November 5, 2004 CDER Critical Path Opportunities 1

CDER Critical PathOpportunities

Douglas C. Throckmorton, M.D.November 5, 2004

November 5, 2004 CDER Critical Path Opportunities 2

OutlineCritical Path in CDER

Identified Critical Path opportunities in CDER

Examples of proposed opportunities

November 5, 2004 CDER Critical Path Opportunities 3

CDER Goals for 2005

HHS Strategic

Goals

CDERInitiatives

FDAStrategic

Goals

Achieve Excellence

in Management Practices

Increase Science

Enterprise Research

Improve Quality of

Health Care Services

Enhance health care system to

respond to bioterrorism

and other public health challenges

StrongFDA

RiskManagement/

Innovation

PatientSafety

BetterInformed

Consumers

ProtectingAgainst

Terrorism

QualitySystem

StrategicObjectives

CGMPsCritical

Path

StructuredProductLabeling

CounterTerrorism

Efforts

Follow-on

Biologics

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Identified Critical Path Opportunities in CDER

November 5, 2004 CDER Critical Path Opportunities 5

CDER Critical Path OpportunitiesCDER received around 60 written proposals with variable levels of detail. Two types of proposals:(1) Issues Addressable with FDA Data & Resources

Goals: Data review and analysis to facilitate guidance and standards-setting

(2) Longer-Term Projects Related to new, complex issues in drug developmentRely more on external sources of expertise and dataGoals: Identify sources of expertise, work towards guidance and standards-setting

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Proposals from All 3 Key Dimensions on 'Critical Path' of Development

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CDER Critical Path OpportunitiesData Review and Analysis to Facilitate Guidance and Standards-Setting

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Assessing SafetyDevelopment of Safety Biomarkers/Surrogates

Database on pre-clinical and clinical evaluation of arrhythmic risk; Search for pre-clinical markers to reduce/eliminate need for clinical studies

Data warehouse of electronic electro-cardiograms (ECGs) accessible by Industry and FDA

Databases to facilitate rodent models of carcinogenicity, genotoxicity, and reproductive/ developmental toxicology

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Assessing Safety (continued)

Develop database of existing Controlled Substances Staff recommendations on product abuse liability

Develop a centralized approach to monitor outcomes of exposure to drug products during pregnancy

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Demonstrating Medical Utility(Proof of Efficacy)

Development of Efficacy Biomarkers/Surrogates Development and evaluation of new rapid diagnostic tests for infectious diseaseDevelopment of vascular imaging techniques in development of drugs for neuro-cognitive disorders, cardiovascular disease, and depression Assessment of imaging techniques (e.g., MRI) in development of drugs for rheumatoid arthritis and osteoarthritis Assessment of novel biomarkers and clinical surrogates for Systemic Lupus Erythematosus, Inflammatory Bowel Disease, and Sepsis. Evaluate degree of correlation of Hepatitis C viral load in blood with histologic findings of the liver in Hepatitis C disease to assess potential utility of Hepatitis C as a surrogate marker in clinical trials.

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Demonstrating Medical Utility (cont) (Proof of Efficacy)

Develop data driven model for prediction of bioavailability/ bioequivalence from data on drug dissolution

Facilitate or conduct investigations to better define the benefit and risk components and to improve trial designs of clinical investigations for menopausal symptom therapy

Develop library of pharmacogenomic variation to enrich clinical studies of antidepressant drugs in the pediatric population

November 5, 2004 CDER Critical Path Opportunities 12

IndustrializationDevelop methods to assess comparability of biologic products, including following manufacturing changes (e.g., changes in cell culture conditions):

Use of Gene arrays to assess impact of changes

‘Follow-on Biologics’

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CDER Critical Path Opportunities

Guidance and Standards-Setting in New Areas of Drug Development

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New Areas of Drug Development

Develop Statistical guidance applicable to multiple therapeutic areas

Non-inferiority testing, Bayesian methods, Missing data, and Adaptive trial designs

Create a new framework for understanding product manufacturing and assessment within the ‘Context of Complexity of Products and Manufacturing Processes’

Develop instrument calibration standards

Evaluate statistical methods to supplement pre-clinical safety data: bootstrap methodologies and re-sampling

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New Areas of Drug Development (continued)

Develop guidance pertaining to patient-reported outcomes (PRO) endpoints in phase III studies

Develop adequate analytical methods to fully characterize novel dosage forms

e.g., liposomes, patches, topicals, inhalants

Determine bioequivalence of locally-acting drug products

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CDER Critical PathNear-Term Opportunities

Examples…

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ECG Research Database and Toolkit (Assessing Safety)

Needs: To improve FDA’s ability to evaluate drugs for cardiac safety To enhance efficiency of ECG data collection and submission

Goals:Develop standard for electronic exchange of ECGsDevelop ECG research database and web-based toolSupport development of clear standards, guidance, and tools to test and guide development of product safety

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ECG Research Database and Toolkit (continued)

Contributes to:A more efficient assessment of cardiac risk

Increases ability of sponsors to predict success and failure in earlier stages of product development

identification of novel ECG markers to predict clinical toxicity

Lower costs for new product developmentmore efficient ECG data collection and submission

Increases ability of sponsors to produce high quality products and applications

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ECG Research Database and Toolkit (continued)

Target timeline:Completion of database tool and database: <12 months

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Pediatrics Trial Database Development and Analysis (Demonstrating Medical Utility)

Needs: To evaluate the assumptions used to design pediatric drug studies

Goals:Develop analytic database of pediatric trials conducted since initiation of pediatric exclusivity and Best Pharmaceuticals for Children Act (BPCA)Assess appropriateness for extrapolation of safety and efficacy data from adults to childrenDetermine best practices for novel trial designsDevelop guidance for future pediatric trials based on this review

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Pediatrics Trial Database(continued)

Contributes to:Increased interest in and feasibility of product development for unmet public health needs

Increased sponsor ability to produce high quality products and applications

Target Timeline:Develop analytical database (12-24 months)

Determine best practices (24-36 months)

Discuss and publish guidance on best practices (36-48 months)

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Instrument Calibration Guidance (Industrialization)

Needs: Expand concept of product quality by designFacilitate more efficiently produced and consistently formulated drug productsProactively support the use of new instrumental methods for drug manufacture as described in CGMP initiative

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Instrument Calibration Guidance (continued)

Goals:Develop methods for defining and validating calibration standards

Develop instrument calibration standards

Publish guidance describing standards

Provide training to CDER staff on new instrumentation and standards

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Instrument Calibration Guidance(continued)

Contributes to:Increase FDA Utilization of Quality by Design and Risk-Based Assessment in Product Quality Review by promoting the use of novel analytic methods to assess manufacturing quality and consistency

Reduce Likelihood of Production of Low Quality Products by promoting consistent use of new technology in ensuring quality of products

Maintain Low Risk of Defective and Contaminated Products Reaching Market

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Instrument Calibration Guidance(continued)

Target Timeline:Research and identify candidate instrument reference standards (12 months)

Conduct studies on instrumentation (12-24 months)

Discuss and publish guidance (36 months)

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CDER Critical Path SummaryPresent state of health product development is not sustainable

FDA must lead effort to question any assumptions that limit or slow new product development:

Are they justified?

Are there more efficient alternatives?

If so, why are the alternatives not being utilized?

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CDER Critical Path Summary

Critical Path is integrated into the CDER goals

CDER has identified a preliminary list of Critical Path opportunities that will have substantial impact if funded