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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 ?

New ! Whats new at FDA ? 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
 # of Guidances

100

0
10
20
30
40
50
60
70
80
90
Adve
rtisi ng
Biop
harm
Chem
istry
Clin
Antim
ic
Clin
Med
Clin
Phar
m
Com
plian
ce
Elec
Subm
Gene
ric
ICH

Category
Indu

UCSF-CDDS 2007
stry
Labe
ling
Guidances by Category

OTC
Phar
m/To
x
Proc
dura
l
User
Fee
Planned Guidances (as of 2000)

To Date
Planned
 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 UCSF-CDDS
Studies (April 2005)
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....

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 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, 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 whats 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
Woodcocks 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

Adapted 2007
UCSF-CDDS 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
Commissioners 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
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UCSF-CDDS 2007
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 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 Alzheimers 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
 QuickTime and a
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Public/Private Partnerships - II

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

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 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 Years 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: Late phase clinical trial (2b, 3) unnecessary failure
Format: non-binding scientific interchange. Marketing issues should be in the
development plan, not at this meeting
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: ~ 6 weeks
Key sponsor & FDA participants: physician, biostatistician, clinical
pharmacology (pharmacometrics), project management

Adapted from R. Powell, FDA

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 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- 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
Late IND 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