UCSF-CDDS 2007

Role of FDA in Role of FDA in Guiding Drug DevelopmentGuiding Drug Development

Carl PeckCenter for Drug Development Science

UCSF, UC-Washington Center

Washington DC

Principles of Clinical PharmacologyPrinciples of Clinical PharmacologyNIH,NIH, April 26, 2007April 26, 2007

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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 ! New !New !

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Guiding Drug DevelopmentGuiding Drug Development

WhyWhy FDA? 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

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WhenWhen does FDA get involved ?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 CriticalPath to New Medical Products, March 2004

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HowHow does FDA guide drug development?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

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WhatWhat comprises FDA guidance ?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 GuidancesHow Many Guidancesand are they Binding ?and are they Binding ?

•GUIDANCES (http://www.fda.gov/cder/guidance.htm)

– 344 344 guidancesguidances (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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Planned Guidances (as of 2000)

Guidances by Category

0102030405060708090

100

Category

# of

Gu

idan

ces

PlannedTo Date

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EXAMPLE 1EXAMPLE 1Clinical/Pharmacological GuidancesClinical/Pharmacological Guidances

• CDER Comprehensive List of Guidance CDER Comprehensive List of Guidance DocumentsDocuments (April 2006; n ~ 500)(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)Population Pharmacokinetics ( 99)• Exposure-Response (02)Exposure-Response (02) • Exploratory IND Studies (April 2005)Exploratory IND Studies (April 2005)

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EXAMPLE 2EXAMPLE 2Clinical/Pharmacological GuidancesClinical/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 3EXAMPLE 3Clinical/Medical GuidancesClinical/Medical Guidances

• Providing Clinical Evidence of Effectiveness for Providing Clinical Evidence of Effectiveness for Human Drug and Biological ProductsHuman Drug and Biological Products (98) (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 4EXAMPLE 4Statutory Guidance: Statutory Guidance:

FDA Modernization Act of 1997FDA Modernization Act of 1997“FDAMA“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 FDAMA, Sec. 111 PediatriPediatricc studies of drugs 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 RegulationsPediatric Labeling Regulations(21 CFR 201.56)(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. 115aFDAMA, Sec. 115a Clinical investigationsClinical investigations

“If the Secretary determines, based on based on relevant relevant sciencescience, that data from oneone adequate and adequate and well-controlled clinical investigationwell-controlled clinical investigation and confirmatory evidenceconfirmatory evidence …. are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence..”

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FDAMA, Sec. 115aFDAMA, Sec. 115aClinical investigations Clinical investigations

CONGRESSIONAL COMMITTEE CONGRESSIONAL COMMITTEE REPORTSREPORTS11

• ““confirmatory evidenceconfirmatory evidence”” = “scientifically sound data “scientifically sound data from any investigationfrom 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, pharmacokineticpharmacokinetic 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 New Formulations and Doses of Already Approved DrugsAlready 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

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FDA – what’s new?FDA – what’s new?• Leadership

– Commissioner Eschenbach, (Henney), (McClellan) (Crawford) – Deputy Commissioner (Woodcock)

• Initiatives – Improving drug development

• FDA leadership to improve drug development (2003)FDA leadership to improve drug development (2003)• Critical Path Initiative (2004)Critical Path Initiative (2004)

– End-of-Phase 2a (EOP2a) meeting (04)End-of-Phase 2a (EOP2a) meeting (04)– Model-based Drug Development (05)Model-based Drug Development (05)– Critical Path Opportunities List (06)Critical Path Opportunities List (06)

– Safety• Drug withdrawals (Vioxx et al) (04)

– Safety Oversight Board (05)Safety Oversight Board (05)

• CBER CDER: protein therapeutics

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McClellan Initiative (2003): McClellan Initiative (2003): FDA leadership to improve drug developmentFDA 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” MeetingApril 5, 2003

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How can academics helpHow 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’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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US Pharmaceutical R&D

Total NIH Budget

10 year Trend in Biomedical R&D Spending

Adapted from J. Cossman: “The Critical Path Institute” 2007 & FDA Critical Path Initiative 2004

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New Drug Applications

New Biological Applications

10 year Trend in New Applications to FDA

Adapted from J. Cossman: “The Critical Path Institute” 2007 & FDA Critical Path Initiative 2004

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PrototypeDesign orDiscovery

Clinical DevelopmentBasicResearch

FDA Filing/Approval &Launch

PreclinicalDevelopment

MarketApplication Approval

CRITICAL PATH

Adapted from S. Buckman: “Biomarkers 101”, RAPS, 2006

UCSF-CDDS 2007

• 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

Guiding Principles Guiding Principles of Critical Path Initiativeof Critical Path Initiative

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 Organization of Critical Path Initiative within FDAInitiative 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 2007http://www.fda.gov/oc/initiatives/criticalpath/

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Executive SummaryExecutive Summary Six Priority Public Health Challenges Six Priority Public Health Challenges

• BiomarkerBiomarker development• Streamlining clinical trialsclinical trials• BioinformaticsBioinformatics• Efficient, quality manufacturingmanufacturing• antibiotics and countermeasures to combat

emerging infectionsinfections and bioterrorismbioterrorism• Developing therapies for children and children and

adolescentsadolescents

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UCSF-CDDS 2007http://www.fda.gov/oc/initiatives/criticalpath/opportunities06.html

UCSF-CDDS 2007

Critical Path Collaborations with NIHCritical 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 - IPublic/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

““American Course on Drug Development American Course on Drug Development and Regulatory Science”and Regulatory Science”

Website: http://acdrs.ucsf.eduWebsite: http://acdrs.ucsf.edu

Ellen G. Feigal, M.D.Ellen G. Feigal, M.D.

Course Director

University of California, San FranciscoDepartment of Biopharmaceutical Sciences/CDDS

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are needed to see this picture. Public/Private Partnerships - IIPublic/Private Partnerships - II

““ACDRS” Vision and MissionACDRS” 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 ACDRS” Emphases

• Three Principles of Optimal Development

– Learn-Confirm ApproachLearn-Confirm Approach

– Regulatory CollaborationRegulatory Collaboration

– Efficient Program ExecutionEfficient Program Execution

““ACDRS” Faculty and Teaching ACDRS” Faculty and Teaching MethodsMethods

• 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 The Launch

• East and West coasts

– Washington DC in September 2007• CDDS, FDA

– San Francisco in September 2008• UCSF Mission Bay Campus

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Critical Path Initiative ProjectsCritical Path Initiative Projectsthat impact Exploratory Clinical that impact Exploratory Clinical

Development - two examplesDevelopment - two examples

Exploratory IND

End-of-Phase 2a Meeting

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Goals of the Exploratory INDGoals 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 INDExploratory 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 StudiesTypes of Exploratory Studies

• Single Dose– PK, Imaging

• Multiple Dose– Pharmacological, Pharmacodynamic

endpoints

• CMC– GLP (+/-)– Summary report

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RequirementsRequirements• 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 meetingEnd of Phase 2a meeting

Two Year’s Experience Reviewed at FDA Pharmaceutical Sciences AdvisoryCommittee 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 MeetingsEnd of Phase 2a Meetings• PurposePurpose: ↓ Late phase clinical trial (2b, 3) unnecessary failure• FormatFormat: non-binding scientific interchange. Marketing issues should be in the

development plan, not at this meeting• DeliverablesDeliverables:

– 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-courseTime-course: ~ 6 weeks• Key sponsor & FDA participantsKey sponsor & FDA participants: physician, biostatistician, clinical

pharmacology (pharmacometrics), project management

Adapted from R. Powell, FDA

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• 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

End of Phase 2a MeetingsEnd of Phase 2a Meetingscurrent status*current status*

* Bob Powell, LBS SymposiumDecember 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 DevelopmentModel Based Drug DevelopmentWhat is it?What is it?

• ModelModel: mathematical explanation of relationships thought to explain outcome over time period of interest

• Drug-Disease ModelDrug-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

• SimulationSimulation- 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

R. Powell, FDA

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Model Based Drug Development : Model Based Drug Development : Drug, Efficacy (Potency) & Safety InformationDrug, Efficacy (Potency) & Safety Information

Late Discovery Pre-Clinical Phase I Phase II Phase III

NDAIND

a:Proof of Principle b:Dose Ranging

DESIGN DECIDESELECTEOP2

EOP2a

Pre-INDPre-IND

•Clinical Development Plan Recommendations

• Quantitate drug effect & disease progression (biomarker strategy)• Define Proof of Concept criteria• Phase I-IIa Study Plans• Criteria for risk assessment• Data submission format

• Provide comments on Phase IIb & III trial designs based on modeling & clinical trial simulation• Estimate dose-response• Propose bridging strategy for subpopulations

• Approve Phase III trial design or recommend alternative designs based on modeling including IIb trial results & trial simulation

•Support approval decision based on cross-trial efficacy & safety modeling analysis for:

• Drug approval• Label dosage regimen & claims• Phase IV commitments

R. Powell, FDA

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Universities’ Responses to Universities’ Responses to ‘Critical Path’ Initiative‘Critical Path’ Initiative

• UCSF - “JETS”“JETS” “ACDRS”“ACDRS”

• U Arizona - “CPATh Institute”“CPATh Institute”

• SUNY Buffalo - “CE-PK/PD”“CE-PK/PD”

• U Indiana - “ICIS”“ICIS”

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SOME FINAL OBSERVATIONSSOME 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