FY24 BAA Notice v4.0.pdf

FDABAA-24-00123

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 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 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 Free Standing Full Proposal shall be submitted no later than 11:59 pm, Eastern Standard Time, February 19, 2024, 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 FY24. Optional Early Concept Paper submission is NOT needed as a qualification step for consideration of a Stage One Package for FY24 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 40

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: FY24 BAA Application Checklist

Attachment 4: FY24 BAA Application Concept Paper Template

Attachment 5: FY24 BAA Volume I Technical Proposal Template

Attachment 6: FY24 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.

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.

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 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-24-00123.”

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 10/13/2023; 10/27/2023; 11/10/2023; 11/24/2023; 12/8/2023; 12/22/2023; and/or 1/12/2024. Amendments indicated with #. Amendment added on 12/22/2023 to Charge I, Topic I for Devices.

http://www.beta.sam.gov/

Save the date for the 2023 FDA Broad Agency Announcement (BAA) Day! October 25, 2023. BAA Day for 2023 will be hosted on October 25th, 2023, as a virtual only event and will provide an opportunity to learn more about the application process and FDA’s priorities for regulatory research.

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.

https://www.fda.gov/science-research/2023-fda-broad-agency-announcement-day-10252023 https://www.fda.gov/science-research/2023-fda-broad-agency-announcement-day-10252023 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 24. For each charge (rows), the “x” marks priority areas for relevant FDA regulated product areas, and demographics & populations (columns). Cr os s-cu tti ng Bi ol og ics Bi os im ila rs

De vi ce s Dr ug s

To ba cc o

Pr od uc ts

Ra cia l a nd

Et hn ic

W om en Pe rs on s w ith

Ra re D ise as es Pe rs on s w ith 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 X X D. Biomarkers X X X X X X E. Clinical Outcome Assessment (COA) X 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 X H. Methods for Assessing Be havioral, Economic, or Human Factors

X X X

I. Approaches to Incorporate Patient and Consumer Input

X

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

X 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

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

FDA-Regulated Areas

Demographics & 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

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 minority populations, women’s health, persons with cancer and persons with rare diseases (including rare cancers).

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.

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. Improve the efficiency of Biosimilar product development

b. 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.

3. Rare diseases

a. Develop new alternate methods (MPS and CIVM) to support regulatory submissions demonstrating efficacy and safety assessment of drugs for rare diseases.

4. 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 MPS model);

i. Predict threshold of toxicological concerns resulting from exposure to Electronic Nicotine Delivery Systems (ENDS) aerosols and/or their constituents.

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

iii. Feasibility evaluation of quantitative data analysis methods designed to assess the relative mutagenicity/genotoxicity potencies (using Ames assay, micronucleus assay, or other standard OECD approved genotoxicity assays) of chemical mixtures and individual entities commonly found in ENDS aerosols for which there are limited or no carcinogenicity data via the inhalation route (such as, but not limited to, ethyl maltol, benzaldehyde, veratryl aldehyde, maltol, d,l-isomenthone, furan, furfurals, diacetyl, bisphenol A, chloroform, phthalate; and heavy metals such as, but not limited to, nickel (Ni), chromium (Cr), cadmium (Cd), iron (Fe), and lead (Pb)).

Methods that are robust and amenable are of interest. Of particular interest is (1) whether such relative mutagenicity/genotoxicity potency approaches could assess possible additive, synergistic, or antagonistic responses between different mutagens/genotoxins in mixtures and (2) if calculated mutagenicity/genotoxicity potencies can predict known relative cancer potencies identified in carcinogenicity studies.

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

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, or medical devices.

iii. 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. 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. 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

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

4. Drugs

a. Develop improved methods and tools for the validation and lifecycle maintenance of digital technologies for Industry 4.0 for pharmaceutical manufacturing including novel sensors, data management, adaptive process control, digital twins, and cybersecurity.

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

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) https://www.sciencedirect.com/science/article/pii/S0378517321003598 https://www.sciencedirect.com/science/article/pii/S0378517321003598 https://www.sciencedirect.com/science/article/pii/S0378517321003598 https://www.sciencedirect.com/science/article/pii/S0378517321003598 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 antigen targets, and 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: 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. AI/ML application to quality system activities, such as, complaint management, trending, or others,

iv. Intelligent Design Control

v. 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 Improving the efficiency of biosimilar product development

a. Review and evaluate opportunities for streamlining and targeting biosimilar product development in consideration of scientific advancements in analytical (including physical, chemical, and biological function assays), and pharmacological assessments and experience with prior biosimilar product development and marketed biosimilar products.

4. Devices

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

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.

5. Drugs

a. Develop and evaluate the use AI and hybrid mechanistic AI models in drug manufacturing including model validation, transparency of model outputs, and model lifecycle maintenance. For more information see the Artificial Intelligence in Drug Manufacturing discussion paper

b. Advance methodologies to generate clinical evidence using AI/ML sufficient to support regulatory use:

i. Demonstrate how clinical evidence generated from the use of AI/ML 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

c. 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).

d. 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 associated impurity profiles that can 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 https://www.fda.gov/media/165743/download https://www.fda.gov/drugs/generic-drugs/generic-drug-research-priorities-projects information, see the GDUFA science and research priority initiatives for FY.

e. 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.

f. 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.

g. Enhance the Efficiency of Equivalence 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 a prospective generic and the reference listed drug 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.

h. 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 under ICH M13A. 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 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 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.

i. 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.

j. 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.

6. 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.

7. Neo-antigen-based therapies, Oncology

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

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

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

8. 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 artificial intelligence/machine learning.

9. 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 surface-ome of health 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

10. Racial and Ethnic Minority Health

a. Examine the distinctive health characteristics and attributes of racial and/or ethnic minority populations 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.

11. 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.

12. 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.

13. 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/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 ENDS or heated 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. 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).

h. 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 endpoints 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 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;

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 populations, 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…