FDABAA-16-00122.pdf

FDABAA-16-00122

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, 5630 Fishers Lane, Rockville, MD 20857

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: Food and Drug Administration solicits the advanced research and development for regulatory science. 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

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 FAR 35.016(c) of the Federal Acquisition Regulation (FAR). The purpose of this BAA is to fulfill an FDA requirement to utilize industry 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 considered to be 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 Food and Drug Administration (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. 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. Since 2009, it has also been responsible for regulating the manufacture, marketing, and distribution of tobacco products.

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 every day. 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 for human and non-human animal use. FDA must make decisions based on the best available scientific data and using the best tools and methods available in order 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 to post-market product surveillance to review of product quality. 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, etc.) 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 under this BAA will depend on the quality of the proposals received and the availability of funds. Anticipated funding for the program (not per contract or award) may range from $200,000 to $75,000,000 dollars subject to congressional appropriations. This funding profile is an estimate only and will not be a contractual obligation for funding. All funding is subject to change due 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 options. Additionally, FDA reserves the right to accept proposals in their entirety or to select only portions of proposals for award. In the event that 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 https://www.fda.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 fbo.gov when they occur. Interested parties are encouraged to periodically check these websites for updates and amendments.

https://www.fda.gov/

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. Offeror’s shall 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 markers of harm associated with exposure to tobacco products or tobacco product constituents; and

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

1.1.7 Develop modern methods for biocompatibility and biological risk evaluations for new device materials.

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

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 markers of toxicity and determine how the performance of these markers 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 safety.

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 and implement approaches to link chemical structures and substructures to a wide range of 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 based on demographic attributes of the users and usage patterns.

1.4 Develop Alternative Models to Inform the Toxicological Characterization of Veterinary Drugs

1.4.1 Assesses whether zebrafish (Danio Rerio) or fathead minnows (Pimephales promelas) may serve as good models to investigate the potential toxicity or health effects of approved and unapproved animal drugs.

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, patient enrichment, and adaptive designs;

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 assess the bioequivalence of locally acting drugs, including inhalants, topicals, and intraluminal GI drugs.

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

2.1.7 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.

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

2.2 Leverage existing and future clinical trial 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 other 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 methodologies to harness big data for regulatory decision making.

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 process (e.g.

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

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 continuous manufacturing (manufacturing using a continuous process, rather than a batch approach) on product quality;

The FDA and the HHS Biomedical Advanced Research and Development Authority (BARDA) which has identified continuous manufacturing (CM) as an emerging technology within the pharmaceutical industry that has significant potential to improve agility, flexibility, cost, and robustness in the development of manufacturing processes. Although the continuous input of active pharmaceutical ingredient in the manufacturing of small-molecule drug products has been met with some success, as has the production of biotechnology products (e.g. monoclonal antibodies) by means of continuous perfusion bioreactors, end to-end continuous manufacturing from reagents to drug product at a commercial scale has not been realized.

3.1.1.1 Enabling Technologies for Continuous Manufacturing

This research will advance continuous manufacturing by developing and making technologies accessible to industry in the near term (1-3 years), by bridging the gap between discoveries in academia or industry and implementation by industry. Results of this research will support the control of integrated end-to-end continuous processes (raw materials to final dosage form) as well as continuous process for the manufacture of drug substance and/or drug product. Additionally, this research is intended to support advances in regulatory science that allow for development of science and risk based guidelines to facilitate faster CM adoption. Some specific CM enabling areas of research could include the following, but 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:

• Continuous processing equipment (e.g., crystallizers, coaters, and viral clearance)

• Enhanced in-line process analytical technologies

• Integrated data management and plant-wide control systems

• Process modeling and simulation

• Advanced process control (e.g., feedback, feedforward or plant-wide control)

3.1.1.2 Continuous Manufacturing Innovation

Research aimed towards new processes or process improvements that may have an impact in 3-5 years, for example towards capabilities where CM can afford improvement that would not be achievable by batch production. Some specific research areas for CM innovations could include the following, but the proposal should clearly quantify the improvement metric for implementation of CM at commercial scale as compared to batch or pilot production if relevant:

• Synthetic processes that would benefit from flow processing; syntheses that could be affected through a reduced number of steps or that would not be feasible by batch production; highly selective chemistries that allow use of simple and effective continuous workup technologies, etc.

• Modular or plug and play type equipment with re-usable or flexible, interchangeable parts that allows the development of platform technologies for drug substance, drug product or end-to-end continuous manufacturing processes.

• Non-column based chromatography and alternative purification techniques (e.g.

continuous precipitation).

• Continuous processes for homogeneous production of final dosage forms (e.g., strip film manufacturing system, injection molding, and printing).

• Alternatives to inherently batch unit operations (e.g. viral and sterile filtration)

• Process control systems with improved user interface (e.g. GUI) and capability for integration with new unit operations and ancillary equipment, with reduced need for programmer hours.

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

3.1.3 Evaluate the role excipient ingredients and complex dosage forms on product safety, efficacy, and quality and further two state-of-the-art manufacturing strategies-Process Analytical Technology, and Quality-By-Design approaches-for impact on manufacturers’ ability to maintain consistent quality.

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.

3.2 Develop new analytical methods:

3.2.1 Investigate feasibility and value of using improved analytical technologies like NMR

(Nuclear Magnetic Resonance), mass spectrometry, or near infrared or Raman spectroscopy 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 etc.) 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 example jerky pet treats for animals, drugs for humans and animals).

3.3 Reduce risk of microbial contamination of products:

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

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

3.3.3 Enhance safety and performance of reusable devices by improving the quality and effectiveness of reprocessing

3.4 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. The research activities related to the FY 2014 topic areas are as follows:

3.4.1 Post-market Evaluation of Generic Drugs

3.4.1.1 Develop surveillance and monitoring methods for generic drugs.

3.4.1.2 Understand patient perceptions of generic drug quality and effectiveness.

3.4.1.3 Evaluate and verify therapeutic equivalence via brand to generic switching studies inpatients for anti-epileptic drugs, immunosuppressant drugs, bupropion, ADHD drugs and cardiovascular drugs.

3.4.2 Equivalence of Complex Products

Develop research studies to establish bioequivalence methods for complex products such as liposomes, sustained release parenterals, and complex mixtures.

3.4.3 Equivalence of Locally Acting Products

Develop research studies into new bioequivalence (BE) methods and pathways for local acting drugs for inhalation, topical dermatological, nasal, GI acting, ophthalmic and otic products.

3.4.4 Therapeutic Equivalence Evaluation and Standards

3.4.4.1 Develop risk-based equivalence standards for narrow therapeutic index (NTI) drugs.

3.4.4.2 Investigate patient use factors such as tablet size for their impact on generic substitutability.

3.4.4.3 Evaluate IVIVC/predictive dissolution for solid oral dosage forms.

3.4.5 Computational and Analytical Tools

3.4.5.1 Develop modeling and simulation tools including PBPK/absorption models, PD models/clinical trial simulation, and quantitative risk modeling for generic drugs.

3.4.5.2 Develop analytical methods to characterize peptides and other complex mixtures and particle size and surface chemistry for potential generic products.

3.5 Identify and Qualify Pain-Associated Biomarkers that are Associated with Therapeutic Control of Pain in Food Producing Animals

3.5.1 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.

3.6 Develop a Regulatory Database for Species Identification

3.6.1 Develop a DNA barcode sequence database for species identification

3.7 Develop methods to improve the cybersecurity of medical devices

3.7.1 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.

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, nanotechnology in medical products);

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

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

and

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

4.1.5 Develop methods to predict clinical performance of devices and materials

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

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

FDA seeks to develop agency information sciences capability. Areas of interest include:

5.1 Develop and apply simulation models for product life cycles, risk assessment, and other regulatory science uses:

5.1.1 Identify opportunities and develop computer simulation and modeling to streamline data analysis and model biological systems and their responses to agents of concerns, such as toxins, pathogens, electromagnetic energy, and biomaterials; and

5.1.2 Promote novel clinical trial design using simulation, new statistical models, and novel animal models/animal model alternatives.

5.2 Analyze large scale clinical and nonclinical data sets:

5.2.1 Refine methods for analysis of post-market data, including data mining of spontaneous reports and analysis of electronic health records from accessible large healthcare databases.

5.2.2 Develop methods to harness clinical evidence and evidence synthesis from multiple domains.

5.2.3 Develop data mining methods for analyzing standardized electronic data submitted to the Agency such as CDISC SEND datasets and for extracting data from FDA created reviews and other documents

5.3 Computer Modeling and Simulation to Assess Product Risk

5.3.1 Develop new approaches to assess the risk of new tobacco products that will potentially enter the market by considering how such products are likely to harm, or potentially harm the users of this product based on demographic attributes of the users and usage patterns.

5.3.2 Develop novel methods to model the carcinogenicity, toxicity, and contribution to adverse health conditions of each component in a tobacco product based on available data – literature, EPA, legacy nonclinical studies, or submitted studies by industry.

5.3.3 Develop novel methods to model the demographics of a synthetic population in terms of probability distribution curves (normal distribution) based on:

a. Usage of tobacco product

b. Race

c. Gender

d. Age

e. Body Weight

f. Family structure and position within (i.e. child exposure to secondhand smoke in the home, car, or other locations)

g. Occupation and work premises (susceptibility to secondary ingestion)

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

5.3.5 Develop and disseminate computational models and simulations that can be used as evidence for the safety and effectiveness of medical devices; establish medical device modeling validation requirements.

5.3.6 Develop novel methods to model inputs to allow one to compare at least two products and see a change reflected on the risk summary. Changes should be able to be qualitative (e.g. moderate smoker translated into 20 cigarettes per day) or quantitative (e.g. 40 cigarettes per day).

Changeable parameters should include:

a. Type of product (average US, brand A, and/or brand B – as well as others when present in the database)

b. Group of chemicals (e.g. vapor phase versus particulate phase)

c. Concentration in the smoke (mean, maximum, etc)

d. Cigarette intake rate – cigarettes per day (i.e. 5, 10, 20, 40, etc)

e. Exposure frequency - How frequently a user is exposed (i.e. daily, one time per week, five days per month etc)

f. Exposure duration – How long a person smokes (in years)

g. Body weight (i.e. Caucasian male, Asian female, etc.)

h. Averaging time – Lifespan for a given population (differing population dynamics)

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

Food Safety Modernization Act (FSMA) mandates a new approach to FDA’s current food safety system, emphasizing prevention and risk-based priority setting and resource allocation to address the challenges of the modern food safety environment. Although prevention is paramount, enhanced response and investigation efforts to foodborne outbreaks when they occur, is also critical. To effectively implement this new food safety mandate, it is imperative that FDA ensures a strong science infrastructure that clearly identifies its research needs and collaborates with other public health and research agencies in the Federal government, state government agencies, academia, and private industry. Areas of interest include:

6.1 Establish and implement centralized planning and performance measurement processes:

6.1.1 Harmonize microbiological and chemical analytical methods development and validation across the Foods Program to enhance detection and removal of unsafe contaminants from the Nation’s food and feed supply.

Note: Improved, validated rapid methods, with high levels of sensitivity and specificity, would enable FDA investigators and laboratories to quickly and accurately identify sources of contamination throughout the food supply chain, thereby protecting public and animal health. In addition, improved methods would also provide defensible data to show food products are free from microbial and chemical hazards and reduce the number of unnecessary recalls which currently result in significant repercussions for industry, consumers and FDA. Research that gives FDA validated, practical and usable regulatory tools would be of great benefit in making regulatory decisions or providing guidance to industry. By sharing and leveraging resources, FDA would like to keep pace with new food technologies, the expanding array of foods in the marketplace, and identifying emerging hazards such as new pathogens and chemical contaminants that would require strategic investments in regulatory science and review.

6.2 Maintain mission critical science capabilities:

6.2.1 Identify emerging disciplines, sciences, and technologies to mitigate future risks in food safety.

Note: The primary focus would be to advance research and development (R&D) into more rapid, sensitive and specific methods to detect, identify and quantify a variety of microbial and chemical hazards (e.g. Listeria, Salmonella, E. coli O157:H7, melamine, arsenic) in foods and animal feeds, as well as dietary supplements and cosmetics.

7. Facilitate Development of Medical Countermeasures (MCMs) to Protect Against Threats to U.S. and Global Health and Security

FDA seeks to facilitate development of safe and effective MCMs through both intramural research and collaboration with external partners (e.g., academia, U.S. government agencies, non-governmental organizations, and industry). The FDA’s MCM regulatory science mission has a responsibility to develop the tools, standards, and approaches to assess medical safety, quality, and performance of MCMs. Additional information on the FDA MCMi initiative and projects is available at:

http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMRe gulatoryScience/ucm263071.htm.

FDA will conduct a review for the potential of Dual Use as defined and in accordance with USG policy:

http://oba.od.nih.gov/oba/biosecurity/pdf/united_states_government_policy_for_oversight_of_durc_fina http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMRegulatoryScience/ucm263071.htm http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMRegulatoryScience/ucm263071.htm http://oba.od.nih.gov/oba/biosecurity/pdf/united_states_government_policy_for_oversight_of_durc_final_version_032812.pdf.

l_version_032812.pdf.

Areas of interest include:

7.1 Develop, characterize, and qualify animal models for MCM development:

7.1.1 Develop and evaluate animal models for Chemical, Biological, and Radiological and

Nuclear (CBRN) threat agents and emerging infectious diseases for the ability to demonstrate a response to the MCM that will be predictive for humans, including the ability to extrapolate pharmacokinetic/pharmacodynamic (PK/PD) data and/or immune correlates of protection to determine appropriate clinical dosing; and

7.1.2 Refine existing animal models for CBRN threat agents and emerging infectious diseases to demonstrate a response to the MCM that will be predictive for humans, including the ability to extrapolate pharmacokinetic/pharmacodynamic (PK/PD) data and/or immune correlates of protection to determine appropriate clinical dosing

7.2 Modernize tools to evaluate MCM product safety, efficacy, and quality:

7.2.1 Identify and evaluate methods to improve the availability, performance, design, and reuse of personal protective equipment;

7.2.2 Enhance FDA’s capabilities to collect, monitor, and track real time data on adverse events associated with the use of drug, biologic, and device MCMs during public health emergencies (e.g., continue to develop and refine data standards and reporting methods to facilitate rapid assessment of the safety and efficacy of deployed MCMs);

7.2.3 Develop reference materials related to relevant CBRN threat agents and emerging infectious diseases to facilitate development of preventive vaccines, therapeutics, and detection and diagnostic methods;

7.2.4 Develop and evaluate high throughput, sensitive, specific, cost-effective methods to detect

CBRN threat agents and infectious diseases, diagnose the disease or condition, and perform broad-based pathogen detection.

7.2.5 Refine existing technologies to improve the sensitivity, specificity, and robustness of assays used to measure MCM potency and in-process and final drug substance characteristics; and

7.2.6 Improve the performance and quality of existing in vitro diagnostic tests for CBRN threat agents and emerging diseases.

7.3 Identify and qualify biomarkers of diseases or conditions:

7.3.1 Improve knowledge of natural history of pathophysiology of human diseases or conditions caused by CBRN threat agents and emerging infectious diseases to identify, qualify, and evaluate biomarkers; and

7.3.2 Identify and qualify biomarkers that enhance the understanding of the mechanism of action of MCMs, and may provide measures of MCM product efficacy.

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

FDA seeks to identify and improve science-based approaches, including rapidly evolving communications technologies, to clear and effective communications on the appropriate uses http://oba.od.nih.gov/oba/biosecurity/pdf/united_states_government_policy_for_oversight_of_durc_final_version_032812.pdf.

of regulated products (Tobacco products are excluded from this for the purpose of the BAA at this time) in order to promote health and reduce harms through informed decision making by consumers and health care professionals. There are four priority areas in which FDA seeks to improve comprehension among the recipients of FDA communications. Areas of interest include:

8.1 Assessment of how communications are understood, especially among diverse audiences and populations, and methods to improve the comprehension of content, including numerical information.

8.1.1 Identify effective ways to communicate so that patients and consumers, including those with low health literacy and limited English proficiency, are informed but not alarmed, assess knowledge and understanding of risk associated with use of FDA-approved products, assess the frequency and means of changing messages in order to promote continued attention to advice that is not new but remains important, evaluate methods to identify and accommodate cultural and language differences and assess the cost of these methods to the Government, and study the impact of different formats and amounts of numerical information in FDA communications for patients, health care providers, health educators and informal caregivers.

8.2 Exploration of how FDA communications can best complement those communicated by industry to enhance audience comprehension.

8.2.1 Assess awareness of direct-to-consumer advertising among patients and consumers, including those with low literacy and limited English proficiency, develop tools for measuring the effectiveness of messages that are being communicated to the public by industry advertisements and by FDA communications.

8.2.2 Develop patient preference and patient-reported outcomes studies

8.3 Research to assess public understanding of the regulatory terms in use.

8.3.1 Study the impact of FDA terms on the public’s ability to comprehend FDA communications, and identify explanatory strategies or alternatives. Examples of FDA terms include: “safe and effective,” Over-The-Counter (OTC) monograph drugs (GRAS, GRAE, “voluntary recall,” “product correction,” and disclaimers like “These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.”

8.4 Evaluation of timing of release of recall or warning messages, when the messages should be changed to enhance impact, and how to communicate the end of a recall or warning.

8.4.1 Characterize how consumers, patients, and caregivers understand and use emerging information including various types of uncertainty about newly identified potential risks of products; also, evaluate the ideal frequency and means of changing messages in order to promote continued attention to advice that is not new but remains important.

8.5 Studies to increase the safety of post approval drug use

8.5.1 Develop innovative methods to create, facilitate and encourage research in the area of safe medication use that seeks to reduce preventable harm from drugs.

Approaches could include the use of clinical studies, education, innovative messaging strategies, electronic health records, or mobile technologies. Sub areas of research interest include but are not limited to the following:

8.5.1.1 Develop and test novel dissemination methods that enhance FDA’s ability to target distribution of intervention materials to specific clinical practice audiences and/or patient populations.

8.5.1.2 Test safe use interventions that advance the field of implementation science within the healthcare system. Develop systems engineering approaches that could serve as a foundation to address multiple safe use issues.

8.5.1.3 Evaluate the capacity of big data analytics to empirically prioritize safe medication use issues within one or more health systems. Empiric prioritization could potentially complement expert-derived prioritization due to its speed, agility, and responsiveness to contextual factors within a health system.

8.5.1.4 Determine if new safe use management options might potentially be available for one or more identified medication safety risks as a result of the emerging precision medicine evidence base. Risks that have been probabilistically associated with medications through epidemiologic study in populations may be mediated by factors such as genetic polymorphisms in individuals.

Knowledge of individual factors could guide therapeutic decisions and enhance safe use.

9. Strengthening the Global Product Safety Net

Globalization has made FDA’s responsibilities increasingly challenging, affecting every type of product FDA regulates. In 2002, 8 million import entry lines of FDA-regulated products arrived at our borders; in 2012, it grew to 28 million and in 2013, it’s expected to be 34 million.

Additionally, more and more products come from developing countries where manufacturing systems may be less sophisticated and regulatory and manufacturing oversight may be minimal. As FDA continues to transform into a public health agency fully prepared for a complex, global regulatory environment, there are 3 priority areas in which FDA seeks to improve its knowledge and capabilities to enhance its international operating model. Areas of interest include:

9.1. Advancing Global Public Health

9.1.1. Determine how to promote and assure implementation of the essential elements of a strong regulatory system in developing economies, including (a) determining core competencies for a regulatory workforce and components of a global regulatory workforce curriculum, (b) assessing other areas related to regulatory systems’ performance including conducting, costing, and financing analyses for regulatory systems, and (c) identifying and assessing existing regulatory strengthening evaluation tools utilized by governments and international organizations.

Note: Research in this area could include advancing innovative regulatory science through the development of cutting-edge investigative, inspectional and analytical rapid-screening tools.

9.2. Leveraging and Collaborating

9.2.1. Determine how to best identify and leverage the efforts of public and private third parties to more effectively deploy resources against risk-based priorities. This could include researching, assessing and developing recommendations regarding the landscape of existing efforts, activities, and capabilities.

9.2.2. Work with other public and private stakeholders to ensure that standards are well understood and applied, foster best practices in industry, and promote innovation to drive safety and quality.

9.2.3. Foster global coalitions of regulators by, among other actions, developing strategic approaches to the harmonization and convergence of standards, contributing to the sharing of useful information, recognition determinations, mutual reliance, and an improved ability to make appropriate regulatory decisions in real time.

Note: Research in this area could include development and use of a tool to assess the governing authorities, regulations, and operating models of various regulatory agencies in order to inform comparability determinations; and the development and use of mechanisms to share information and best practices via existing or new electronic platforms. Research might also include an assessment of the current extent of standards implementation (intended use), gaps in implementation, and priorities for broadening and harmonizing the application of standards.

9.3. Analyzing and Utilizing Global Data to Manage Risks

9.3.1. Define analytical methods and tools to foster improved utilization of risk analytics to inform strategies, priority-setting, and timely decision-making in the areas of inspections, training, regulatory cooperation and surveillance.

9.3.2. Develop predictive risk models that treat like risks in like ways across the supply chain regardless of the origin of the product.

9.3.3. Adopt new approaches to better aggregate and analyze multiple sources of information to fully identify risks and emerging trends based on comprehensive assessments of existing information platforms. The developed approach should include data mining of intelligence related sources (event reporting, testing results, alerts, customer complaints, news reports) to enable statistical analysis of correlations and threats. As an extension, integrate intelligence-based threat analysis into the risk-based allocation of inspection and testing resources.

9.3.4. Filter and analyze external indicators/signals/environmental vulnerabilities in the supply chain from various open-source intelligence and other sources to proactively identify the need for appropriate FDA interventions.

Note: Research in this area could include the development of informatics tools to connect multiple sources of information such as regulatory, economic, environmental, political and industrial factors to detectable risk signals and emerging risk trends. It could also include the development of data collection and analysis systems for external indicators/signals/environmental vulnerabilities in the supply chain from various sources intelligence and other media to alert FDA at early onset of the need for appropriate FDA actions or interventions.

9.4. Manage Risks Related to Intentional Disruptions to Food Supply

9.4.1. Conduct empirically-based, quantitative analyses to evaluate the risk of intentional disruptions to the food supply system. Scenario-based risk analysis shall include evaluation of the magnitude of specific threats to each supply chain component, identification of supply chain vulnerabilities, and determination of expected consequences for each scenario.

9.4.2. Utilize results of the risk assessment of intentional…