Quality Systems for Clinical Pharmacology and Biopharmaceutics Review Lawrence J. Lesko, Ph.D. Director, Office of Clinical Pharmacology and Biopharmaceutics (OCPB) Center for Drug Evaluation And Research Food and Drug Administration FDA Science Board Rockville, Maryland April 9, 2003

Outline of Topics Organization and Responsibilities Quality Systems Approach to Reviews Benefits to Customers Metrics of Improvement Future Goals

OCPB Organizational Chart Down to Divisions and Teams

Demographics of Scientific Staff All have advanced degrees –many with post-doctoral experience –several with dual degrees Recruitment –Colleges of Pharmacy –Clinical Pharmacology Training Programs –Schools of Medicine Current Staffing –95 (70 reviewers)

Definition: Clinical Pharmacology Clinical Pharmacology –science dealing with human properties of the drug substance after release from a dosage form, and nonclinical characteristics of the drug substance that relate to human properties –examples pharmacokinetics (ADME properties) in healthy volunteers or patients with renal disease solubility and permeability (absorption)

Definition: Biopharmaceutics Biopharmaceutics –science dealing with in vivo performance of the drug product and in vitro properties that relate to it –examples bioavailability (% absorbed) or bioequivalence rate of dissolution of drug product

Hierarchy of Scientific Categories Data: raw measurements –dissolution, plasma levels, Cmax, AUC, biomarkers, observational Information: processed data (who, what, when, where) –address relational connections to formulations (dissolution, food effects) and intrinsic and extrinsic patient factors (gender, age, disease, drugs), confirmatory Knowledge: application of information (how) –optimize dosage form, minimize risks, adjust dosing, and label products, interpolative and probabilistic –prerequisite of effective risk management Understanding: synthesize new information (why) –mechanistic modeling and simulation, sensitivity analysis, predictive and extrapolative

The Drug Development Process Provides Data and Information DiscoveryPhase IPhase IIPhase IIIApprovalMarket Nonclinical IND NDA Clinical Pharmacology solubility, permeability, metabolism ADME, single and multiple dose PK exposure-response relationships special population PK/PD initial and adjusted dosing regimens Biopharmaceutics formulation and in vitro dissolution BA, dose proportionality in vitro-in vivo relationships BA changes in special populations BE of to-be-marketed formulations

The Regulatory Review Process Converts Data to Customer-Related Knowledge Reviewer becomes an interpreter –assess all data, but selectively analyze some –discern factors most likely to impact efficacy and safety –identify what data are missing –emphasize mechanistic understanding at all levels –translate science into therapeutics (risk/benefit) Primary science focus on adverse effect risk –exposure-response relationships –drug-drug interactions –use of new technology and evolving science

Quality Systems Approach to Review: Internal Customer Needs and Expectations A systems approach involves placing as much emphasis on reviewing and describing the connections between data and studies as on reviewing and describing the data and studies themselves. Good Review Practices 1. Generate knowledge 2. Be Decision Makers 3. Know Patient Context 4. Recognize Medical Need 5. Communicate clearly

GRP Based on the Question-Based Review Focus on questions, not studies Integrate nonclinical and clinical data Address key safety and efficacy issues Critically assess evidence supporting label claims Manage risks using label language June 1999

Timeline for GRP

5 Quality Subsystems of a Systems Approach NDA Clin Pharm/Biopharm Briefing GRP/QBR: Clin Pharm/Biopharm Review (Template) Domestic and International Guidances Science and Process MAPP’s and Decision Trees NDA Clin Pharm/Biopharm Briefing Package Standardize order and placement of subject matter, not content Review Standards Scientific Policies Executive summary, key review issues, unresolved questions, recommendations Draft review posted on OCPB intranet Uniformity and consistency TL Meetings Formal presentation, interdisciplinary audience interactive dialogue, finalize review

Internal Customer Needs and Expectations and Benefit to Reviewers Standardized method of delivering a comprehensive CP/BP review (quality) Meet, usually exceed, and frequently anticipate customer expectations (trust) Greater ability to derive clinical inferences from CP/BP data (communication) Enhanced critical thinking of reviewers through question-based review (efficiency) Better able to recognize deficiencies in CP/BP data set (confidence)

CPBP Briefing: Critical Component of Quality System Presentation compels reviewers to think more about their review –increased individual accountability –pride of ownership Feedback from attendees is critical to continual learning (knowledge sharing) –greater consideration of comments before speaking Briefing aids new reviewers or those with weaker backgrounds –good teaching tool, professional growth

Health Professionals Patients Quality Systems Approach to Review: External Customer Needs and Expectations “…drug interactions represent 3-5% of preventable ADRs and are an important contributor to ER visits and hospital admissions.” JAMA 1995;274(1):35–43 “Top two concerns of patients in primary medical care: 62% worry about being given the wrong drug and 59% worry about being given drugs that interact” ASHP Patient Concerns National Survey Research Report, 1999 ASHP Patient Concerns National Survey Research Report, 1999

The Work Product: Delivery of Prescribing Information in the Label Past: drug interaction section –fact-based changes in PK (AUC, Cmax) –many potentially harmful drug combinations –often poorly utilized by “customers” difficult to find in the label descriptive terminology inconsistent and unclear clinical significance uncertain

Bringing Added Value to the Work Product: Improved Labels Future: drug interaction information –fact-based changes in PK (AUC, Cmax) –prominent warning near top of label –common language to describe interactions classification of metabolic inhibition or induction –standard method to assess clinical significance analysis of PK changes using E/R relationships express results in terms of odds ratio or probability –will survey customers to assess value

Metrics of Process Improvement Since Introducing QBR/GRP Consistent format of review packages across Divisions –very readable (various levels of detail) and predictable High quality NDA CPBP briefings that address issues relevant to therapeutics –more informative questions of the sponsor data –increase in attendance by MO’s and other disciplines –greater OCPB staff participation in AC meetings Greater recognition of expertise and leadership –frequent requests from OND for more reviewers –additional invitations to speak at advisory committee meetings –increased role in industry meetings

Metrics of Science Improvement Since Introducing QBR/GRP Efficiency and informativeness of drug development –identified studies most germane to regulatory decision making increased number of drug-drug interactions –identified studies that are unnecessary reduced number of bioequivalence studies Guided emphasis on exposure-response studies –communicate with industry

Dose-Response and PK-PD Relationships Core (“hub”) question in QBR/GRP as applied to NDA's and IND’s, quantitative approach –assess safety and risk of dose selection –evaluate risk of exposure changes in special populations and dosing adjustments –determine the clinical significance of formulation differences in BA Extensive use of pharmacometric tools such as modeling and simulation Guidance for industry on E/R relationships

Impact and Value of Analysis and Review Improved study designs to assess benefit and risk during EOP2 review –increased efficiency in drug development Support approval of doses deemed effective and safe during NDA review –doses different than those sponsor proposed –sometimes without additional clinical studies Identify absent E/R information that could have supported efficacy and safety if it were available –avoid delays in approval and market access

Future Quality System Goals QC/QA check of NDA reviews –compliance with GRP and reviewer feedback More added value with focus on internal and external customers –application of GRP to INDs and supplements –standardize method of assessing exposure-response for dose adjustment –interact with industry at a much earlier state of drug development process