FY23 BAA Amendment 00001.pdf

FDABAA-23-00123

Overview Information Agency Name: Department of Health and Human Services (HHS), Food and Drug Administration (FDA), 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 (BAA)

Eligible Applicants: This BAA is open to ALL responsible sources and Small Businesses are strongly encouraged to respond. 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 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 Only [Not Grants]

Notes: Regarding Funding

To ensure sufficient 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 strongly encouraged to submit Stage One Submittal Packages with:

1. Cover Page

2. Freestanding Quad Chart

3. Freestanding White Paper aligned with the following (please assign the most closely aligned from each below if your proposal is applicable to more than one)

a. Charge Area (i.e., I. modernize development and evaluation of FDA regulated products)

b. Regulatory Science Topic Area of Interest (i.e., A. Alternative Methods)

c. FDA Regulated Areas (i.e., Biologics) and/or Demographics and Populations (i.e., Racial and Ethnic Minority)

4. R&D justification

Whitepapers will be submitted no later than 5:00 pm, Eastern Standard Time, January 23, 2023, and earlier if possible. A submission will be considered incomplete if any of these critical elements are missing. Stage One Submittal Packages received after that date will still be accepted, but due to a lack of lead time, will not be considered for award in FY23.

Notice and Disclosure Regarding Incomplete/Nonconforming Stage One Submittal Packages: All Stage One Submittal Packages received in response to this announcement must be complete and comply with all instructions provided herein (Note: Part III: Proposal Preparation and Submission must be considered; it lays out the details of what is included in Stage I and Stage II package). The FDA reserves the right to reject (or otherwise give no further consideration to) any packages that are found to be (1) missing any pertinent information, (2) submitted in a nonconforming format, or (3) otherwise require exchanges with offerors for the FDA to complete its evaluation due to patent or latent ambiguities contained within the submittal.

TABLE OF CONTENTS

INTRODUCTION

Part I: Research Areas of Interest

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 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 all FDA regulated products.

In the US, FDA-regulated products account for about 20 cents of every dollar spent by American consumers each year on 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, biologics, 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, ranging from pre-market review of efficacy and safety of many of its regulated products to post-market product surveillance, review of product quality, regulation of product manufacture, and 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. In order 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 below and further described in Part I of this announcement.

Research Areas of Interest:

I. Modernize development and evaluation of FDA-regulated products A. Alternative Methods B. Advanced Manufacturing Approaches C. Analytical and Computational Methods D. Biomarkers E. Clinical Outcome Assessment F. Complex and Novel Clinical Trial Design G. Predictive Toxicology H. Methods for Assessing Behavioral, Economic, or Human Factors I. Approaches to Incorporate Patient and Consumer Input J. Methods to Assess Real-World Data to serve as Real-World Evidence K. Methods to Assess Data Source Interoperability

II. Strengthen post-market surveillance and labeling of FDA-regulated products A. Methods to Assess Real-World Data to Support Regulatory Decision-Making B. Using and Validating Artificial Intelligence Approaches C. Novel Clinical Trial Design, Statistical and Epidemiologic Methods D. Automated Reporting Tools for Adverse Events and Active Surveillance E. Methods to Improve Communication About Risk to Patients and Consumers F. Approach to Expand Data Capacity, and Increase Data Quality and Use G. Efforts to Harmonize Existing and Emerging Data Standards

III. Invigorate public health preparedness and response of the FDA, patients, and consumers A. Reinforce Medical countermeasures Initiative (MCMi) B. Antimicrobial Resistance C. Patient and Consumer Engagement D. Substance Use and Misuse E. One Health Approaches F. 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 www.beta.sam.gov using Keyword Search “FDABAA-23-00123.”

This BAA is a continuously open announcement valid throughout the period from the date of issuance through the closing date specified in the www.beta.sam.gov announcement. Amendments to this BAA, if necessary, will be posted in the same site when they occur. Interested parties are encouraged to periodically check the website for updates and amendments.

Please note, beginning this fiscal year, the FDA will be giving preference to proposals that use a cost reimbursement model vice a firm fixed price model. Research, by definition, does not always produce a deliverable, whether due to the nature of the research or the results of the research. By proposing a severable, cost reimbursable contract, risk is reduced to both the government and the awardee. In the future, the FDA may move to only utilizing a cost type model for this BAA award.

Requirements for cost contracts can be found in the list of clauses in attachment 5. Please note, the contract requirements differ between commercial and educational entities. It is HIGHLY recommended that all potential proposal submitters review Part 31 - Contract Cost Principles and Procedures:

31.103 Contracts with commercial organizations.

31.104 Contracts with educational institutions.

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 toward advancing regulatory science, the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products, which include medical devices, drugs, biologics, combination products, veterinary medicine, food, cosmetics, dietary supplements and tobacco products.

In addition to the product areas that FDA regulates, FDA aims to target innovation in regulatory science that advances the health of the following demographic groups and populations, some of which have clinical characteristics that may frequently preclude their participation in clinical research or bear disproportionate burden of tobacco product risk and harm: racial & ethnic minorities, women’s health, persons with cancer and persons with rare diseases (including rare cancers).

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.

https://www.acquisition.gov/far/part-31#FAR_31_103 https://www.acquisition.gov/far/part-31#FAR_31_104

Through collaborative interactions with stakeholders, we aim to foster robust and innovative approaches to advance regulatory science through the following framework.

Additional information regarding specific FDA initiatives, and/or center and office priorities can be found in the appendix.

REGULATORY SCIENCE FRAMEWORK – OVERVIEW

The goal of this framework is to harness regulatory science research to accomplish the following three charges that directly align with FDA’s mission, to:

I. Modernize development and evaluation of FDA-regulated products

II. Strengthen post-market surveillance and labeling of FDA-regulated products

III. Invigorate public health preparedness and response of the FDA, patients, and consumers

These three charges are foundational to FDA’s mission, and thus are not expected to change. We have designated areas to target regulatory science efforts that support the FDA’s mission for each charge. The areas of regulatory science are designed to change with the evolution of science, technologies, and public health needs. Moreover, each area has been designated under a specific charge, and where possible, specific product areas and/or demographics and populations have been labeled. When multiple product areas and/or demographics and populations have been identified for a given regulatory science area, we use the term cross-cutting in place of the specific product area and/or demographic or population. Lastly, please see Table 1, which highlights the topic areas that are priorities for FDA for FY 23.

Table 1: Areas of regulatory science for each charge (rows), and relevant applicable to product areas, and demographics & populations (columns). The “x” marks priority areas for FDA in FY 23.

I. Modernize development and evaluation of FDA-regulated products

The following focus areas of regulatory science are identified to accomplish Charge I, modernize development and evaluation of FDA-regulated products:

A. Alternative Methods Examples: Novel in-vitro, in-vivo, and in-silico methods; Microphysiological System; Organ-on-a-chip;

Use of alternative assays

1. Cross-cutting

a. Integrate an understanding of product quality and safety based on novel genomic, proteomic, metabolomic, and other-omic technologies.

B io lo g ic s

D ev ic es

D ru g s

V et er in ar y

M ed ic in e

To b ac co

P ro d uc ts

Ra ci al a nd E th ni c M in o ri ty

W o m en

's H ea lth

Ra re

D is ea se s

O nc o lo g y

A. Alternative Methods X X X X X X X X B.Advanced Manufacturing Approaches (includes MCMi) X X X X C. Analytical and Computational Methods X X X X X X X X D. Biomarkers X X X X X X E. Clinical Outcome Assessment X X X X F. Complex and Novel Clinical Trial Design X X X X X X X G. Predictive Toxicology X X X X H. Methods for Assessing Behavioral, Economic, or Human Factors X I. Approaches to Incorporate Patient and Consumer Input X X X J. Methods to Assess Real-World Data to serve as Real-World Evidence X X X X X X K. Methods to Assess Data Source Interoperability X

A. Methods to Assess Real-World Data to Support Regulatory Decision-Making X X X X X B. Using and Validating Artificial Intelligence Approaches X X X X X C. Novel Clinical Trial Design, Statistical and Epidemiologic Methods X X X D. Automated Reporting Tools for Adverse Events and Active Surveillance X X X X X E. Methods to Improve Communication About Risk to Patients and Consumers X X X F. Approach to Expand Data Capacity, and Increase Data Quality and Use X X G. Efforts to Harmonize Existing and Emerging Data Standards X X X

A. Reinforce Medical Countermeasures Initiative (MCMi) X X X X X X B. Antimicrobial Resistance X C. Patient and Consumer Engagement X X X X D. Substance Use and Misuse X X X E. One Health Approaches X X X X X X X X X F. Global Product Safety net X X X

III. Invigorate public health preparedness and response of the FDA, patients, and consumers

II. Strengthen post-market surveillance and labeling of regulated products

I. Modernize development and evaluation of FDA-regulated products

Anticipated FY23 Funding for BAA Projects

FDA-Regulated Areas

Demographics & Populations

b. Develop and use microphysiological systems and computational modeling approaches to improve predictivity of nonclinical testing and potentially address the 3Rs (replace, reduce, and refine) of animal use in product testing and scientific research.

2. Devices

a. Develop new methods for biocompatibility testing approaches to research and characterize biological response to extracts of medical devices (e.g., in vitro alternatives) and particulates in line with 21st Century Cures Least Burdensome measures and the reduction in the use of animals.

b. Evaluate the application and validation of modeling and simulation data as digital evidence throughout the total product life cycle to augment and/or replace physical product testing.

c. Develop and validate methods to create digital twins (i.e., highly complex models using artificial intelligence and large amounts of digital and physical data to create simulations of new treatments and personalized innovative devices).

3. Tobacco:

a. 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., differentiated primary lung cells grown at an air liquid interface or lung-on-a-chip and microphysiological systems model);

i. Predict threshold of toxicological concerns resulting from exposure to Electronic

Nicotine Delivery Systems (ENDS) aerosols and other new and emerging tobacco products or their constituents.

ii. Predict levels of tobacco-related toxicants resulting from exposure to ENDS aerosols and other new and emerging tobacco products or their constituents that induce in vitro responses to in vivo exposure levels that could result in human or animal adverse effects.

4. Women’s Health:

a. Develop alternative methods in support of development of diagnostics and therapeutics targeting women, including, but not limited to:

i. methods to evaluate innovative, new devices and diagnostics specifically designed for use in women.

ii. methods to enhance the evaluation of devices used in both men and women to take into consideration sex differences like organ size/anatomy/ physiology/human factors differences that may affect device performance.

iii. Foster development methods to evaluate sex-matched devices and companion diagnostics.

b. Methods to evaluate FDA regulated-product safety and effectiveness during pregnancy and lactation.

5. Rare diseases:

a. Develop new alternate methods (microphysiological systems and Complex in vitro

Methods) to support regulatory submissions demonstrating efficacy and safety assessment of drugs for rare diseases.

B. Advanced Manufacturing Approaches Examples: New medical product manufacturing technologies and processes that can improve quality of FDA regulated products, address shortages of medicines, and/or speed time-to-market; Technologies may include Continuous, Additive and Smart manufacturing

1. Cross-cutting:

a. Facilitate development and evaluation of:

i. automated or semi-automated in-process monitoring and control systems and methods.

ii. test and validation metrics for advanced manufacturing processes including additive manufacturing, integration and intensification of process unit operations, adaptive processes, and automation of operations.

iii. new ways to evaluate gene and cell therapy products and their manufacturing methods develop in this period of face-paced scientific progress.

iv. how implementation of digital technologies in product design, development, and life cycle risk management impacts the control, responsiveness, and product quality.

b. Investigate the effect of advanced manufacturing on product quality. Examine specific novel material and manufacturing technologies to determine how they impact product failure rates;

i. Research focuses on technologies and materials that result in manufacturing technology, tools, or approaches that enhance control of critical quality attributes for drug substances or products.

ii. Improve manufacturing capabilities for devices, complex drugs, and biologics.

c. Investigate the effects in supply chain of implementing advanced manufacturing for specific types of medical products, especially such as biologics, vaccines and medical devices.

Topics may include:

i. Supply chain resilience to disruption

ii. Increased access,

iii. Personalization,

iv. Decreased reliance on foreign supply chains.

d. 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), biological products (e.g., therapeutic proteins or monoclonal antibodies) and complex dosage forms (e.g., transdermal patches, inhalation delivery systems, and targeted drug delivery systems) in FDA-regulated products.

e. Investigate or develop methods to increase implementation and adoption advanced manufacturing methods in critical areas that impact production of vaccines, diagnostics, critical medicines and devices, and potential shortage products.

2. Drugs:

a. Develop improved methods and tools for the validation and lifecycle maintenance of digital technologies for Industry 4.0 for pharmaceutical manufacturing including data capture and storage, adaptive process control, digital twins, and internet of things.

b. Develop improved methods for the manufacturing of sterile drug products including rapid monitoring for the detection of microbial contamination.

3. Biologics:

a. Explore novel applications of advanced (e.g., integrated and continuous) manufacturing processes for complex biologic products, such as vaccines, tissue-engineered products, and cell and gene therapies. Describe the potential impact of the proposed enabling technology on process control strategy and its readiness for broad implementation in the biopharmaceutical industry. Quantify the improvement metric for implementation of advanced manufacturing processes at a commercial scale as compared to traditional batch production or small-scale pilot production, if relevant. Topics may include but are not limited to:

i. Closed and automated manufacturing processes,

ii. Modular manufacturing platforms with integrated in-process testing capabilities,

iii. Manufacturing process modeling and simulation,

iv. Advanced or novel process analytical technologies for real time process control and release,

v. Improved cell lines and improved upstream cell culture production processes for vaccine antigen or viral vector manufacturing.

b. Develop new approaches such as in vitro and in vivo methods to identify measurable characteristics of product safety, quality, and potency when evaluating new biotherapeutics https://www.sciencedirect.com/science/article/pii/S0378517321003598

(e.g., engineered tissues or cell therapy products, including stem cell- derived products), for clinical application in regenerative medicine;

i. Identification of critical quality attributes (CQAs) and development of advanced assays for characterization of CQAs in products for gene and cell therapies,

ii. Development of reference materials and standards for gene and cell therapies.

4. Devices:

a. Develop novel materials intended for use as materials of construction or manufacturing aids for medical devices;

i. Advance the development of novel materials for manufacturing of respirators and other personal protective equipment including the development of integrated virocidal or other infection control blocking capabilities.

b. Develop standardized methods for devices to dynamically update their data dictionary and related embedded software to respond to new data needs, such as those driven by public health response to emerging threats

5. Medical Countermeasure Initiative (MCMi):

a. 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 process analytical technologies).

b. Advance broadly applicable, commercially ready (pilot ready or commercially implementable: MRL 4-6 and 7-9 respectively) 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.

6. Neo-antigen-based therapies, Oncology

a. 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. Examples may include neoantigen-based vaccines, redirecting T-cell specificity by genetically modifying T cells with receptors specific against neoantigen-derived epitopes.

7. Pediatric Oncology:

a. Development of immune based therapies (engineered immune effector cells or bifunctional activators) that recognize tumor specific altered glycan epitopes (glycolipids or glycoproteins) that NK and T-cells do not generally recognize.

C. Analytical and Computational Methods

Examples: Develop and use of computational methods and in-silico modeling; Simulation-based approaches; Advanced quantitative methods-based modeling; Predictive modeling, Model-informed drug development

a. Develop and evaluate the use of model-based digitally integrated systems, artificial intelligence, machine learning and simulation in production or quality system activities.

Proposals may include but are not limited to:

ii. Generative Design

iii. Production simulation and simulated process validation,

iv. AI/ML application to quality system activities, such as, complaint management, trending, or others,

v. Intelligent Design Control

vi. Closed loop risk-management.

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

i. FDA regulated products

ii. ingredients in dietary supplements, including potential interactions with drugs and other dietary supplements.

c. 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.

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

e. Develop novel methods to display model output in both graphical and numeric formats;

f. Explore the role of digital health technologies in the evaluation of new medical products;

g. Identify opportunities and develop computer simulation and modeling to streamline data analysis and model biological systems and their responses to agents of concern, such as toxins, toxic compounds, pathogens, and biomaterials.

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

2. Biologics:

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

3. Devices:

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

b. Evaluate the use of computational modeling and simulation to improve or optimize device sterilization processes. Explore validation requirements and methods to enable the use of the modeling and simulation data as a valid source of digital evidence.

4. Drugs:

a. Improve the efficiency of Biosimilar product development

i. Evaluate advancements in analytical (including physical, chemical and biological function assays), and pharmacological assessments and experience with prior biosimilar product development to identify opportunities to streamline biosimilar product development.

ii. Investigate and evaluate informative, scientifically appropriate methodologies to predict immunogenicity by advancing the knowledge of analytical (including physical, chemical, and biological function assays), pharmacological and clinical correlations as it relates to biosimilarity.

b. Develop Methods for Generics to Address Harmful Impurities such as Nitrosamines:

This research area focuses on understanding how ingredients in generic drug products may either contribute to or mitigate the formation of harmful impurities such as nitrosamine adducts such as nitrosamine drug substance related impurities (NDSRIs), evaluating the risk of human exposure to these impurities, and developing methods for abbreviated new drug application (ANDA) applicants to efficiently address the potential risks. For more information, see the Generic Drug User Fee Amendments (GDUFA) science and research priority initiatives for fiscal year (FY) 2023.

c. Enhance the Efficiency of BE Approaches for Complex Active Ingredients:

This research area focuses on improving advanced orthogonal methods for the characterization of chemical compositions, molecular structures, and distributions of complex active ingredients that can elucidate attributes of complex active ingredients that may be critical to their performance and, thereby, support the development of efficient characterization-based BE approaches. For more information, see the GDUFA science and research priority initiatives for FY 2023.

d. Enhance the Efficiency of BE Approaches for Complex Dosage Forms and Formulations:

This research area focuses on improving efficient characterization-based (in vitro) BE approaches for complex dosage forms by identifying relevant critical quality attributes (CQAs) to characterize and suitable test methods for doing so. For more information, see the https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects

GDUFA science and research priority initiatives for FY 2023.

e. Enhance the Efficiency of BE Approaches for Complex Routes of Delivery:

This research area focuses on understanding of how ingredients and other aspects of a formulation influence drug absorption via complex routes of delivery, building in vivo predictive models and identifying corresponding failure modes for BE, to support the development of efficient BE approaches for these products. For more information, see the GDUFA science and research priority initiatives for FY 2023.

f. Enhance the Efficiency of BE Approaches for Complex Drug-Device Combination Products:

This research area focuses on evaluating the impact of identified differences in the user-interfaces, hardware, software or propellants between prospective generic and the reference standard on the BE, therapeutic equivalence or post-marketing safety of generic drug-device combination products. For more information, see the GDUFA science and research priority initiatives for FY 2023.

g. Improve the Efficiency of BE Approaches for Oral and Parenteral Generic Products:

This research area focuses on understanding of how ingredients in oral and parenteral drug products may modulate bioavailability, and on improving biorelevant dissolution methods as well as in silico models to support the expansion of biowaivers and to support global harmonization. This includes developing evidence to support the feasibility of biowaivers for immediate release (IR) oral drug products with differences in formulations larger than currently recommended in FDA guidance, or for IR oral drug products that do not demonstrate comparable dissolution profiles across strengths. It also includes establishing approaches to manage potential risks related to subject safety more consistently when developing clinical BE study recommendations and elucidating potential failure modes for BE with special populations (e.g., pediatric or geriatric patients) to improve tools and methodologies that can be incorporated into BE study recommendations which ensure the equivalence of therapeutic outcomes in diverse populations. For more information, see the GDUFA science and research priority initiatives for FY 2023.

h. Facilitate the Utility of Model-Integrated Evidence (MIE) to Support Demonstrations of BE:

This research area focuses on developing tools and advancing approaches to integrate complementary in silico (modeling), in vivo and in vitro evidence in ways that collectively mitigate the risk of failure modes for BE and support a framework for virtual BE studies. For example, while it may not be feasible to adequately characterize the long-term bioavailability of drugs from LAI products using in vivo or in vitro methods alone, it may be feasible to integrate limited in vivo and in vitro data with PBPK models that generate the remaining evidence needed to support a demonstration of BE. This area includes research on the use of MIE to evaluate failure modes for BE and to optimize the design of BE studies. For more information, see the GDUFA science and research priority initiatives for FY 2023.

i. Expand the Use of Artificial Intelligence (AI) and Machine Learning (ML) Tools:

This research area focuses on building systems and infrastructure that support the functionality of AI/ML tools which FDA can use to improve the efficiency and consistency of scientific assessments and advice. This includes using AI/ML tools such as natural language processing (NLP) that automate the assembly of key information routinely assessed during the development of recommendations in Product Specific Guidelines (PSGs), or during the assessment of ANDAs, as well as AI/ML tools that facilitate planning and resource allocation to support GDUFA commitments. For more information, see the GDUFA science and research priority initiatives for FY 2023.

5. Immuno-Oncology:

a. Perform analyses of clinical data to develop a better understanding of the proportion of patients with atypical response and/or resistance and explore the development of predictive analytics related to ICI treatment and resistance;

6. Neo-antigen-based therapies, Oncology:

https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects

a. 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.

7. Precision Oncology:

a. Develop novel selection/response biomarkers using algorithms combining different types of medical images including radiology images (e.g., CT, PET) and/or histopathology images combined with novel analysis approaches such radiomics and machine learning.

8. Rare Cancers, Oncology:

a. Investigations using text mining and artificial intelligence to analyze, assess and interpret the scientific literature and other public databases of genomic and transcriptomic analyses in rare cancers to identify drugs that have been used against molecular targets relevant in rare cancers.

9. Minority health:

a. Examine the distinctive health characteristics and attributes of racial and/or ethnic minority groups in the development of innovative health products, new materials, and novel assessment tools and methodologies, including nanotechnology, precision medicine, pharmacogenomics, novel imaging and diagnostic technologies, 3-D printing, stem cells and regenerative medicine, and In- silico modeling.

10. Women’s health:

a. Develop methods to evaluate sex differences in the safety and efficacy of FDA regulated products.

b. Develop novel tools to evaluate regulated-product toxicity or the safety and efficacy during pregnancy and lactation.

11. Rare disease:

a. 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 populations (e.g., pediatrics) and heterogeneity of patients with rare conditions.

12. Tobacco:

a. Develop innovative models for effectively extrapolating in vitro exposure levels that cause toxicological response to in vivo adverse effects for the assessment of human health risk resulting from exposure to ENDS and other new and emerging tobacco products or their constituents.

b. Understand the potential or actual impact of FDA regulatory actions. Priorities for impact analysis include: behavioral economics experiments and modeling (e.g., population modeling, agent-based modeling) studies to estimate the range of potential impacts on behavior and health of potential FDA regulatory actions such as product standards addressing toxicity, appeal, and addiction (e.g., prohibiting flavored cigars other than tobacco flavored, prohibiting menthol as a characterizing flavor in cigarettes and cigars, lowering the nicotine content in combustible cigarettes); and where appropriate to the research question, studies involving populations with disproportionate burden of tobacco product risk and harm are encouraged.

c. Develop new modeling approaches to assess the risk of new tobacco products (e.g., non-tobacco nicotine products) that will potentially enter the market by considering how such products may affect users and non-users of the product based on factors including, but not limited to exposure to toxicants, product characteristics and demographic attributes of the users and usage patterns.

d. Develop new modeling approaches to characterize exposures that reflect long-term non-continuous tobacco product inhalation exposures from use of new/novel tobacco products as well as dual use with conventional cigarettes. Inhaled tobacco product exposure assessment would ideally consider the following modeling parameters:

i. Concentration of chemicals in the smoke or aerosol, or in the tobacco product itself (e.g., e-liquid, tobacco filler),

ii. Puff topography (e.g., sessions per day, puffs per session, puff volume, inter-puff interval),

iii. Tobacco product intake rate (e.g., volume of e-liquid used per day, cigarettes smoked per day),

iv. Exposure frequency (e.g., daily, one day per week, five days per month),

v. Exposure duration – How long a person has been using the tobacco product of interest (in years),

vi. Averaging time – Lifespan for a given population,

vii. Transitions between different tobacco products used in a lifetime,

viii. Potential use of single or multiple tobacco products in the same timeframe (e.g., exclusive, dual, or poly-use),

ix. Transitions between tobacco use and no tobacco use in a lifetime,

x. Potentially different effects of tobacco use earlier in life versus later in life.

D. Biomarkers Examples (includes imaging): Biomarker identification; Biomarker qualification; Biomarker evaluation, Biomarker validation

a. Advance methodologies for qualification of biomarkers and to support analytical and clinical validation of biomarkers that can provide objective measures to replace or compliment subjective classifications of disease diagnosis or progression.

b. Advance biomarker and clinical tool validation to reduce disease heterogeneity in clinical trials by refining clinical disease classification or inform reproducible patient stratification based on risk factors in therapeutic areas with unmet need.

c. 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.

d. Evaluate the biomarkers and the role of the microbiome in contributing to adverse responses through alterations in metabolism or other mechanisms, especially in pediatrics, and the associated long-term health impact.

e. Evaluate strategies for validation of innovative biomarkers or clinical tools that offer a sensitive and specific reflection of the pathophysiologic state for progressive diseases with unmet need.

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

g. 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. Drugs:

a. Evaluate strategies for assessment of innovative non-biomarker drug development tools that offer a sensitive and specific reflection of pathology or treatment responses.

3. Immuno-Oncology

a. Develop biomarkers and/or pharmacodynamic end points to demonstrate the effect of ICI in cancer immunotherapies or as part of a combination regimen in treatment-naïve and immuno-therapy resistance settings.

b. Develop technologies and approaches that better predict or characterize atypical response patterns to ICI such as radiomics, circulating tumor DNA, and/or novel approaches for immune cell profiling of the micro-environment.

4. Precision Oncology:

a. Identify biomarkers (including liquid biopsy biomarkers) for escalation/de-escalation of treatments in the neoadjuvant, adjuvant or advanced disease settings;

b. Conduct studies to compare the performance of local and centralized molecular tests used for patient enrollment on cancer clinical trials;

c. Conduct studies to understand why tumors located at different organ sites with molecular alterations in the same target respond differently to therapies to inform future potential tumor agnostic drug development;

d. Conduct retrospective or prospective studies/biomarker evaluations to understand if there are differences in response to targeted cancer treatment based on somatic vs. germline alterations of the target gene.

5. Pediatric Oncology:

a. Development of preclinical models (e.g., patient-derived xenograft models, orthotopic mouse models, organoids) of pediatric tumors to facilitate decision-making regarding the evaluation of emerging novel agents potentially applicable to tumors which predominantly occur in the pediatric population;

b. Investigations using text mining and artificial intelligence to analyze, assess and interpret the scientific literature and other public databases of genomic and transcriptomic analyses of pediatric cancers to: (1) identify drugs that have been used against molecular targets relevant in pediatric cancers and/or (2) elucidate the relevance of specific molecular targets to the growth and/or progression of pediatric tumors to understand and assess target actionability.

6. Health equity and special population, Oncology:

a. Characterize the prevalence of currently druggable biomarkers in racial/ethnic minorities and assess implications for enrollment in clinical trials.

7. Rare Cancers, Oncology:

a. Innovative approaches to identify new biologically-driven opportunities for clinical development of previously approved drugs (or drugs for which development has been discontinued) in rare cancers.

8. Women’s Health:

a. Identify and qualify biomarkers and study endpoints: 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.

9. Tobacco:

a. Impact of novel product use (e.g., ENDS, heated tobacco products) on biomarkers of exposure and biomarkers of potential harm

b. Identifying biomarkers of potential harm to assess short- and long-term health effects of tobacco products, with a focus on products other than conventional cigarettes, including deemed products or other novel products.

E. Clinical Outcome Assessment (COA)

Examples: Patient-reported outcomes; Clinician reported outcomes; Performance outcomes, Patient focused drug development.

1. Devices:

a. Develop methods for predicting and monitoring clinical performance of devices and materials.

2. Minority Health:

a. Foster and assess the development of culturally and linguistically appropriate clinical outcome assessments and biomarkers to better understand health inequities and develop improved medical products;

b. Conduct studies among racial and ethnic minorities and underserved groups (e.g., rural, elderly) that investigate patient preferences in benefit-risk assessments to advance understanding and aid regulatory decisions.

3. Oncology patient-focused drug development:

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

b. 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.

c. Investigate the sensitivity and measurement characteristics of existing patient-reported physical function measures in patients with rare and ultra-rare cancers.

d. Investigate open label bias: evaluate the impact of patient’s knowledge of their treatment on patient-reported outcomes in cancer clinical trials.

e. Evaluate differences in measurement characteristics between core patient-reported outcomes collecting in US vs. ex-US oncology patient populations

f. Studies to develop and characterize symptom function measures for rare cancers to complement information obtained from traditional clinical trial endpoints used in regulatory submissions.

g. Support research to improve understanding of the side effects of ICIs.

4. Pediatric Oncology:

a. Investigate to solicit children’s self-report of treatment related adverse events to accommodate the child’s voice in assessing patient tolerability of new drugs.

F. Complex and Novel Clinical Trial Design:

Examples: Complex, Adaptive, Bayesian, and other novel clinical trial designs. Methods may include design elements and/or analysis approaches that generally require computer simulations to determine the statistical properties of a clinical trial (e.g., power, Type I error). Methods for considering different endpoints, approaches for utilizing and validating artificial intelligence, machine learning, and natural language processing

1. Devices:

a. Evaluate the effectiveness of interventions designed to enroll diverse populations in device clinical trials such as digital health technologies, decentralized clinical trials, patient/community/language navigators;

b. Understand the impact of remote assessments and decentralized procedures (e.g., e-consent, telemedicine, collecting laboratory and/or imaging data from local facilities) on underrepresented subgroups participating in device clinical trials;

c. Develop framework for assessing clinical site readiness to achieve adequate enrollment of participants from historically under-represented racial/ethnic subgroups in medical device clinical trials.

d. Medical device studies incorporating use of telemedicine and/or decentralized approaches (e.g., collecting laboratory and/or imaging data from local facilities) for patient assessments to facilitate clinical trial enrollment.

2. Oncology:

a. Develop novel statistical approaches for using external controls in oncology trials, which could supplement concurrent control arm data and address key challenges such as differences in…