QuickTime™ and a

TIFF (Uncompressed) decompressor

are needed to see this picture.
Principles of Clinical Pharmacology
NIH, April 26, 2007

Role of FDA in
Guiding Drug Development
Carl Peck
Center for Drug Development Science
UCSF, UC-Washington Center
Washington DC
UCSF-CDDS 2007
 ?
Why FDA ?

When does FDA get involved ?

How does FDA guide drug development?

What comprises FDA guidance ?

What’s new at FDA ?

New ! New !
UCSF-CDDS 2007
 Guiding Drug Development
Why FDA?
• FD&C Act: history and its supporters
– resulted from public safety events or public health
challenges
• ~ 1902/6, 1938, 1962, 1972, 1987, 1997, 2004
– a uniquely American phenomenon
• Evolution of Drug Regulation (R. Temple)

SAFETY EFFECTIVENESS INDIVIDUALIZATION

….. PERSONALIZATION SAFETY
UCSF-CDDS 2007
 When
does FDA get involved ?
• Preclinical (voluntary) phase
– animal testing
– Pre-IND guidance:
• Subpart E, Fast Track, Orphan designations
• Clinical development phase
– IND
• NDA review
• Marketing phase
– ADR surveillance
– new uses, product changes, withdrawals

UCSF-CDDS 2007
 FDA Initiative: Innovation vs Stagnation -
Challenge & Opportunity on the Critical
Path to New Medical Products, March 2004
UCSF-CDDS 2007
 How
does FDA guide drug development?
• Written guidances
– Regulations, guidelines (incl. ICH), guidances1
– Regulatory letters
– (Statute, Congressional Reports)
• Face-to-face meetings
– Pre-IND, EOP2a, EOP2, as-needed
• FDA Advisory Committee meetings
• Podium presentations
1
Website - www.fda.gov
UCSF-CDDS 2007
What comprises FDA guidance ?
• Standards
– chemistry and manufacturing controls (CMC)
– preclinical animal toxicology requirements
– ethics of human clinical trials
– documentary requirements for INDs, & NDAs
– Electronic records (21 CFR part 11)
– Clinical trials
• safety
• effectiveness
• trial design

UCSF-CDDS 2007
 How Many Guidances
and are they Binding ?
•GUIDANCES (http://www.fda.gov/cder/guidance.htm)
– 344 guidances (final/draft, FDA/ICH), 3/31/00
•Guidance documents:
– Cannot legally bind FDA or the public
– Recognizes value of consistency & predictability
– Because a company wants assurance
– So staff will apply statute & regulations consistently

UCSF-CDDS 2007
 Planned Guidances (as of 2000)
100
Guidances by Category
90 Planned
80 To Date
# of Guidances

70
60
50
40
30
20
10
0

Category
UCSF-CDDS 2007
 EXAMPLE 1
Clinical/Pharmacological Guidances
• CDER Comprehensive List of Guidance Documents
(April 2006; n ~ 500)
• Drug Metabolism/Drug Interaction Studies in the Drug
Development Process: Studies In Vitro (97); In Vivo (99)
• Pharmacokinetics in Patients with Impaired Renal
Function (98)
• Population Pharmacokinetics ( 99)
• Exposure-Response (02)
• Exploratory IND Studies (April 2005)
UCSF-CDDS 2007
 EXAMPLE 2
Clinical/Pharmacological Guidances
• General Considerations for Pediatric
Pharmacokinetic Studies for Drugs and
Biological Products

• Pharmacokinetics in Patients With Impaired

Hepatic Function: Study Design, Data
Analysis, and Impact on Dosing and Labeling

UCSF-CDDS 2007
 EXAMPLE 3
Clinical/Medical Guidances
• Providing Clinical Evidence of Effectiveness for
Human Drug and Biological Products (98)

• Study and Evaluation of Gender Differences in the Clinical

Evaluation of Drugs (93)
• Study of Drugs ... used in the Elderly (89)
• Guidance for Institutional Review Boards, Clinical
Investigators, and Sponsors: Exception from Informed
Consent Requirements for Emergency Research

UCSF-CDDS 2007
 EXAMPLE 4
Statutory Guidance:
FDA Modernization Act of 1997
“FDAMA”
• Sec. 111. Pediatric studies of drugs
– PK bridging studies

• Sec. 115a. Clinical investigations

– support of one adequate and well-controlled clinical
investigation by “confirmatory evidence” comprising PK or
PK/PD
UCSF-CDDS 2007
 FDAMA, Sec. 111
Pediatric studies of drugs

“(g) Definitions. - the term `pediatric studies'

or `studies' means at least one clinical
investigation (that .. may include
pharmacokinetic studies) in pediatric age
groups....”

UCSF-CDDS 2007
 Pediatric Labeling Regulations
(21 CFR 201.56)

“FDA may approve a drug for pediatric use based

on ... studies in adults, with other information
supporting pediatric use…. additional
information supporting pediatric use must
ordinarily include data on the pharmacokinetics
of the drug in the pediatric population ….Other
information, such as data on pharmacodynamic
studies…..”
UCSF-CDDS 2007
 FDAMA, Sec. 115a
Clinical investigations

“If the Secretary determines, based on relevant

science,
science that data from one adequate and
well-controlled clinical investigation and
confirmatory evidence …. are sufficient to
establish effectiveness, the Secretary may
consider such data and evidence to constitute
substantial evidence..”

UCSF-CDDS 2007
 FDAMA, Sec. 115a
Clinical investigations

CONGRESSIONAL COMMITTEE
REPORTS1
• “confirmatory evidence” = “scientifically sound data from
any investigation in the NDA that provides substantiation
as to the safety and effectiveness of the new drug”
• confirmatory evidence = “consisting of earlier clinical
trials, pharmacokinetic data, or other appropriate
scientific studies”
1 House Commerce Committee, 10/7/97, and Committee of Conference on
Disagreeing votes of the two Houses, 11/9/97

UCSF-CDDS 2007
 New Formulations and Doses of
Already Approved Drugs *

• Where blood levels ... are not very different, it may be possible to
conclude ... is effective on the basis of pharmacokinetic data
alone.

• Even if blood levels are quite different, if there is a well-

understood relationship between blood concentration and
response, ..., it may be possible to conclude ... is effective on the
basis of pharmacokinetic data without an additional clinical
efficacy trial.

* Guidance for Industry “Providing Clinical Evidence of Effectiveness for Human

Drugs and Biological Products”, May 1998

UCSF-CDDS 2007
UCSF-CDDS 2007
 FDA – what’s new?
• Leadership
– Commissioner Eschenbach, (Henney), (McClellan) (Crawford)
– Deputy Commissioner (Woodcock)
• Initiatives
– Improving drug development
• FDA leadership to improve drug development (2003)
• Critical Path Initiative (2004)
– End-of-Phase 2a (EOP2a) meeting (04)
– Model-based Drug Development (05)
– Critical Path Opportunities List (06)
– Safety
• Drug withdrawals (Vioxx et al) (04)
– Safety Oversight Board (05)
• CBER CDER: protein therapeutics

UCSF-CDDS 2007
 McClellan Initiative (2003):
FDA leadership to improve drug development

• Aims to achieve predictable, 1-cycle NDA/BLA

reviews
– ‘Root cause’ analysis
– Intensified FDA-industry communications
– Continuous marketing application project
– Reviewers and Reviews
• Training
• Review standards
• Peer review
• ‘Quality Systems’ review improvements

UCSF-CDDS 2007
“Academics” Meeting
April 5, 2003

UCSF-CDDS 2007
 How can academics help?
• Investigate ‘root causes’ of inefficient drug development
• Share findings and innovative solutions with FDA
– Causes and remedies for failed phase 3 trials
– Rationale and examples to motivate abandonment of inefficient, costly,
empirical traditional drug development, replacing with a quantitative,
causal-model and simulation approach
• Advance methods for optimization of clinical drug testing
– Learn-confirm approach
– Integration of intensified early clinical pharmacology
– Pharmacometrics - population PK/PD , modeling & simulation of
clinical trials
– Pharmacogenetic guided development
– Effective use of biomarkers and Surrogate Endpoints

UCSF-CDDS 2007
 ‘Academics to CDER’
• History of academic sabbaticals
– Ludden, Weintraub, Amidon, Derendort et al
– Currently - Don Stanski, Bob Powell, Felix Frueh
• Woodcock’s ‘Academics to CDER’ courses
– PK/PD (x2), pharmacogenomics, QT , safety,
scientific basis of drug development

UCSF-CDDS 2007
UCSF-CDDS 2007
10 year Trend in Biomedical R&D Spending

US Pharmaceutical R&D

Total NIH Budget

UCSF-CDDS
Adapted 2007
from J. Cossman: “The Critical Path
Institute” 2007 & FDA Critical Path Initiative 2004
10 year Trend in New Applications to FDA

New Drug Applications

New Biological Applications

UCSF-CDDSAdapted
2007 from J. Cossman: “The Critical Path
Institute” 2007 & FDA Critical Path Initiative 2004
 Prototype FDA Filing/
Basic Design or Preclinical Approval &
Research Development Clinical Development
Discovery Launch

Market
Application Approval

CRITICAL PATH

Adapted from S. Buckman:

“Biomarkers 101”, RAPS, 2006
UCSF-CDDS 2007
 Guiding Principles
of Critical Path Initiative
• Coordinate collaborative efforts among government,
academia, industry & patient groups
• Encourage “toolkits” for better product development,
safety, medical utility & manufacturing
• Build support for academic science bases in relevant
disciplines
• Build opportunities to share existing knowledge &
databases
• Develop enabling standards
Adapted from S. Murphy: “FDA Update on Critical
Path Initiative”, RAPS 2006, & FDA Critical Path
Initiative 2004
UCSF-CDDS 2007
 Organization of Critical Path
Initiative within FDA
• Commissioner’s Office: Office of Critical
Path Programs
– Critical Path Steering Committee
• CDER: Office of Translational Sciences
– Clinical Pharmacology
– Biostatistics
– Critical Path Initiatives
– Intramural Research

UCSF-CDDS 2007
UCSF-CDDS 2007http://www.fda.gov/oc/initiatives/criticalpath/
UCSF-CDDS 2007
 Executive Summary
Six Priority Public Health Challenges
• Biomarker development
• Streamlining clinical trials
• Bioinformatics
• Efficient, quality manufacturing
• antibiotics and countermeasures to combat
emerging infections and bioterrorism
• Developing therapies for children and
adolescents
UCSF-CDDS 2007
UCSF-CDDS 2007
UCSF-CDDS 2007
UCSF-CDDS 2007
UCSF-CDDS 2007
 UCSF-CDDS 2007
http://www.fda.gov/oc/initiatives/criticalpath/opportunities06.html
Critical Path Collaborations with NIH
• Joint workshops with FDA
– Genetic basis of Adverse Events –December
11&12, 2006
– Imaging in Alzheimer’s Disease

• Drug development education for NIH

– NIAID
– National Institute on Aging
– Individual Scientist Assistance

UCSF-CDDS 2007
 Public/Private Partnerships - I
• Predictive Safety Testing Consortium
– CDER-OCP, CPath Institute, 15 pharma firms
– Pre-clinical toxicogenomic biomarkers
• Nephrotoxic biomarkers expected early 07
• Biomarker Consortium
– NIH/ PhRMA/ FDA/CMS
– regulatory pathway for biomarker validation
• FDG-PET in NHL
• Oncology Biomarker Qualification Initiative
– FDA, NCI and CMS
• Microarray Quality Consortium
• Duke/FDA ECG Collaboration

UCSF-CDDS 2007
 Public/Private Partnerships - II
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.

“American Course on Drug Development

and Regulatory Science”
Website: http://acdrs.ucsf.edu

Ellen G. Feigal, M.D.

Course Director

University of California, San Francisco

Department of Biopharmaceutical Sciences/CDDS
 “ACDRS” Vision and Mission
• Modernization of development and regulation of medical
products via

– Certified, comprehensive instruction

– Integration of cutting-edge concepts

– Best practices in medical product development and regulatory

sciences
 “ACDRS” Emphases
• Three Principles of Optimal Development
– Learn-Confirm Approach
– Regulatory Collaboration
– Efficient Program Execution
 “ACDRS” Faculty and Teaching
Methods
• International faculty network from universities, companies, and
regulatory authorities
– Experts in regulatory sciences, medical product discovery and
development, product evaluation and business practices

• Teaching methods
– Lectures
– Workshops
– Panel discussions
– Team-oriented case studies
– Interactive learning
– Accreditation and credit, and certifying examination
 The Launch

• East and West coasts

– Washington DC in September 2007

• CDDS, FDA

– San Francisco in September 2008

• UCSF Mission Bay Campus
 Critical Path Initiative Projects
that impact Exploratory Clinical
Development - two examples

Exploratory IND

End-of-Phase 2a Meeting

UCSF-CDDS 2007
UCSF-CDDS 2007
 Goals of the Exploratory IND
• Reduce time & resources on drugs unlikely
to succeed
– Select most likely to succeed from group of
candidate drugs
– To learn PK, biodistribution, mechanism of
action
– Reduced preclinical requirements due to less risk

UCSF-CDDS 2007
 Exploratory IND
• “Phase 0” studies – prior to traditional drug
development Phase I trials

• Microdose, sub-pharmacologic or
pharmacologic dose
– Single dose or limited period of administration

UCSF-CDDS 2007
Types of Exploratory Studies
• Single Dose
– PK, Imaging
• Multiple Dose
– Pharmacological, Pharmacodynamic
endpoints
• CMC
– GLP (+/-)
– Summary report

UCSF-CDDS 2007
 Requirements
• CMC
– GLP (+/-)
– Incomplete impurity profile
– Summary report
• Toxicology - depends upon goal
– Single Dose - 1/100 est. pharmacological dose or < 100 ug
• Single species (rodent), 14 day observation
– Multiple Dose (<1/50 NOAEL + max 1/4 of 2 wk NOAEL)
• Two species, 14 day repeat dose

UCSF-CDDS 2007
UCSF-CDDS 2007
UCSF-CDDS 2007
End of Phase 2a meeting

Two Year’s Experience Reviewed at

FDA Pharmaceutical Sciences Advisory
Committee Meeting, November 14, 2005
http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_Slide-Index.htm

UCSF-CDDS 2007
 End of Phase 2a Meetings
• Purpose:
Purpose ↓ Late phase clinical trial (2b, 3) unnecessary failure
• Format:
Format non-binding scientific interchange. Marketing issues should be in the
development plan, not at this meeting
• Deliverables:
Deliverables
– Perform modeling (relevant phase 1/2a data) & simulation of next trial design
employing
• Mechanistic or empirical drug-disease model
• Literature estimates for comparative drug effects if relevant
• Placebo effect (magnitude & time-course)
• Rates for dropout and compliance. (prior FDA experience)
– Recommendation on sponsors trial design + alternative including patient selection,
dosage regimen,…
– Code from FDA work, Sponsor can extend work (EOP2, NDA)
– Answers to other questions from the clinical and clinical pharmacology
development plan
• Time-course:
Time-course ~ 6 weeks
• Key sponsor & FDA participants:
participants physician, biostatistician, clinical
pharmacology (pharmacometrics), project management

Adapted from R. Powell, FDA

UCSF-CDDS 2007
 End of Phase 2a Meetings
current status*
• Completed 12-15 EOP2a meetings
• Mixed, mostly positive value
• Suspending EOP2a ‘experiment’
– Resource issue
– Functional EOP2a meetings permitted as ‘Type C’
– Important to notify OCPB to ensure FDA clin pharm
involvement

* Bob Powell, LBS Symposium

December 5, 2006
UCSF-CDDS 2007
 Of about a total of 244 NDAs,
42 included a pharmacometrics component….

Pharmacometric analyses were pivotal in regulatory

decision making in more than half of the 42 NDAs.

Of 14 reviews that were pivotal to approval decisions,

… 6 reduced the burden of conducting additional trials.

UCSF-CDDS 2007
 PM analyses were ranked as important in
regulatory decision making in over 85% of the 31 NDAs.
UCSF-CDDS 2007
 Model Based Drug Development
What is it?
• Model: mathematical explanation of relationships thought to
explain outcome over time period of interest
• Drug-Disease Model (empiric & mechanistic)
• Disease model: relationship of patient (e.g., gender, age, genotype),
biomarker (e.g., biochemical, imaging) relationship to disease
morbidity and mortality
• Drug-Disease model: addition of drug (dose, concentration,
combination, placebo) and patient (e.g., size, age, adherence,
dropout) effects and adverse effects to the disease model
• Simulation-
Simulation Target
• Clinical trial design- optimal
– New designs-enrichment, randomized withdraw, adaptive
• Dosage regimen(s) selection
• Go/No go- Sponsor &/or FDA
• Labeling- Sponsor &/or FDA
UCSF-CDDS 2007 R. Powell, FDA
 Model Based Drug Development :
Drug, Efficacy (Potency) & Safety Information
SELECT DESIGN DECIDE
D EOP2
Pre-IN EO
Late P2
IND a NDA
Discovery Pre-Clinical Phase I Phase II Phase III

a:Proof of Principle b:Dose Ranging

•Clinical Development Plan •Support approval

• Provide comments on
Recommendations • Approve Phase III trial
Phase IIb & III trial designs decision based on cross-
• Quantitate drug effect design or recommend
trial efficacy & safety
based on modeling &
& disease progression alternative designs basedanalysis
modeling on for:
clinical trial simulation
(biomarker strategy) modeling including• IIb trialapproval
Drug
• Estimate dose-response
• Define Proof of results & trial simulation
• Label dosage
• Propose bridging strategy
Concept criteria regimen & claims
for subpopulations
• Phase I-IIa Study Plans • Phase IV
• Criteria for risk commitments
assessment
• Data submission
format
UCSF-CDDS 2007 R. Powell, FDA
 Universities’ Responses to
‘Critical Path’ Initiative
• UCSF - “JETS” “ACDRS”

• U Arizona - “CPATh Institute”

• SUNY Buffalo - “CE-PK/PD”

• U Indiana - “ICIS”

UCSF-CDDS 2007
 SOME FINAL OBSERVATIONS
• FDA clinical guidances are increasingly based on
principles of clinical pharmacology
• “guidance” versus “regulation”
– value added versus barrier
• FDA guidance
– national “treasure” versus “national nuisance”
– a bargain !
• Value of FDA guidance is related to the quality of
sponsor data and preparation

UCSF-CDDS 2007