Regulatory Science at the US Food and Drug Administration: Enhancing SCIENCE-based

regulation of medical products

Carolyn A. Wilson, Ph.D. Associate Director for Research

Center for Biologics Evaluation and Research

My comments are an informal

communication and represent my own best judgment.

These comments do not bind or

obligate FDA.

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FDA’s Regulatory Scope: 25 cents of every GDP dollar

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Using Science and Regulation to Advance Medical Product Development

www.fda.gov

Regulatory Challenge Public Health

Novel Product

Regulatory Science Discovery

New Tools Regulatory Policy/Decision

Licensed Product

Improved Data – Benefit/Risk

Post-market Surveillance

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FDA’s Regulatory Science • Product Centers oversee and conduct

intramural laboratory and non-lab (i.e., epidemiology and biostatistics) research

• Office of the Commissioner and Office of the Chief Scientist: – Coordination/communication via working

groups – Intramural funding programs – Extramural funding programs

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FDA Regulatory Science: Regulatory Product Center Programs

Commissioner

Office of Foods and Veterinary

Medicine

ORA

CFSAN

CVM

Office of Medical

Products and Tobacco

CBER

CDER

CDRH

CTP

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2016 CBER Goals Regulatory Science and Research

Goal 1. Advance the scientific basis for regulation of biologics, human tissues and blood to enhance safety, effectiveness, quality and consistency through development and evaluation of new concepts, methods, models, and reagents.

Goal 2. Develop and assess nonclinical models and methods with improved predictive value, and, as feasible, reduce, refine, or replace the use of animals, for evaluation of safety and effectiveness of CBER-regulated products.

Goal 3. Improve clinical evaluation related to CBER-regulated products through the use of new biomarkers, large scientific and healthcare datasets, and innovative design and analysis of clinical studies by applying new statistical, epidemiological, and mathematical modeling approaches, and considering patient input to inform benefit-risk assessment of general and special populations.

Goal 4. Prepare for future regulatory and public health challenges through investments in emerging science and technology, and develop and sustain varied scientific expertise.

www.fda.gov

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What about Zika Virus?

Initial focus: protect the blood supply:

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Zika and Protecting the Blood Supply….

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CBER: Mesenchymal Stem Cells Consortium

Sponsors have used some of CBER’s published methods to characterize their products; data provided in INDs

• Objective: Develop ways to identify quality attributes that predict safety and effectiveness.

• Outcomes – Demonstrated that Consensus MSC Markers do not

Correlate with Functional Heterogeneity • Donor or Tissue Culture Age Differences

– Developed assays to identify and qualify predictive product characteristics for cell therapy products – Published findings

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Lo Surdo JL et al., Cytotherapy, 2013.

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MSC Consortium Publications

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• Differentiation – Quantitative Approaches to Detect Donor and Passage Differences in Adipogenic Potential and

Clonogenicity in Human Bone Marrow-Derived Mesenchymal Stem Cells. 2012. Lo Surdo, JL, and Bauer, SR. Tissue Engineering: Part C 18: 877-889.

– Automated Microscopy as a Quantitative Method to Measure Differences in Adipogenic Differentiation in Preparations of Human Mesenchymal Stem Cells. 2013. Lo Surdo, JL, Millis, B. and Bauer, SR: Cytotherapy. 2013 15: 1527-40

• Proteomics – Improved proteomic profiling of the cell surface of culture-expanded human bone marrow

multipotent stromal cells. 2013. Samuel T. Mindaye, Moonjin Ra, Jessica Lo Surdo, Steven R. Bauer, Michail A. Alterman. J Proteomics 78: 1-14.

– Global proteomic signature of undifferentiated human bone marrow stromal cells: Evidence for donor-to-donor proteome heterogeneity. Mindaye, ST, Ra, M, . Lo Surdo, JL, Bauer, SR, and Alterman, MA. 2013.. Stem Cell Research 11: 793-805

– System-wide survey of proteomic responses of human bone marrow stromal cells (hBMSCs) to in vitro cultivation. Mindaye, ST, Lo Surdo, JL, Bauer, SR, and Alterman, MA. 2015. Stem Cell Research in press

• Immunomodulation – Assessment of immunosuppressive activity of human mesenchymal stem cells using murine antigen

specific CD4 and CD8 T cells in vitro. 2013. Nazarov, C., Lo Surdo, J.L., Bauer, S.R., Wei, C-H. Stem Cell Research & Therapy 4:128.

• Genomics – Gene markers of cellular aging in human multipotent stromal cells in culture. 2014. Ian H Bellayr,

Jennifer G Catalano, Samir Lababidi, Amy X Yang, Jessica L Lo Surdo, Steven R Bauer and Raj K Puri. Stem Cell Research & Therapy, 5:59

• Epigenetics – Chromatin Changes at the PPAR-g2 Promoter During Bone Marrow-Derived Multipotent Stromal Cell

Culture Correlate With Loss of Gene Activation Potential. Lynch, PJ, Thompson, EE, McGinnis, K, Rovira-Gonzalez, YI, Lo Surdo, JL, Bauer, SR, Hursh, DA. Stem Cells 33: 2169-2181.

• Sector Overview – MSC-based product characterization for clinical trials: An FDA Perspective. 2014. Mendicino, M,

Bailey, AM, Wonnacott, K, Puri, RK., and Bauer, S.R. Cell Stem Cell 14:141-145

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Improve Access to Post-market Data Sources and Explore Feasibility of Their Use in Different Types of Analyses

Improve Risk Assessment and Management Strategies to Reinforce the Safe Use of Drugs

Evaluate the Effectiveness and Impact of Different Types of Regulatory Communications to the Public and other Stakeholders

Evaluate the Links among Product Quality Attributes, Manufacturing processes, and Product Performance

Develop and Improve Predictive Models of Safety and Efficacy in Humans

Improve Clinical Trial Design, Analysis, and Conduct

Enhance Individualization of Patient Treatment

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http://www.fda.gov/Drugs/ScienceResearch/ucm264327.htm

CDER: 7 Regulatory Science Topics

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Supporting evaluation of biosimilars: Analytical technologies to evaluate recombinant proteins 2D-NMR analysis of the higher-order structure of filgrastim (G-CSF, biosimilar for Neupogen): approval of this first biosimilar in 2015 • Originator product, Neupogen, and three unapproved drug

products evaluated at four labs on 6 instruments • Same analytical software applied to all data • Sufficient resolution to obtain high degree of similarity with

quantitative analysis revealing shifts tracking to variations in temperature, pH/ionic strength of solvent, or change in higher order structure.

Ghasriani, Houman, et al. "Precision and robustness of 2D-NMR for structure assessment of filgrastim biosimilars." Nature Biotechnology 2016 http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm436648.htm

www.fda.gov

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FDA Regulatory Science: OC Programs

OC

Office of the Chief Scientist

Office of Counter-Terrorism and

Emerging Threats

National Center for Toxicological

Research

Office of Regulatory Science

and Innovation Office of Women’s

Health

Office of Minority Health

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National Center for Toxicological Research:

Supporting Multi-Agency Tox21 FDA’s Modernizing Toxicology

• Develop better models of human adverse response • Identify and evaluate biomarkers and endpoints that can be

used in non-clinical and clinical evaluations • Use and develop computational methods and in silico

modeling

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Predictive Pharmacology in silico* QSAR (Quantitative Structure Activity Relationship)

• 50 years - Traditional drug discovery tool

• Based on classical (large body) mechanics

• Regression/classification outcomes based on measurement of 2D and 3D structural/reactive chemical descriptors.

• E.g. EDKB

QSDAR (Quantitative Spectral Activity Relationship)

• QSDAR patent 2004 3D QSDAR* patent 2011

• Based on quantum (very small body) mechanics; e.g. NMR chemical shift data

• Partial least squares and discriminant analysis of experimental or in silico generated NMR data

• E.g. PLD and hERG binding *incorporates inter-atomic distance

www.fda.gov

Bioimaging: Replace?

* "All models are wrong but some are useful“ George Box 1978

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• 15N- and 13C NMR 3D-QSDAR

• NCATS experimental PLD testing (n=1070; acc=83%), used a HepG2 cell line while the hERG assay (n=1385; acc=86%) used U-2 OS viral transduced cells

• Tendency 3D-QSDAR to predict false positives/ No tendency to predict false negatives

PLD n=1070 hERG n=1385

Experimental Validation Of the hERG and PLD 3D-QSDAR in silico Model

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Office of Regulatory Science and Innovation

• Oversees two major extramural programs in regulatory science: – Broad Agency Announcement http://www.fda.gov/ScienceResearch/SpecialTopics/RegulatoryScience/ucm301667.htm – Centers of Excellence in Regulatory Science (CERSI) http://www.fda.gov/ScienceResearch/SpecialTopics/RegulatoryScience/ucm301667.htm

• University of Maryland • Georgetown University • Johns Hopkins University • UCSF/Stanford • Yale/Mayo

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Objective: Develop an anatomical and functional population model of the musculoskeletal system to facilitate virtual clinical trials

Collaboration with Dr. Thor Besier, Auckland Bioengineering Institute and CDRH

Overview and Outcomes: • Open source software enables users to visualize the

musculoskeletal system; create computational models of anatomical structures based on patient data.

• Database enables access to raw medical image data, motion capture and muscle performance data gathered in the international Physiome Project. Includes pelvis, femur, tibia, fibula and patella.

• Users query database for similarities and differences in range of anatomical data.

BAA example: The Musculoskeletal Atlas Project (MAP)

https://simtk.org/home/map

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CERSI Program Joint efforts between FDA and academic institutions to collaborate on projects that promote regulatory science, including innovative research, education, and scientific exchange under a cooperative agreement grant (U01).

Address scientific challenges arising from new medical product development and regulatory activities

Collaboration with academic partners on research that supports FDA’s regulatory mission & improves public health.

Support training needs for FDA, new scientists, & scientific community.

Enhance extramural partnerships and expand scientific exchanges.

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CERSI Example: Eliciting Patient Preferences to Enhance

Regulatory Science Research Project

Objective • Advance and apply stated preferences among people with

type 2 diabetes Overview & Outcomes • National survey assessed priorities for diabetes self

management and treatment preferences • Collaborated with patient organizations to create patient-

centered studies for lung cancer, acute myeloid leukemia and Duchenne muscular dystrophy

• Direct impacts of patient organizations – pilot results from collaboration with Leukemia and Lymphoma Society to be presented at FDA patient preference meeting

www.fda.gov

Johns Hopkins University

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FDA Regulatory Science: OC Programs

OC

Office of the Chief Scientist

Office of Counter-Terrorism and

Emerging Threats

National Center for Toxicological

Research

Office of Regulatory Science

and Innovation Office of Women’s

Health

Office of Minority Health

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Medical Countermeasures Initiative Regulatory Science Program • Established in 2010 under the Medical Countermeasure

Initiative (MCMi) to support intramural and extramural research

• Priority research areas – Identifying, developing, and qualifying drug development

tools (e.g., animal models, biomarkers) – Developing methods to assess product quality and related

product release assays – Validating next-generation in vitro diagnostics platforms – Assessing the performance of emergency medical equipment – Enhancing emergency preparedness and response

capabilities, including risk communication and tracking and evaluating the safety and clinical benefit of MCMs used during public health emergencies

www.fda.gov/medicalcountermeasures

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MCMi extramural regulatory science example: Cross-Species Immune System Reference Garry Nolan, Stanford University

Objective: Conduct a comprehensive cross-species analysis of immune system function to inform the choice of appropriate models for MCM development Overview & Outcomes • Universal antibody panels for humans, macaques, African green

monkeys, and mice • Exposed blood from humans, three species of non-human primates, and

mice to cytokines, viral and bacterial antigens, or receptor ligands; analysis via CyTOF mass cytometry

• Species- and gender-specific differences in immune response, the effect of anesthesia on NHP immune function and blood chemistry, and macaque-specific sensitivity to bacterial threat agent

• Open access cross-species immune response database: http://immuneatlas.org

www.fda.gov/medicalcountermeasures

361 Projects

17 Disease Areas

31% Sex Differences

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FDA Office of Women’s Health Established 1994

www.fda.gov/womenshealthresearch Obias-Manno et al. The Food and Drug Administration Office of Women’s Health: Impact of science on regulatory policy. J Women’s Health 2007;16(6):807-817. Elahi et al. The Food and Drug Administration Office of Women’s Health: Impact of Science on Regulatory Policy: An Update. J Women's Health 2016; 25(3):222-234.

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OWH-funded research has contributed to FDA policy and advanced knowledge of SEX DIFFERENCES IN HEART DISEASE

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OWH-FUNDED RESEARCH, Example Higher Risk for Drug-Induced Arrhythmias for Women Investigator: David Strauss – FDA CDER

• Between 1991 and 2003, 6 drugs were withdrawn from marketing in the US because of Torsade de Pointes (TdP) tachycardia

• Women are at higher risk

• Project assessed the ability of novel ECG biomarker strategies to differentiate benign from malignant drugs that prolong the QT and sex difference in QTc prolongation

• Regulatory Impact: Understanding the mechanisms of QTc prolongation and determining if drug-induced abnormal heart rhythms may be prevented by combining drugs will ensure safety of approved drugs for women and men.

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Vision: A world where health equity is a reality for all Mission: The Office of Minority Health advances FDA’s regulatory mission in addressing the reduction of racial and ethnic health disparities and in achieving the highest standard of health for all.

Goal 1- To improve and strengthen regulatory science informing the research and evaluation of sub-population data associations with race and ethnicity.

Goal 2- To strengthen FDA capacity to address minority health and health disparities across the Agency.

Goal 3- To promote effective communication and the dissemination of information to the public, particularly underserved, vulnerable populations.

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FDA Office of Minority Health March 2010 Affordable Care Act- Section 10334 mandated creation of OMH across all HHS divisions

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Research and Collaboration Strategies

• Intramural Challenge Grants • Intramural ORISE Fellows • Extramural ORISE Fellows

Support/Fund Research Projects

• FDA Centers for Excellence in Regulatory Science and Innovation Program

• 2015 Genomics and Health Disparities Lecture Series with the National Human Genome Research Institute (NHGRI)

Collaborations

• OMH Speaker Series • CDER Scientific Seminars • Pharmacy Intern Program • Institute of Medicine Roundtable on Promotion of Heath

Equity and the Elimination of Health Disparities • Part 15 Hearings/CERSI Workshop

Training/Workshops

FDA Office of Minority Health

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Project: Improving Health Literacy and Cultural Competency in Current FDA Risk Communication PI: Olivia Carter-Pokras, PhD Objective: Evaluate how health information is relayed by examining health literacy and cultural competency of Food and Drug Administration (FDA) consumer materials on HIV/AIDS and Hepatitis B/C Outcomes: • Majority of pages scored at the college or graduate reading level (>12). • Epidemiology of population health and health care disparities are key

components of cultural competency training for health professionals • Although many websites contain data and statistics, statistics presented

are not representative of the intended audience and material is not useful • Publication: Health Literacy and Cultural Competency of FDA Consumer

Materials

FDA Office of Minority Health, Example

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Summary Science-based regulation is improved when

FDA engages in research proactively and reactively to address critical knowledge

gaps that reduce uncertainty in regulatory decision-making.

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With Thanks

• Robert Fisher, OCET, OCS • York Tomita, Khaled Bouri, Shaila Shaheed, ORSI • Martin Mendoza, OMH • Emmanuel Fadiran, OWH • Steve Bauer, Maria Rios, CBER • Ruth Barratt, CDER • Tom Flammang, NCTR