# Presentation: 090495

## Role of FDA in Guiding Drug Development

**Carl Peck**
**Center for Drug Development Science**
- UCSF, UC-Washington Center
- Washington DC

-  **Principles of Clinical Pharmacology**
**NIH,**** ****April 26, 2007**

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## ?

_***Why***_** FDA ?**
_***When***_** does FDA get involved ?**
_***How***_** does FDA guide drug development?**
_***What***_ **comprises FDA guidance ?**
**What’s new at FDA ?**

**New !**

**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        SAFETY ***

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## 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), guidances****1**
**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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## 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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## Planned Guidances (as of 2000)

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## 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)***

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## 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. __***Pediatri***__**c**__ 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 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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## Slide 19

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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

**“****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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## Slide 25

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## US Pharmaceutical R&D

**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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## 10 year Trend in New Applications to FDA

**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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## Stagnation

- PrototypeDesign orDiscovery

- Clinical Development

- BasicResearch

- FDA Filing/
- Approval &Launch

- PreclinicalDevelopment

- MarketApplication

- Approval

***CRITICAL PATH***

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

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## Guiding Principles of Critical Path Initiative

**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 ****of 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 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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## http://www.fda.gov/oc/initiatives/criticalpath/

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## Slide 32

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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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## Slide 34

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## Slide 35

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## Slide 36

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## Slide 37

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## http://www.fda.gov/oc/initiatives/criticalpath/opportunities06.html

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## 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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## “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***

**Public/Private Partnerships - II**

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## “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**** **

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## “ACDRS” Emphases 

**Three Principles of Optimal Development**
***Learn-Confirm Approach***
***Regulatory Collaboration***
***Efficient Program Execution***

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## “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**

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## 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 Projectsthat impact Exploratory Clinical Development - two examples

**Exploratory IND**
**End-of-Phase 2a Meeting**

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## Slide 47

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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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## Slide 52

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## Slide 53

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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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## 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

**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 Meetings*****current status****

- * Bob Powell, LBS Symposium
- December 5, 2006

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## Of about a total of 244 NDAs,  

- 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 

- 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**

**R. Powell, FDA**

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

**Late Discovery**

**Pre-Clinical**

**Phase I**

**Phase II**

**Phase III**

***NDA***

***IND***

**a:Proof of Principle**

**b:Dose Ranging**

**DESIGN**

**DECIDE**

**SELECT**

**EOP2**

**EOP2a**

- Pre-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 ‘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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