1. Translating Patient Diversity into Optimal Drug Therapy A Tour of FDA’s Office of Clinical Pharmacology
Joseph A. Grillo, Pharm.D.
Associate Director of Labeling and Health Communication
Office of Clinical Pharmacology (OCP)
Office of Translational Sciences
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
This presentation reflects the views of the author and should not be construed to represent FDA’s views or policies.

2. Overview
History and organizational overview of the Office of Clinical Pharmacology (OCP)
Regulatory review resources
Transforming public health through research
Prescription Drug User Fee Act (PDUFA) VI
Model informed drug development (MIDD)
Physiologically based pharmacokinetic (PBPK) modeling
Integration of precision medicine and genomics
OCP labeling and guidance initiatives
External engagement and collaborative opportunities with OCP

3. Evolution of Clinical Pharmacology at FDA
Applied regulatory science | Evidence assessment | Dose optimization Therapeutic individualization | Policy | Communication
NOW
1980s
Early 1990s
Mid 1990s
Late 1990s
2000s
BA/BE
Dosage forms
Metabolism
Early modeling
(IVIVC, PK-PD)
Organ impairment
Sex effects
Advanced PM
(D/R, E/R, disease
modeling, trial
simulation)
Pediatric pharmacology
Pharmacogenomics
PBPK
Mechanistic safety
Systems pharmacology

4. Clinical Pharmacology in Drug Development and Evaluation
EOP1
EOP2
NDA
sNDA
PRECLINICAL
PHASE I
PHASE II
PHASE III
PHASE IV
Chemical, MOA,
safety characteristics
First in human
Dose-ranging studies
Early PK/PD
Dose identification
PK/PD in patients
E-R/E-S
PK/PD & E-R/E-S in
target population
Labeling
Develop BA method
PMC/PMR
In vivo DDI
Extrinsic
factors
Dose optimization
Mitigation strategies
in the target population
In vitro metabolism, transporter, & DDI
Early
food-effect
Mass balance
ACTION
In vitro protein binding,
cellular/tissue
distribution
Renal/hepatic,
disease, intrinsic
factors
Food-effect
BA/BE
Surveillance
Relevant animal/POC
QTc study
Target, mechanistic, &/or
physiologic biomarker
identification
Pharmacogenomics
Pharmacostatistical Modeling & Simulation
Discovery
Learn
Confirm

5. Office of Clinical Pharmacology (OCP)
OUR
VISION
MISSION
Improve public health by building and translating knowledge of drug response into patient-centered regulatory decisions of the highest quality
Play a pivotal role in advancing development of innovative new medicines by applying state-of-the- art regulatory science and clinical pharmacology principles
Promote therapeutic optimization and individualization through best practices in research, policy development, and drug evaluation throughout the product lifecycle
OCP is a dynamic, purpose-driven organization whose goals are to:
Enhance drug development
Promote regulatory science and innovation
Inform the optimal use of medications

6. Through the application of state-of-the-art regulatory science and clinical pharmacology principles we:
Conduct research, use data-based tools, & formulate best practices
Promote therapeutic individualization &
personalized medicine
Use experimental
& analytical approaches
Employ mechanistic & model-informed
drug development strategies
Generate, evaluate, & use knowledge of
drug disposition, pharmacology, & disease biology
WHAT
WE DO
Progressively reduce regulatory uncertainty & inform public health decision-making
Maximize the value of early & late phase clinical drug development
Identify, account for, & ultimately predict patient variability in drug responses
Translate knowledge of patient diversity into clinical recommendations for safe & effective drug use
Address immediate & emerging issues that impact development, regulatory evaluation, & utilization of therapeutic products
Functions
Outcomes

7. OFFICE OF CLINICAL PHARMACOLOGY Issam Zineh – Director
Shiew-Mei Huang – Deputy Director
Michael Pacanowski
Associate Director for Genomics & Targeted Therapy
E. Dennis Bashaw
Senior Science Advisor
Gil Burckart
Associate Director for Pediatrics
Colleen Kuemmel
Staff Fellow
Peter Lee
Associate Director for Knowledge Management
Karen Graves
Program Support Specialist
Genomics & Targeted Therapy Group
Raj Madabushi
Team Leader, Guidance & Policy
Guidance & Policy Team
Joseph Grillo
Associate Director for Labeling & Health Communication
Labeling & Health Communication Group
Jessica Benjamin
Chief Program Manager
Yow-Ming Wang
Director, Therapeutic Biologics
Executive Program & Project Management Staff
Therapeutic Biologics Program
DIVISION OF CLINICAL PHARMACOLOGY I
DIVISION OF CLINICAL PHARMACOLOGY IV
Mehul Mehta – Director
Ramana Uppoor – Deputy Director
John Lazor – Director
Kellie Reynolds – Deputy Director
DIVISION OF CLINICAL PHARMACOLOGY II
DIVISION OF CLINICAL PHARMACOLOGY V
Chandra Sahajwalla – Director
Suresh Doddapaneni – Deputy Director
Atiqur Rahman – Director
Brian Booth – Deputy Director
DIVISION OF CLINICAL PHARMACOLOGY III
DIVISION OF PHARMACOMETRICS
Shirley Seo – Director
Doanh Tran – Deputy Director
Yaning Wang – Director
Hao Zhu – Deputy Director
DIVISION OF APPLIED REGULATORY SCIENCE
David Strauss – Director
Rodney Rouse – Deputy Director

8. Novel Product Approvals in 2018

9. Critical NDA & BLA Review Examples in 2018
LIBTAYO (cemiplimab-rwlc): Utilized pharmacokinetic/pharmacodynamic (PK/PD) relationships to support a flat dosing regimen versus the weight-based regimen studied in clinical trials in patients with squamous cell carcinoma (SCC).
TAKHZYRO (lanadelumab): Leveraged E/R information to support approval of new dosing regimen to treat patients with types I and II hereditary angioedema.
TPOXX (tecovirimat): Established pediatric dosing recommendations based on PK modeling and simulation for treatment of smallpox infection under FDA’s Animal Rule regulatory pathway.
DOSAGE
OPTIMIZATION
TIBSOVO (ivosidenib): Used physiologically-based PK (PBPK) modeling to support dosage reductions for TIBSOVO when administered with strong cytochrome (CYP) 3A4 inhibitors in treating patients for relapsed or refractory acute myeloid leukemia.
YUPELRI (revefenacin): Evaluated metabolite exposures in moderate hepatic impairment patients to support a recommendation not to use YUPELRI to treat chronic obstructive pulmonary disease (COPD) patients with any degree of hepatic impairment.
ZEMDRI (plazomicin): Integrated pharmacologic and E/R information from limited clinical data to inform therapeutic drug monitoring recommendations to mitigate acute kidney injury risk in patients with complicated urinary tract infections (cUTI) including pyelonephritis.
RISK
MITIGATION
GALAFOLD (migalastat): Designed a labeling strategy that incorporates in vitro assay data to expand the treatment indication in adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant.
SYMDEKO (tezacaftor/ivacaftor): Expanded cystic fibrosis (CF) indication based on in vitro data for patients 12 years or older who have two copies of the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene or have at least one mutations that is responsive to the drug.
TIBSOVO (ivosidenib): Informed labeling for selecting adult patients for treatment with TIBSOVO for relapsed or refractory acute myeloid leukemia based on the presence of isocitrate dehydrogenase 1 (IDH1) mutations in the blood or bone marrow.
GUIDING PATIENT SELECTION

11. 11

12. Drugs@FDA An Untapped Resource
Drug X (drugoxide) Capsules
Company: X , Inc.
Application No: ######
Approval Date ##/##/####
Approval Letter(s) (PDF)
Printed Labeling (PDF)
Summary Review (PDF)
Officer/Employee List (PDF)
Office Director Memo (PDF)
Cross Discipline Team Leader Review (PDF)
Medical Review(s) (PDF)
Chemistry Review(s) (PDF)
Pharmacology Review(s) (PDF)
Statistical Review(s) (PDF)
Microbiology Review(s) (PDF)
Clinical Pharmacology Biopharmaceutics Review(s) (PDF)
Risk Assessment and Risk Mitigation Review(s) (PDF)
Proprietary Name Review(s) (PDF)
Other Review(s) (PDF)
Administrative Document(s) & Correspondence (PDF)
An Untapped Resource
Searchable database of FDA-approved drug products, OTC human drugs and biological therapeutic products
Updated daily
Includes most drug products approved since 1939
Provides patient information, labels, approval letters, reviews, and other information for the majority of drug products approved since 1998

13. Research Within OCP
OCP staff routinely conduct regulatory-based research as part of their professional development
Competitive Internal Grants
Research Grant
Critical Path Grants
Regulatory Science Research and Review Enhancement Grant
Office of Women’s Health
Medical Countermeasures
Scientific Interest Groups
Division of Applied Regulatory Science (DARS)
Designs and conducts computational and laboratory research that can inform regulatory decision making and improve how drugs are developed and reviewed

14. OCP Unit Scope & Research Focus
DCPI
DCPII
DCPIII
DCPIV
DCPV CV
Renal
Neurology
Psychiatry
Biomarkers for PAH and MDD
Bioequivalence criteria for depot injection drugs in schizophrenia
Optimization of trial designs in schizophrenia, rare diseases in neurology space and pediatric programs
Allergy
Analgesia/Anesthesia
Diabetes/Endocrine/
Metabolism
Pulmonary
Rheumatology
Derm/Dental
GI/Inborn errors
Bone/Repro/Uro
Special monographs
DDIs & BMI/BW on contraceptives
BTM for BMD prediction
Psoriasis biomarkers
Antivirals
Anti-infectives
Solid organ transplant
Ophthalmology
Animal rule
Anti-infective PK/PD & breakpoints
DDIs in labeling
Transporter mediated DDIs
Animal doses to humans
Oncology
Hematology
Medical
Imaging
Dose optimization
PPI-oncology DDIs
CIPN predictors
Biologics DDIs & immunogenicity
Therapeutic protein interaction, immunogenicity, E-R, biosimilarity and interchangeability, pediatrics
Rare autoimmune disease dose selection
E-R in pain/addiction
CV= cardiovascular, PAH= pulmonary arterial hypertension, MDD= major depressive disorder, E-R= exposure-response, GI=gastrointestinal, DDI=drug-drug interaction, BTM= bone turnover markers, BMD= bone mineral density, PK/PD pharmacokinetics/pharmacodynamics, PPI= Proton-pump inhibitor, CIPN= chemotherapy-induced peripheral neuropathy

15. OCP Unit Scope & Research Focus
TBP
DPM
DARS
LHC
GTTG
All
Therapeutic
Areas
All
Therapeutic
Areas
All
Therapeutic
Areas
All
Therapeutic
Areas
Scope
Biologic Products
Scope
Scope
Scope
Scope
E-R relationships
Disease models
Safety visualization tool
Dose optimization
Mechanistic safety
Assays & biomarkers
Chemical & biomedical informatics
Impact of labeling enhancements
Parity between labeling & DI resources
HCP literacy
Impact of CP related labeling decisions
Biosimilar & interchangeable products
Immunogenicity
Bioanalytical Methods
Glycosylation or PEGylation and PK variability
Genetic epidemiology
Biomarker utilization
Knowledge management
Bioinformatics
Research
Research
Research
Research
Research

16. Transforming Public Health Through Research

17. Integrating Scientific Innovation & Regulatory Review

18. PDUFA VI: Regulatory Decision Tools
Complex Innovative Trial Designs
Model-Informed Drug Development
[Including PBPK]
Biomarker Qualification
Real World Evidence
Benefit/Risk Assessment
Patient Voice
PDUFA: Prescription Drug User Fee Act

19. Model-Informed Drug Development
PK/PD
Exposure-Response
In Silico
Clinical Trial Simulations
Human PK
Dose Prediction
Study Design Optimization
Predict/Characterize:
ADME
Intrinsic /Extrinsic Factors
Early Risk/Benefit
Dosage Selection
Labeling
Population Bridging
Development and application of exposure-based, biological, and statistical models derived from preclinical and clinical data sources to address drug development or regulatory issues* PK
PopPK
PBPK
MIDD
Disease Models
Clinical Trial Models
QSAR
QSPR
Systems Biology
QSP
CiPA
QSAR: Quantitative structure–activity relationship
QSPR: Quantitative structure–property relationship
* From PDUFA 6; Excludes statistical designs involving complex adaptations, Bayesian methods, or other features requiring computer simulations to determine the operating characteristics of a confirmatory clinical trial.

20. MIDD: PBPK Modeling
Note: A total of 254 submissions were reviewed by OCP including 94 NDAs, from Each submission might have more than one area of application. For example, one submission may include one or more PBPK models to be used to support enzyme-, transporter- mediated DDI, as well as food effect.
Grimstein, et al. J Pharm Sci. 2019;108(1):21-25.

21. Ibrutinib
Applicant’s proposed model predicted untested lower potency inhibitors on "drug as substrate" DDI effects
FDA initiated analyses Identified potential difference between reversible inhibitors & time dependent inhibitor effects
Applicant simulations and FDA analysis informed prescription drug labeling (PDL) and provided decision support for potential dose staggering and dose reduction mitigation strategies

22. Precision Medicine
An innovative approach to disease prevention and treatment that takes into account individual differences in people’s genes, environments, and lifestyles
Precision medicines or targeted therapies*: Drugs or biologics intended for use with a genomic, proteomic, or other biomarker
Identifies patients within a clinically-defined disease who are eligible for treatment based differences in efficacy or safety
Aids in determining the appropriate dose
Allows for monitoring of responses to individualize therapy
Biomarkers may have diagnostic, prognostic, predictive, or other value and often mechanistically related to the drug
* Unofficial definition

23. Uses of Genomics in Drug Development
PREEMPTIVE
Validate targets for drug development
Predict drug toxicities
Define target population
PROSPECTIVE
Predict drug exposure
Minimize noise
Identify patients at risk for disease or event
Select patients likely to respond to drug
RETROSPECTIVE
Explain variable responses to drug
Identify (non-)responders or patients with adverse reactions
Identify risk for serious drug interactions

24. Novel Drugs Approved with Genomic and Other Biomarker Information in Labeling
Actionable biomarker: specific prescribing recommendation that is included in one of the following sections of labeling: 1) Boxed Warning, 2) Indications and Usage, 3) Dosage and Administration, 4) Contraindications, or 4) Warnings and Precautions.
Biomarkers may be any genomic biomarker or other selected protein biomarker that are used for patient selection.

25. Clinical Pharmacology Labeling Footprint25
Highlights
D&A
BW, CI, W&P, AR,
PCI, and others
Drug Interactions
Specific Populations
Clinical Pharmacology
Highly Actionable,
Brief,
Limited Context
Less Actionable,
Detailed,
Additional Context
D&A: Dosage and Administration
BW: Boxed Warning
CI: Contraindications
W&P: Warnings and Precautions
AR: Adverse Reactions
PCI: Patient Counseling Information 25

26. CDER Labeling Initiative
Prescription Drug Labeling Improvement & Enhancement Initiative (PDLIEI) established 2013
Enhance the safe and effective use of prescription drugs by facilitating optimal communication through PDL
Increase percentage of PDLs that complies with PLR content and format requirements
Develop and evaluate approaches to enhance clarity, utility, and comprehension of PDL across CDER
Foster consistency in PDL across CDER by establishing guidances and best practices

27. HCP Perception Drug Interaction Information in PDL
Current Presentation
Ideal Presentation
Confusing structure
Too much information
Wrong/out-of-date information
No conveyance of risk
No real guidance
Easy to access and navigate
Minimizes pharmacology jargon
Clinically intuitive structure
Imparts sense of severity or risk
Provides risk management instructions
Omits unnecessary information
Up to date
HCP= Healthcare Provider; PDL = Prescription Drug Labeling (also called Prescribing Information or the “PI”)
OCP Advisory Committee for Pharmaceutical Science and Clinical Pharmacology September 25, 2013

28. Tabular Presentation for Complex or Highly Technical Information
Disclaimer: Any tables and presented today are meant to be illustrative only; these examples are not intended to limit the use of other possible formats and approaches to convey critical information

29. Focus on Essential Information
Consistency Through Tabular Formats
Preferred Example:
12.3 Pharmacokinetics
Drug Interaction Studies
Strong CYP3A Inhibitors: Coadministration with a strong CYP3A inhibitor (ketoconazole) increased drugoxide Cmax by 1.3-fold and AUC by 2-fold.
Non-Preferred Example:
12.3 Pharmacokinetics
Drug Interaction Studies
Coadministration of a single 40 mg dose of drugoxide with the strong CYP3A inhibitor ketoconazole (200 mg twice daily for 14 days) increased the Cmax and AUC of drugoxide by 1.3 and 2-fold, respectively, compared to when drugoxide was given alone in 14 healthy volunteers. Tmax was unchanged. A reduced starting dosage is recommended.

30. Complex Therapeutic Individualization Strategies
Table X: Recommended Dosage Adjustments in Patients Taking Strong CYP2D6 Inhibitors, CYP3A
Inhibitors, and/or CYP3A Inducersa and/or in Patients who are CYP2D6 Poor Metabolizers
Current Dosage
(mg)
Dosing Frequency
(hours)
Perpetrators
Modified Dosage
Modified Frequency
2D6 Poor Metabolizer
Concurrent/ strong
CYP2D6 INH
CYP3A INH
CYP3A IND
200 mg 6
Yes No
Avoid Use NA
400 mg
600 mg 12
a = CYP3A inducers taken for greater than 2 weeks; INH = inhibitor; IND = inducer; NA = not applicable

31. Guidance Development Initiative
Guidance document
Represent FDA's current thinking on a particular subject
Does not create or confer any rights for or on any person
Does not bind FDA or the public
Draft guidances are published to collect public comments prior to finalization
Comments made to a docket # found in the Federal Register (FR) notice
Identify
Issue
Final Guidance
Published
FDA
Working
Group
Guidance Development
WG Reviews
Comments
&
Revises
Draft
Guidance
&
FR Notice
Stakeholder
Comments To
Docket

32. Published or Planned OCP-Led Guidances
GUIDANCES PUBLISHED IN 2018
Bioanalytical Method Validation (Final)
Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease (Final)
Maximal Usage Trials for Topical Active Ingredients Being Considered for Inclusion in an Over-the- Counter Monograph: Study Elements and Considerations (Draft)
Physiologically Based Pharmacokinetic Analyses- Format and Content (Final)
GUIDANCES PUBLISHED OR PLANNED IN 2019
Bioavailability Studies Submitted in NDAs or INDs – General Considerations (Draft)
Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations (Draft)
Maximal Usage Trials for Topical Active Ingredients Being Considered for Inclusion in an Over-the-Counter Monograph: Study Elements and Considerations (Final)
General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products (Planned)
Pharmacokinetics in Patients with Impaired Renal Function-Study Design, Data Analysis and Impact on Dosing and Labeling (Planned)
Pharmacogenomic Data Submission (Planned)
Population Pharmacokinetics (Planned)
General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products (Planned)

33. Public Outreach and Engagement
Leveraging Quantitative Methods and Modeling to Modernize Generic Drug Development and Review
Drug Interactions with Hormonal Contraceptives: Public Health and Drug Development Implications
Mechanistic Absorption Modeling and Simulations in Oral Bioequivalent Product Development Workshop
Pediatric Trial Design and Modeling Workshop
Webinar: Section 12 Labeling Guidance
Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting
Extrapolation of Efficacy in Pediatrics Workshop
Primary Pediatric Hypertension Workshop: Epidemiology and Treatment Gaps
Brookings Meeting: Improving Productivity in Pharmaceutical Research and Development: The Role of Clinical Pharmacology
and Experimental Medicine
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34. OCP & DARS Annual Reports Available Online

35. Collaboration Opportunities
Academic Institutions
Collaborative Agreements (e.g., MOU, CRADA)
CDER Network of Experts (NoE) Program
Academic Faculty
Faculty Sabbatical/Scientific Visit Program
Advisory Committees (AC)/Special Government Employee (SGE)
Professional & Graduate Students
Doctor of Pharmacy APPE Rotations
Clinical Pharmacology
Drug Labeling
Student Summer Internships (Salaried)
Professional and Graduate Students
ORISE/Commissioner Fellows
At the AACP Annual Meeting:
FDA will be at Booth 212
Sunday, July 14, 2019 from 3:30 pm to 6:30 pm
Monday, July 15, 2019 from 9:00 am to 1:30 pm
OCP will have a networking session
Monday, July 15, 2019, from 9:00 am to 10:00 am in Monroe Boardroom 1
MOU: NoE: AC: APPE: ORISE:

36. Conclusion Take the first step today!
Clinical pharmacology is well poised to continue to advance drug development and regulatory evaluation
OCP recognizes it is a member of a community and values and fosters quality interactions
There are opportunities to actively (e.g., MOU) or passively (e.g., information) interact and collaborate with OCP
Take the first step today!

37. ACKNOWLEDGEMENTS: Kimberly Bergman, Eric Brodsky, Janelle Burnham, Shiew Mei Huang, Rajanikanth Madabushi, Michael Pacanowski, Sherbet Samuels, David Strauss, Mongthuong Tran, Ping Zhao (Gates Foundation), Issam Zineh.