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 BoardRockville, 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)

Academic Training

82%

11%7%

Ph.D. Pharm.D. M.D.

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

Discovery Phase I Phase II Phase III Approval MarketNonclinical

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.

ODE I ODE II ODE III ODE IV ODE VOCPB

Biopharmaceutics

ClinicalPharmacology

Good Review Practices

1. Generate knowledge2. Be Decision Makers3. Know Patient Context4. Recognize Medical Need5. 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 June 19991999

Timeline for GRP

DATE ACTIVITY

July 1999 Initiated question-based review in OCPB

November 1999 CDER educational GRP seminar

September 2000 OCPB retreat to discuss GRP principles

November 2000 Formed GRP working group to develop MAPP

June 2001 Voluntary implementation of GRP’s

October 2001 MAPP for required GRP review

March 2003 Assessment of GRP impact and MAPP compliance

5 Quality Subsystems of a Systems

Approach

NDAClin Pharm/Biopharm

Briefing

GRP/QBR:Clin Pharm/Biopharm

Review (Template)

Domestic andInternationalGuidances

Science andProcess MAPP’s and

Decision Trees

NDAClin Pharm/Biopharm

Briefing Package

Standardize order and placement of subject matter, not content

ReviewStandards

ScientificPolicies

Executive summary, key review issues, unresolved questions, recommendations

Draft review posted on OCPB intranet

Uniformityand consistency

TL Meetings

Formal presentation,interdisciplinary audience interactive dialogue, finalize review

1

5

4 3

2

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