Complex active ingredients, formulations, or dosage forms

3.5.2.1. Improve advanced analytics for characterization of chemical compositions, molecular structures and distributions in complex active ingredients

3.5.2.2. Improve particle size, shape and surface characterization to support demonstration of therapeutic equivalence of suspended and colloidal drug products

3.5.2.3. Establish predictive in silico, in vitro and animal studies to evaluate immunogenicity risk of formulation or impurity differences in generic products

3.5.2.4. Develop predictive in vitro bioequivalence (BE) methods for long-acting injectables including the identification of the critical quality attributes (CQA) for these products

3.5.2.5. Develop better methods for evaluating abuse deterrence of generic solid oral opioid products, including in vitro alternatives to…