Transcript Role of FDA in Guiding Drug Development Carl Peck

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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
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?
Why FDA ?
When does FDA get involved ?
How does FDA guide drug development?
What comprises FDA guidance ?
New ! What’s new at FDA ? New !
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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
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SAFETY
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
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FDA Initiative: Innovation vs Stagnation Challenge & Opportunity on the Critical
Path to New Medical Products, March 2004
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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
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Website - www.fda.gov
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
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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
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# of Guidances
Planned Guidances (as of 2000)
Guidances by Category
Planned
To Date
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
Studies2007(April 2005)
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
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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
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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
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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…..”
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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..”
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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
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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 wellunderstood 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
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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
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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
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“Academics” Meeting
April 5, 2003
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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
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‘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
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10 year Trend in Biomedical R&D Spending
US Pharmaceutical R&D
Total NIH Budget
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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
Basic
Research
Prototype
Design or
Discovery
Preclinical
Development
Clinical Development
Market
Application
CRITICAL PATH
Adapted from S. Buckman:
“Biomarkers 101”, RAPS, 2006
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FDA Filing/
Approval &
Launch
Approval
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
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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
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UCSF-CDDS 2007http://www.fda.gov/oc/initiatives/criticalpath/
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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PM analyses were ranked as important in
regulatory decision making in over 85% of the 31 NDAs.
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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
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R. Powell, FDA
Model Based Drug Development :
Drug, Efficacy (Potency) & Safety Information
SELECT
Late
Discovery
DESIGN
DECIDE
IND
Pre-Clinical
NDA
Phase I
Phase II
a:Proof of Principle
Phase III
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
on
modeling
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
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R. Powell, FDA
Universities’ Responses to
‘Critical Path’ Initiative
• UCSF - “JETS”
“ACDRS”
• U Arizona - “CPATh Institute”
• SUNY Buffalo - “CE-PK/PD”
• U Indiana - “ICIS”
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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
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