FY25 BAA Notice V5.pdf

FDABAA-25-00123

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 5 for FFRDC eligibility requirements) and academic institutions.

Research Opportunity Description: The FDA solicits 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 I and still be considered for an award within the current fiscal year, prospective Offerors are strongly encouraged/required to submit Stage One Submittal Packages with:

1. Checklist following required template (See attachment 3)

2. Freestanding Concept Paper following required template (See attachment 4)

3. Freestanding Full Proposal following required template (see Part III for details)

Freestanding Concept Papers and Freestanding Full Proposal shall be submitted no later than 11:59 pm, Eastern Standard Time, March 4, 2025, and earlier if possible. A submission will be considered incomplete if any of these critical elements are missing.

Stage One Submittal Packages (Checklist, Freestanding Concept Paper, Freestanding Full Proposal) received after that date will still be accepted, but due to a lack of lead time, will not be considered for award in FY25.

Optional Early Concept Paper submission is NOT needed as a qualification step for consideration of a Stage One Package for FY25 BAA Applications (See Optional Early Concept Paper of Part III for details). Please note that FDA is not obligated to provide feedback for Optional Early Concept paper after high-level review.

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.

Contents

INTRODUCTION

PART I: Research Areas of Interest

I. Modernize development and evaluation of FDA-regulated products

II. Strengthen post-market surveillance and labeling of regulated products 39

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

Part II: Reporting Requirements and Deliverables

Reports

Invoices

Part III: Proposal Preparation and Submission

Section 1: The Application Process Stage 1 Stage 2

Section 2: Stage 1 Concept Paper and Full Proposal Preparation of Concept Paper:

Preparation of Full Proposal:

Section 3: Stage 2 Revised Full Proposal

Section 4: Withdrawal of Full Proposals

Section 5: Representation and Certifications

Section 6: Studies That Involve Human Subjects

Section 7: Animal Welfare

Section 8: Prohibition on the Use of Appropriated Funds for Lobbying Activities

Section 9: Use of Select Agent

Section 10: Laboratory License Requirements

Section 11: Data Rights Clause

Section 12: Advanced Understandings

Section 13: Conflict of Interest

Section 14: General Information

Part IV: Proposal Evaluation

A. Evaluation Criteria:

B. Past Performance Information

C. Cost Evaluation

Award Decision

Part V: Attachments

Attachment 1: Summary of Related Activities

Attachment 2: Government Notice for Handling Proposals

Attachment 3: FY25 BAA Application Checklist

Attachment 4: FY25 BAA Application Concept Paper Template

Attachment 5: FY25 BAA Volume I Technical Proposal Template

Attachment 6: FY25 BAA Application Statement of Work Template

INTRODUCTION

Advancing Regulatory Science and Innovation

This Broad Agency Announcement (BAA), which sets forth research areas of interest for FDA, 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.

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. 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. 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. 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 FDA regulated products. 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 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. FDA also collaborates with other federal agencies to award research contracts.

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 Serving Institutions (MSI), 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 in the regulatory science framework and further described in Part I of this announcement. The goal of this regulatory science 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

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.

This BAA is available on www.beta.sam.gov using Keyword Search “FDABAA-25-00123.”

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 on the same site when they occur.

Interested parties are encouraged to periodically check the website for updates and amendments. Potential dates for posting amendments to this announcement are 11/15/2024; 11/29/2024; 12/13/2024; 12/27/2024; 1/17/2025. Any amendments posted to this announcement will be highlighted and indicated with #. BAA Day for 2024 will be hosted on November 14th, 2024 from 1:00 PM- 4:00 PM Eastern Standard Time, as a virtual only event and will provide an opportunity to learn more about the application process and FDA’s priorities for regulatory research (2024 FDA Broad Agency Announcement Day - 11/14/2024 | FDA). #FY25 FDA Broad Agency Announcement http://www.beta.sam.gov/ https://www.fda.gov/science-research/advancing-regulatory-science/2024-fda-broad-agency-announcement-day-11142024 https://www.fda.gov/science-research/advancing-regulatory-science/2024-fda-broad-agency-announcement-day-11142024 https://www.fda.gov/science-research/advancing-regulatory-science/fy25-fda-broad-agency-announcement-question-and-answer-session-01162025

Question and Answer Session will be hosted on January 16th, 2025 from 1:00 PM - 2:30 PM Eastern Standard Time, as a virtual only event and will provide an opportunity to clarify questions for the BAA Program. Additional information for FDA BAA Program is available at Regulatory Science Extramural Research and Development Projects | FDA.

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. 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.

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 (See Table 1, which highlights the topic areas that are priorities for FDA for FY 24). This section presents the technical objectives that FDA seeks to achieve through this BAA. 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. 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.

https://www.fda.gov/science-research/advancing-regulatory-science/fy25-fda-broad-agency-announcement-question-and-answer-session-01162025 https://www.fda.gov/science-research/advancing-regulatory-science/fy25-fda-broad-agency-announcement-question-and-answer-session-01162025 https://www.fda.gov/science-research/advancing-regulatory-science/regulatory-science-extramural-research-and-development-projects https://www.acquisition.gov/far/part-31#FAR_31_103 https://www.acquisition.gov/far/part-31#FAR_31_104

Table 1: Areas of regulatory science research priority for FDA in FY 25. For each charge (rows), the “X” marks priority areas for relevant FDA regulated product areas, and demographics & populations (columns). C ro ss

-c ut ti ng

B io lo gi cs B io si m ila rs

D ev ic es

To ba cc o

D ru gs V et er in ar y M ed ic in e

M ed ic al

C ou nt er m ea ur es

In it ia ti ve

Re pr es en ta ti ve W om en

Pe rs on s w it h Ra re D is ea se s

Pe rs on s w it h ca nc er s

A. Alternative Methods X X X X X B. Advanced Manufacturing Approaches X X X X X C. Analytical and Computational Methods X X X X X X X X D. Biomarkers X X X X X E. Clinical Outcome Assessment (COA) X X X X X X F. Complex and Novel Clinical Trial Design X X X X X X G. Predictive Toxicology X X X X H. Methods for Assessing Behavioral, Economic, or Human Factors

X X

I. Approaches to Incorporate Patient and Consumer Input

X X

J. Methods to Assess Real-World Data to serve as Real-World Evidence

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

C. Novel Clinical Trial Design, Statistical and Epidemiologic Methods

X X

D. Automated Reporting Tools for Adverse Events and Active Surveillance

X X X X

E. Methods to Improve Communication About Risk to Patients and Consumers

X X

F. Approach to Expand Data Capacity, and Increase Data Quality and Use

X X X

G. Efforts to Harmonize Existing and Emerging Data Standards

X

A. Reinforce Medical Countermeasures Initiative to Increase Preparedness and Response for Emerging Public Health Threats

X X X X

B. Antimicrobial Resistance X

C. Patient and Consumer Engagement X X

D. Substance Use and Misuse X X E. One Health Approaches X X F. Strengthen Global Product Safety Net X X X G. Emerging Technologies X

FDA-Regulated Areas & Initiatives

Groups & Populations

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

In addition to the product areas that FDA regulates, FDA aims to target innovation in regulatory science that advances the health of the following groups and populations, some of which have clinical characteristics that may frequently preclude their participation in clinical research resulting in a disproportionate burden of product risk and harm:

representative populations , women, persons with cancer and persons with rare diseases (including rare cancers).

FDA funded regulatory science researchers are encouraged to evaluate diverse populations by including analyses according to sex, age, race, ethnicity, pregnancy, lactation status, and comorbidities, as appropriate. Investigators should consider sex as a biological variable with regard to research aims, study designs, data collection and analyses, and reporting of research findings on cell lines, vertebrate animals, and humans. Consideration of both sexes in research and disaggregation of data by sex allows for a deeper understanding of health, disease, and treatment effects. Justification is required for studies proposing to focus on only one sex for non-sex-specific health conditions.

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

Charge 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 (RWD) to serve as Real-World

Evidence (RWE) K. Methods to Assess Data Source Interoperability

Charge 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

Charge 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 G. Emerging Technologies

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

#Amendments (General, Executive Order Related)

2/12/2025: Updated scope and Table 1 to align research priorities with the recent executive orders listed below Ending Radical and Wasteful Government DEI Programs and Preferencing (Jan. 20, 2025) Defending Women from Gender Ideology Extremism and Restoring Biological Truth to the Federal Government (Jan. 20, 2025)

2/12/2025: Updated template for attachment 5 and contract related clarifications;

removed COVID-19 related research scope from Charge II A and Charge III A

11/15/2024: Added scope to #I.A.5.a, #III.D.1.i, and #III.E.2.a; Updated Table 1 to include Veterinary Medicine related priority research areas.

12/6/2024: Added scope to #I.C.13.a, and #I.H.2.a; Updated Table 1 to include Tobacco related priority research areas; template changes to Concept Paper and Technical Volume I of Full Proposal to screen for proposals involving dual use research of concern (DURC), and/or development of pathogen with enhanced pandemic potential (PEPP).

and/or nucleic acid synthesis https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwiahvC1u6-LAxU_K1kFHRNJAgkQFnoECBoQAQ&url=https%3A%2F%2Fwww.whitehouse.gov%2Fpresidential-actions%2F2025%2F01%2Fending-radical-and-wasteful-government-dei-programs-and-preferencing%2F&usg=AOvVaw0dDwlPANQVLOR0AIaWE21Z&opi=89978449 https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwiP7ZnGu6-LAxVmE1kFHXFSKjwQFnoECBUQAQ&url=https%3A%2F%2Fwww.whitehouse.gov%2Fpresidential-actions%2F2025%2F01%2Fdefending-women-from-gender-ideology-extremism-and-restoring-biological-truth-to-the-federal-government%2F&usg=AOvVaw0DG_aZL0sSnF3UM87rUi-D&opi=89978449 https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwiP7ZnGu6-LAxVmE1kFHXFSKjwQFnoECBUQAQ&url=https%3A%2F%2Fwww.whitehouse.gov%2Fpresidential-actions%2F2025%2F01%2Fdefending-women-from-gender-ideology-extremism-and-restoring-biological-truth-to-the-federal-government%2F&usg=AOvVaw0DG_aZL0sSnF3UM87rUi-D&opi=89978449

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 Systems (MPS); Organ-on-a-chip; Complex In Vitro Models (CIVM); 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. Develop and use microphysiological systems (MPS), complex in vitro models (CIVM), 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. Biosimilars

a. Develop alternatives to and/or reduce the size of studies involving human participants.

i. Develop alternatives to the comparative clinical immunogenicity assessment(s)

ii. Define approaches that will increase feasibility of biosimilar development (e.g., PD biomarkers, modeling and simulation)

For more information, see the BsUFA III Research Roadmap for more information.

3. Rare diseases

a. Develop new alternate methods such as MPS and CIVM to support regulatory assessments of drug efficacy and safety for rare diseases (such as evaluating the relevance of a biomarker to disease pathology or effects of genetic variants on response to targeted therapies).

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 https://www.fda.gov/media/175799/download?attachment size/anatomy/ physiology/human factors differences that may affect device performance.

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

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

5. Veterinary Medicine

a. Data on per- and polyfluoroalkyl substances (PFAS) toxicity and bioaccumulation in companion animals is currently very sparse. Using new approach methods (NAMs) to address PFAS risk in companion animals can be a valuable tool for ensuring the safety of animal food.

NAMs are able to generate toxicity data through use of in-vitro testing, adverse outcome pathways (AOP), in-vitro in-vivo extrapolation (IVIVE), physiologically based pharmacokinetic (PBPK) modeling, and other techniques. FDA’s Center for Veterinary Medicine is interested in developing a strategy for using NAMs to provide comprehensive data on potential PFAS toxicity to cats and dogs.

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

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

iv. How implementation of digital technologies, remote monitoring, and data are fed back into 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:

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

ii. Research focuses on technologies and materials that result in manufacturing technology, tools, or approaches that enhance control of critical quality attributes of medical products and key inputs, including drug substances, products.

iii. Improve manufacturing capabilities for 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. Topics may include:

i. Supply chain resilience to disruption,

ii. Supply chain visibility, monitoring, and data sharing processes and platforms,

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 of advanced manufacturing methods in critical areas that impact production of vaccines, diagnostics, critical medicines and devices, and potential shortage products. This may include demonstrations of the value proposition and advantages of implementing advanced manufacturing and processes to patient access, economics, efficiency, and increased supply chair resilience

2. 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. 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 (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.

3. Drugs

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

4. 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.

5. 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.

6. 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: Development and use of computational methods and in-silico modeling; Simulation-based approaches; Advanced quantitative methods-based modeling; Predictive Analytics such as Predictive modeling, Model-informed drug or device development; Artificial Intelligence and Machine Learning

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:

i. Generative Design

ii. Production simulation and simulated process validation

iii. Digital twins of manufacturing processes for product quality control

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.

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

3. Biosimilars

a. Increase the reliance on analytical data in a demonstration of biosimilarity.

i. Characterize relationships between product quality attributes (physiochemical or biological) with clinical performance

ii. Explore how modernization of analytical technologies could better and/or more efficiently detect relevant quality attributes

iii. Define best practices for assessing and reporting quality attributes

b. Develop alternatives to and/or reduce the size of studies involving human participants

i. Develop alternatives to the comparative clinical immunogenicity assessment(s)

ii. Define approaches that will increase feasibility of biosimilar development (e.g., PD biomarkers, modeling and simulation)

For more information, see the BsUFA III Research Roadmap for more information.

4. Devices

a. Develop computational modeling and simulation methods to promote the use of in-silico assessment of devices for pediatrics. and special populations.

b. Explore methods for patient input (e.g., through patient-generated data) into the development of analytical and computational methods related to medical devices.

5. Drugs

a. Advance methodologies to generate clinical evidence using AI sufficient to support regulatory use:

i. Demonstrate how clinical evidence generated from the use of AI could inform clinical studies for regulatory use

ii. Develop and validate tools and models that assess fitness of AI/ML use to support regulatory decision making (e.g., using a placebo digital twin)

iii. Develop and validate methods to predict medical product performance using AI/ML,

iv. Evaluate ML methods with a focus on identifying and/or addressing sources of (methodological) bias

v. Advance causal AI inference

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, including 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) 2025.

c. Enhance the Efficiency of Equivalence 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 and https://www.fda.gov/media/175799/download?attachment https://www.fda.gov/media/175799/download?attachment https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects associated impurity profiles so as to elucidate attributes of complex active ingredients and support immunogenicity risk assessments that may be critical to their performance and, thereby, support the development of efficient characterization-based bioequivalence (BE) and pharmaceutical equivalence (PE) approaches. For more information, see the GDUFA science and research priority initiatives for FY 2025.

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 GDUFA science and research priority initiatives for FY 2025.

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 2025.

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

This research area focuses on evaluating the impact of identified design differences in the user-interfaces, hardware, software or propellants between a prospective generic and the reference listed drug. The research is intended to elucidate how such design differences may cause medication errors if the product was dispensed to a patient, or impact 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 2025.

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 bio-predictive 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 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 feasibility of both, biopharmaceutics classification system (BCS)-based biowaivers and additional strength biowaivers for immediate release (IR) oral drug products. It also includes establishing approaches to manage potential risks related to subject safety more consistently when developing in vivo 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 and ensure the equivalence of therapeutic outcomes in all diverse populations. For more information, see the GDUFA science and research priority initiatives for FY 2025.

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 for long-acting injectable, insertable or implantable (collectively, 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 2025.

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 2025.

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

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 analytic approaches to identify patients who will eventually respond to ICI treatment from those who will not respond.

7. Neo-antigen-based therapies, Oncology

a. Develop, optimize, and standardize bioinformatic algorithms for neoantigen identification and development of personalized therapies.

These are important to ensure the efficacy and safety of these products in the treatment of patients with cancer.

8. Pediatric Oncology

a. Investigations using text mining and/or 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.

9. 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 as radiomics and artificial intelligence/machine learning.

10. 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.

b. Investigations to characterize the plasma membrane surfaceome of healthy cells/tissues and ultra-rare tumors such that logic gated CAR-T cell therapeutic approaches can be encouraged, and potential on-target, off-tumor safety issues can be identified

11. Representative Populations Racial and Ethnic Minority Health

a. Examine the distinctive health characteristics and attributes of representative populations in the development of innovative health https://www.fda.gov/about-fda/oncology-center-excellence/pediatric-oncology 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.

12. Rare disease

a. Develop rare disease clinical trial simulation models that can reveal interactions between drug or device effects and prognostics or predictive variables (e.g., some patient characteristics and disease variables influencing outcomes). These models should address the challenges posed by small populations (e.g., pediatrics population, patients with rare diseases) and heterogeneity of patients within the small populations.

13. Tobacco

a. Develop an inter-laboratory repeatability and reproducibility (R&R) study for validating the reliability of the Universal Smoking Machine Adaptor (USMA) design.

i. The developed plan should demonstrate the USMA’s analytical robustness (i.e., measurement accuracy and precision) for multiple tobacco product types relative to known standard values.

ii. Include a variety of technicians in a variety of locations testing similar products with results compared both internally (repeatability) and externally (reproducibility).

iii. Comparison of the UMSA’s performance to existing smoking machine adaptor systems.

iv. The project scope and statistical robustness should be sufficient to demonstrate the USMA is fit for its intended purposes, given the number of products, laboratories, and testing apparatus involved.

14. 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.

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, including those that are derived from digital health technologies, 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.

f. Demonstrate how terminology for encoding biomarkers in real-world data can integrate with patient care data encoding standards recommended by the Office of the National Coordinator (SNOMED, LOINC, and RxNorm).

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.

b. Identify and evaluate improved clinical endpoints and related biomarkers to monitor and reduce treatment-related neuropsychiatric adverse drug events in specific populations (children).

3. Immuno-Oncology

a. Develop biomarkers and/or pharmacodynamic endpoints to demonstrate the effect of ICI in cancer immunotherapies or as part of a combination regimen in treatment-naïve and immuno-therapy resistant 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 and explore approaches to validate 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 analytical and clinical 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. A particular area of interest is to improve understanding of any differences in activity of PARP inhibitors in patients with BRCA mutations vs. other individual homologous recombination repair (HRR) mutations.

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;

6 #Health equity and special populations, Oncology Safety a Characterize the prevalence of currently druggable biomarkers…