FDABAA-20-00123.pdf

FDABAA-20-00123

Overview Information

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

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

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

Announcement Type: Broad Agency Announcement

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

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

Types of instruments that may be awarded: Procurement Contracts

Notes: Regarding Funding

In order to ensure enough time to conduct the two-tiered evaluation described in Section IV and still be considered for an award within the current fiscal year, prospective Offerors are encouraged to submit white papers no later than 5:00 pm, Eastern Standard Time, March 13, 2020, and earlier if possible. White papers submitted after that date will still be accepted, but due to a lack of lead time, will not be considered for award in FY20.

TABLE OF CONTENTS

INTRODUCTION

Part I: Research Areas of Interest Part II: Reporting Requirements and Deliverables Part III: Proposal Preparation and Submission

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

Part IV: Proposal Evaluation Award Decision Part V: Attachments

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

INTRODUCTION

Advancing Regulatory Science and Innovation

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

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

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

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

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

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

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

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

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

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

1. Modernize Toxicology to Enhance Product Safety

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

Product Development and Patient Outcomes

3. Support New Approaches to Improve Product Manufacturing and Quality

4. Ensure FDA Readiness to Evaluate Innovative Emerging Technologies

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

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

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

and Global Health and Security

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

Understanding

9. Strengthening the Global Product Safety Net

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

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

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

This BAA is available on the following websites:

https://www.fbo.gov

This BAA is a continuously open announcement valid throughout the period from the date of issuance through the closing date specified in fbo.gov. Amendments to this BAA will be posted to www.fbo.gov when they occur. Interested parties are encouraged to periodically check these websites for updates and amendments.

Part I: Research Areas of Interest

Through this BAA, FDA seeks to support advanced research and development strategies in the following research areas of interest. 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.

1. Modernize Toxicology to Enhance Product Safety

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

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

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

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

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

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

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

and the onset of tobacco related diseases; and http://www.fbo.gov/ http://www.fbo.gov/

1.1.6 Initiate in vitro studies to identify potential markers of harm associated with exposure to medical products.

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

1.1.7 Develop methods for biocompatibility and toxicological risk assessments for new device materials In line with public policies of e.g. Least Burdensome measures and the reduction in the use of animals.

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

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

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

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

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

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

1.2.1 Evaluate the accuracy (specificity and sensitivity) with which animal models and in vitro assays correctly predict potential human and animal risk;

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

1.2.3 Evaluate quantitative imaging (e.g. positron emission tomography, magnetic resonance imaging, computed tomography) and other advanced approaches (e.g.

metabolomics) for identifying new biomarkers and predictors of efficacy and adverse responses of novel materials and chemicals.

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

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

1.2.6 Evaluate critical toxicity mechanisms and modes of action for key constituents of

ENDS and other tobacco products, including HPHCs that drive cancer and non-cancer toxicological risk

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

1.3 Use and develop computational methods and in silico modeling:

1.3.1 Improve the value of chemical Structure-Activity Relationship (SAR) models in the prediction of human risk.

1.3.2 Develop, validate and implement approaches to link chemical structures and substructures to information about product risk and safety, disease targets, and toxicity mechanisms;

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

1.3.4 Develop computer models of cells, organs, and systems to predict product risk, safety and efficacy;

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

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

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

1.3.8 Develop data analysis techniques and perform data profiling in order to improve overall regulatory data quality and support mathematical, statistical modeling and analysis capabilities to derive enhanced analytical results for human drug regulatory operations.

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

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

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

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

Product Development and Patient Outcomes

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

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

2.1.1. Refine clinical trial design and statistical methods of analysis to address issues such as missing data, multiple endpoints, composite endpoints, patient enrichment, and adaptive designs;

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

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

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

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

Pilot research to assess the impact of Accelerated approval (AA), and Fast track

(FT), priority review (PR), and Breakthrough (BT) designations to help assess adequacy of pre-market efficacy and safety assessments and the generalizability of the findings from smaller clinical trial populations to larger more diverse populations. The impact of incentives for the respective programs such as marketing exclusivity, priority review vouchers and the application of flexibility and scientific judgment available under existing regulations needs to be assessed. The intent is to identify factors or metrics that may further enhance drug development and safe and effective use post-approval. Approaches include:

A. Assessing the adequacy of currently available data sources to conduct appropriate analyses and tracking and B. Identifying appropriate comparators for assessing impacts.

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

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

• Timelines, achievement of milestones or costs during drug development

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

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

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

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

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

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

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

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

2.2 Leverage existing and future data:

2.2.1 Develop quantitative models and measures of disease progression; and

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

2.2.3 Develop new tools and methodologies to harness big data and real-world data (e.g. data derived from electronic health records (EHRs); medical claims ad billing data; data from product and disease registries; patient-generated data, including from in-home-use settings; and data gathered from other sources that can inform on health status, such as mobile devices) to support regulatory decision-making.

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

2.2.5 Advance methodologies to generate clinical evidence from real world data sufficient to support regulatory use

• Incorporate real world data sources in innovative clinical trial designs

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

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

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

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

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

2.2.8 Design and optimize data infrastructure to facilitate information exchange and data extraction

2.3 Identify and qualify biomarkers and study endpoints:

2.3.1 Facilitate identification and qualification of new and improved biomarkers for safety and efficacy, pharmacodynamic response - dose selection, disease severity, progression and prognosis, and pharmacogenomics (to predict safety and efficacy or guide dosing); and

2.3.2 Develop and evaluate novel approaches for biomarker identification, including -omics, systems biology, and high throughput methods.

2.3.3 Develop robust techniques to evaluate the ability of patient-matching processes

(e.g. algorithms, workflows, software) used to fit implants and surgical guides across the variability within a desired population.

2.4 Facilitate Antibacterial Drug Development and Address Antibacterial Drug

Resistance

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

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

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

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

2.4.4 Advance the science of antibacterial drug susceptibility testing

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

Illness.

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

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

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

2.5.3 The identification and qualification of biomarkers or other study endpoints that could be used for SMI drug development. This includes the topics listed above in Section 2.3, but should consider and specifically be tailored to SMI drug development, including pediatric patients.

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

2.6 Facilitate Development of Drug Therapies for Youth Tobacco Cessation

Despite major progress over the past half-century, tobacco use remains the leading cause of preventable disease and death in the United States, with at least 480,000 people dying prematurely each year from diseases caused by cigarette smoking or secondhand smoke exposure.1 Nearly all tobacco product use begins during youth and young adulthood.2 While the current use of any tobacco product among U.S. middle and high school students has decreased from 2011-2017, there has been an alarming increase in e-cigarette use over this time. In fact, since 2014, e-cigarettes have been the most commonly used tobacco products among youth, used by 1.73 million (11.7%) high school students and 390,000 (3.3%) middle school students in 2017.3 Youth e-cigarette use raises a number of health concerns including risk of addiction to nicotine, potential harm to the developing adolescent brain, and exposure to chemicals including carbonyl compounds and volatile

1 US Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 2014.

2 Ibid.

3 Wang TW, Gentzke A, Sharapova S, et al. Tobacco Product Use Among Middle and High School Students — United States, 2011–2017. MMWR Morb Mortal Wkly Rep. 2018;67:629–633. In this study participants were asked about their use of the following tobacco products: cigarettes, cigars, smokeless tobacco, e-cigarettes, hookah, pipe tobacco, and bidis (small imported cigarettes wrapped in a leaf).

organic compounds known to have adverse health effects; the full range of possible health effects is not yet completely understood.4

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

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

2.6.2 The development of data or methods to identify youth tobacco users who may benefit from treatment with drugs intended for cessation, either alone or in combination with behavioral interventions. Factors to consider include age (older vs. younger adolescent), patterns of use (duration and frequency of use), clinical features (level of addiction, presence/absence of comorbidities including psychiatric disease), and type of tobacco product.

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

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

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

2.7 Immuno-oncology

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

4 US Department of Health and Human Services. E-Cigarette Use Among Youth and Young Adults: A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2016.

Additionally, a large proportion of patients do not respond or become resistant to these treatments. There is a high unmet need to develop therapeutics for ICI-refractory or resistant patients, yet the field lacks a consistent definition of response for these drugs.

Response is well defined for cytotoxic drugs and targeted therapies using images analyzed by Response evaluation criteria in solid tumors (RECIST) criteria v 1.1; however, RECIST analyses reveal that a considerable proportion of patients treated with ICI demonstrate late response or may show initial-- potential accelerated--tumor growth that can be followed by tumor shrinkage. These atypical response patterns complicate FDA’s ability to provide advice to sponsors about clinical trial design.

FDA is interested to support research in two areas to improve understanding of atypical response patterns observed in patients treated with immune checkpoint inhibitors:

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

2.7.2 Support the development of technologies and approaches that better predict or characterize atypical response patterns to immune checkpoint inhibitors.

Promising technologies for consideration include:

• Radiomic analysis of tumor images. This approach can capture features of the tumor that are not addressed by RECIST measurements and may incorporate information about changes in the tumor microenvironment in addition to information about tumor size.

• Circulating tumor DNA to monitor response to treatment by measuring cancer-associated somatic mutations at multiple time points during a patient's treatment.

• Novel approaches for immune cell profiling of the tumor microenvironment

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

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

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

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

3. Support New Approaches to Improve Product Manufacturing and Quality

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

3.1 Enable development and evaluation of novel and improved

materials and manufacturing methods:

3.1.1 Investigate the effects of advanced manufacturing on product quality.

Proposals could include research on technologies and materials that:

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

- Improve manufacturing capabilities for complex drugs as defined within the GDUFA II Commitment Letter.

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

3.1.3 Evaluate complex drug substances and complex drug product dosage forms, especially potential regulatory questions related to drug quality.

Some specific areas of research could include the following (1) appropriate analytical methods for complex drug substances or products, (2) in-process controls during manufacturing processes to ensure product quality, and (3) raw material quality control. Proposals should clearly describe the potential impacts of the proposed enabling technology on readiness for broad implementation in pharmaceutical industry, control strategy, and/or regulatory evaluation for complex drug substances and complex drug product dosage forms, including natural products

3.1.4 Explore novel approaches to incorporating medical device development concepts and methodologies, including quality and risk management.

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

3.1.6 Explore novel application of large-scale continuous manufacturing processes for more complex biologic products, such as vaccines, and cell and gene therapies. Proposals should clearly describe the potential impacts of the proposed enabling technology on readiness for broad implementation in pharmaceutical industry, control strategy, and/or regulatory evaluation of CM, and should clearly quantify the improvement metric for implementation of CM at a commercial scale as compared to batch or pilot production if relevant:

• Closed and automated manufacturing technologies

• Modular platforms for complex biologics manufacturing and testing

• Process modeling and simulation

• Advanced manufacturing technologies for cell cultures used to manufacture vaccines

3.2 Develop new analytical methods:

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

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

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

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

3.2.5 Develop methods to assess quality of glycerin; develop methods to identify the quality (crude vs industrial vs USP) and potential contaminants in the various glycerin grades used in finished products (for e.g. jerky pet treats for animals, drugs for humans and animals).

3.2.6 Advance tests and methods for predicting and monitoring medical device clinical performance.

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

3.3.1 Advance the study of quality metrics and quality culture, including pharmaceutical quality systems, manufacturing operations, continuous improvement, and overall quality culture in domestic and international establishments.

3.3.2 Develop methods for data collection, validation, and assessment of such metrics

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

3.4 Reduce risk of microbial contamination of products:

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

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

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

3.5 Improve scientific approaches to evaluate generic drugs

In July 2012, Congress passed the Generic Drug User Fee Amendments (Title III of the Food and Drug Administration Safety and Innovation Act (Public Law 112-144)). The Generic Drug User Fee Amendments (GDUFA) is designed to enhance public access to safe, high-quality generic drugs, and to reduce costs to industry. To support this goal, FDA agreed in the GDUFA commitment letter to consult with industry and the public in order to create an annual list of regulatory science initiatives specific to research on generic drugs for each year covered by GDUFA. This commitment continues in the Generic Drug User Fee Amendments of 2017 (GDUFA II). The research activities related to the FY 2018 topic areas are as follows:

3.5.1 Post-market Evaluation of Generic Drugs

3.5.1.1 Develop surveillance and monitoring methods for generic drug substitutions.

3.5.1.2 Understand patient perceptions of generic drug quality and effectiveness.

3.5.2 Complex active ingredients, formulations, or dosage forms

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

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

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

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

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

3.5.3 Complex routes of delivery

3.5.3.1 Improve Physiologically-Based Pharmacokinetic (PBPK) models of drug absorption via complex routes of delivery (e.g., nasal, inhalation, dermal, ophthalmic)

3.5.3.2 Expand characterization-based BE methods across all topical dermatological products

3.5.3.3 Expand characterization-based BE methods across all ophthalmic products

3.5.3.4 Develop more efficient alternatives to the use of forced expiratory volume in one second

(FEV1) clinical endpoint BE studies for inhaled corticosteroids

3.5.3.5 Develop alternatives to clinical endpoint BE studies for locally-acting nasal products that are more predictive of and sensitive to differences in local delivery

3.5.4 Complex drug-device combinations

3.5.4.1 Evaluate the impact of identified differences in the user-interface from the RLD on the substitutability of complex generic drug-device combination products

3.5.5 Tools and methodologies for bioequivalence and substitutability evaluation

3.5.5.1 Improve quantitative pharmacology and bioequivalence trial simulation to optimize design of BE studies for complex generic drug products

3.5.5.2 Integrate predictive dissolution, PBPK and PK/Pharmacodynamic (PD) models for decision-making about generic drug bioequivalence standards

3.5.5.3 Expand the scientific understanding of the role of excipients in generic drug products to support the expansion of the Biopharmaceutics Classification System of Class 3 bio-waivers to non-Q2 (quantitatively inequivalent) formulations

3.5.5.4 Develop methods that will allow FDA to leverage large data sets (such as bioequivalence study submissions, electronic health records, substitution/utilization patterns and drug safety and quality data) to support regulatory decisions and improve post-market surveillance of generic drug substitution

3.6 Identify and Qualify Pain-Associated Biomarkers that are Associated with Therapeutic

Control of Pain in Food Producing Animals

3.6.1 Identify molecular biomarkers (proteomic or genomic) that can be qualified against clinical signs to serve as surrogate endpoints in assessing the capacity of therapeutic agents to alleviate pain in food animals such as cattle, pigs, and goats.

3.7 Develop a Regulatory Database for Species Identification

3.7.1 Develop a DNA barcode sequence database for species identification

3.8 Develop methods to improve the cybersecurity of medical devices

3.8.1 Enhance performance of Digital Health and medical device cybersecurity: Digital Health and cybersecurity are some of the fastest growing areas impacting medical devices.

Devices are being increasingly used in networked environments and are expected to communicate with one another securely and accurately. To ensure these technologies and technological environments achieve the desired public health impact, research is needed to enhance performance and security of medical devices and interoperability, and to understand the impact of software modifications on device performance.

Pilot the use of a benchmark test set for the use of artificial intelligence (AI) in medical devices to enhance consistency of submissions and review by enabling AI with similar instructions for use (IFU) to be tested and compared.

1. Develop a full test case and/or methodology for adaptive algorithm use in medical device submissions to help stakeholders to better understand and evaluate use of AI in a medical device context of use.

2. Develop framework on how to structure post launch real world evidence data to support clinical claim modification and provide greater clarity and guidance to industry while potentially streamlining device review.

3. Investigate and evaluate strategies to detect and assess the performance of artificial intelligence (AI) algorithms including employing synthetic data sets, leveraging the Medical Device Development Tool (MDDT) program, identifying novel methods, and conducting statistical analyses of regulatory device submissions to facilitate greater utilization of AI within medical devices.

4. Develop and deploy secure medical device reference architectures that support the needs of the clinical use environment by applying formal methods, leveraging hardware and software reuse, facilitating timely updates and patching, and highlighting failures while collecting forensically sound evidence of performance to improve medical device security at the systems level.

5. Develop methods for efficiently communicating design vulnerabilities such as tools for analyzing cybersecurity risk (e.g. threat modeling, attack trees) to increase stakeholder understanding of cybersecurity considerations and risks.

4. Ensure FDA Readiness to Evaluate Innovative Emerging Technologies

FDA seeks to evaluate new and emerging technologies through active research intramurally and collaboratively with external partners. Areas of interest include:

4.1 Develop assessment tools for novel therapies:

4.1.1. Develop new approaches such as in vitro and in vivo methods to identify measurable characteristics of product safety, quality, and potency when evaluating new therapeutics (e.g., engineered tissues or cell therapy products, including stem cell-derived products, for clinical application in regenerative medicine, additive manufacturing in medical products medical products.

4.1.1.1 Identification of critical quality attributes (CQAs) and development of advanced assays for characterization of CQAs in products for cell therapies

4.1.1.2 Development of reference materials and standards for cell therapies

4.1.2 Develop new ways to evaluate gene therapy products developed in this period of fast-paced scientific progress;

4.1.2.1 Improved cell lines for viral vector production and improved vector purification technologies

4.1.2.2 Identification of critical quality attributes (CQAs) and development of advanced assays for characterization of CQAs in products for gene therapies

4.1.2.3 Development of reference materials and standards for gene therapies

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

4.1.4 Explore the role of digital health in new medical therapies and diagnostics.

4.1.5 Develop methods for predicting and monitoring clinical performance of devices and materials

4.1.6 Explore human factors engineering principles in device design and review.

4.2 Develop assessment tools to evaluate packaging, storage, delivery and disposal solutions, as well as product formulations, designed to prevent or deter misuse and abuse of opioid analgesics.

4.2.1. Perform research to enhance FDA’s understanding of the features of existing and emerging packaging, storage, delivery and disposal solutions, how they fit into the continuum of opioid misuse and abuse, and the evidence available to support these features.

4.2.1.1. Evaluate whether any existing data requirements in other fields may be applicable for packaging, storage, delivery and disposal solutions to prevent or deter misuse and abuse of opioid analgesics. Exploratory research should include abuse deterrent packaging, medication adherence packaging, or child resistant packaging.

4.2.1.2. Research whether there are any existing data requirements in other countries to have packaging, storage, delivery and disposal solutions approved or labeled as being able to prevent or deter misuse and abuse of opioid analgesics.

4.2.1.3. Identify and evaluate appropriate endpoints for studies undertaken to support packaging, storage, delivery and disposal solutions approved or labeled as being able to prevent or deter misuse and abuse of opioid analgesics.

4.2.2. Combine findings from 4.2.1.1 and 4.2.1.2 and work with FDA to define what the data needs and guiding principles should be for industry to follow to have their packaging, storage, delivery and disposal solutions approved or labeled as being able to prevent or deter misuse and abuse of opioid analgesics. Draft and provide to FDA a Final Report for its use.

4.2.3. Perform research to enhance FDA’s understanding of the uptake and use of abuse deterrent opioid product formulations after approval and their impact on patterns of misuse, abuse, addiction, overdose and death in communities, improve our knowledge about the data systems and methods available to study their impact, and develop new data resources and methods in this area.

4.2.3.1. Perform research to enhance FDA’s understanding of the relationship between the number of dispensed prescriptions and abuse rates for opioid products. Relevant activities would include qualitative and/or quantitative research to better understand the reasons for decreases in prescription volume that often occur after the marketing of opioid products reformulated with abuse deterrent properties.