CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT 70 CONCENTRATION 60 50 40 30 20 10 0 0 5 10 15 20 25 30 TIME IN HOURS Ramana S. Uppoor, R.Ph., Ph.D. Division of Clinical Pharmacology-1 ASENT meeting, March 6, 2008 Office of Clinical Pharmacology, CDER, FDA Disclaimer Views expressed are mine and do not necessarily reflect official FDA Policy. New Molecular Entity Approvals by Fiscal Year 50 45 28 44 44 34 40 39 40 21 37 27 35 Number Approved 31 32 30 28 30 25 8 25 13 17 22 11 20 14 13 18 19 15 17 10 10 13 13 12 9 10 5 8 8 5 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 Fiscal Year of Approval Priority NME Approvals Standard NME Approvals Number of NMEs Filed * as of 30-Sep-2003 High attrition rate even in late development Kola I, Landis J.Can the pharmaceutical industry reduce attrition rates? Nat.Rev.Drug.Disc. Aug 2004. Need/Opportunities for Innovative Methods in Drug Development Assess Decrease useful avoidable Biomarkers trial failures e.g. imaging Evaluate Individualization rational of trial dosing designs, endpoints Providing solutions for these issues calls for optimal early trials and efficient use of prior knowledge OUTLINE Definitions Clinical Pharmacology domain Clinical Pharmacology studies Biopharmaceutics studies Value Case examples Conclusions Clinical Pharmacology is… Translational science in which basic information about the relationship between dose, exposure and response (efficacy or safety) is applied in the context of patient care Major contribution of Clinical Pharmacology: Knowledge of E-R relationship (key to successful therapeutics) and how it is altered by intrinsic (age, gender, renal function etc.) and extrinsic (diet, drugs, life-style) factors of an individual patient Definitions Clinical Pharmacology: Pharmacokinetics (PK): What the body does to the drug (Absorption, Distribution, Metabolism, Excretion). For drug review purpose, PK also covers extrinsic and intrinsic factors like drug interactions, effect of age, gender, race, organ dysfunction, etc. PK gives you Exposure. Pharmacodynamics (PM): What the drug does to the body. PD covers desirable and undesirable effects, from biomarkers to surrogates to clinical endpoints. PD gives you Response. FIRST PRINCIPLES Why Drugs Work In Vivo Dose Pharmacokinetics Pharmacodynamics Effect Absorption Distribution Metabolism Excretion Concentration MEC Free Total Time PK-PD MEASURES Relationships Between Exposure & Response Effect (e.g., Survival, % change in seizure Serum Drug Concentration Emax Peak conc. (Cmax) frequency AUC EC50 PK-PD Measure Time (e.g., AUC) Clinical Trials Spectrum Phase I, II,III and IV clinical trials Early and Late phase clinical trials Learn and Confirm trials Clinical Pharmacology (= Learn; phase 1 and 2) including dose response trials and Efficacy (= Confirm; phase 3) trials Safety Trials: All phases Bioequivalence Trials Clinical Pharmacology Domain PK (ADME) PD PM PG Clinical Pharmacology & Biopharmaceutics Studies Pharmacokinetics/Biopharmaceutics: Mass Balance studies with radiolabelled drug Single and multiple dose pharmacokinetics Absolute bioavailability Dose proportionality Food effects studies Bioequivalence studies to establish the link between the market and clinical formulations Metabolism and drug interactions Clinical Pharmacology & Biopharmaceutics Studies .. contd. Clinical Pharmacology: Pharmacokinetics in the target population Special population studies Age, Gender, Race, etc. Disease states such as renal and liver impairment Establishment of pharmacokinetic pharmacodynamic correlations Bioavailability and Bioequivalence - Definitions Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. BIOAVAILABILITY MEASUREMENT MONITORING PARAMETERS Peak Concentration: Cmax Time to Peak Concentration: Tmax Area Under the Drug Concentration-Time Curve: AUC Single dose & Multiple dose Bioavailability 70 120 60 100 50 CONCN. 80 CONCN. 40 60 30 40 20 20 10 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 TIME IN HOURS TIME IN HOURS Cmax and AUC Food effect study High fat meal: 70 2 eggs fried in butter CONCENTRATION 60 2 strips of bacon 50 fed fasting 2 slices of toast with butter 40 4 ounces of hash brown 30 potatoes 20 8 ounces of whole milk 10 1000 calories, 50 % derived 0 from fat 0 5 10 15 20 25 30 TIME IN HOURS Evaluate the food effect by comparing the PK parameters obtained in fed vs. fasted state BIOEQUIVALENCE MEASUREMENT PHARMACOKINETIC PARAMETERS MULTIPLE SINGLE DOSE DOSE AUC0-Tlast AUCss AUC 0-Tinf Cmax Cmax Cmin Tmax Tmax STATISTICAL REQUIREMENTS FOR Bioequivalence Current Decision Rule: Two one-sided test procedure: (ALSO CALLED THE 90% CONFIDENCE INTERVAL APPROACH) • Recognizes that there will be a difference in mean values between treatments • Provides reasonable assurance that mean treatment differences are acceptable General Requirement: 90% confidence intervals for AUC and Cmax have to be within the range of: 80 – 125% (based on log transformed data) Common CPR Encounters Exposure-Response Pater Current Controlled Trials in Cardiovascular Medicine 2004 5:7 GENERAL THOUGHTS/VALUES OCP: The Right Dose of the Right Drug at the Right Time for the Right Patient Optimal bioavailability Dose selection Dosing regimen selection Dose adjustment for special populations Dose adjustment in presence of intrinsic and extrinsic factors GOAL: To develop good drugs/drug products with adequate information to improve therapeutics (with an ultimate goal of optimal treatment for a patient) Exposure Response Relationship Selection of appropriate dose/regimen Efficacy Percentage of Response Toxicity Exposure Selection of optimal release profile Case example 1 – Dosing regimen FDA’s proactive model-based analysis identified that the proposed dosing is sub- optimal. Simulations suggested alternatives. Development cycle extended. Regulatory Issue Short t1/2 drug for lowering BP Sustained effect desired Proposed dosing - QD Very large trial conducted Typically pivotal trials are not large for hypertension Exposure-Response analyses conducted Effectiveness and Safety Is this really a once-day-drug? s-Lercanidipine Steady-Stat 6.0 6. ER Analysis 3.0 3. 0.0 X mg daily 0. ID: 101 Clear concentration-effect 3.6 4. relationship EC50 3. 2.4 No delay between PK and Cp PD 1.2 1. Nonlinear concentration- 0.0 0. effect relationship FDA performed the analysis 6 12 0 Time, h18 24 during NDA review Modeling demonstrated inadequacy of once a day regimen Value Delivered by the Exposure Response Analysis Supported evidence for effectiveness Aided in judging that QD dosing is sub- optimal Provided alternatives for future development Prospective modeling of early PK/PD data could have (and an EOP2A meeting) Avoidedlengthening drug development time Been more economical Case example 2 - Use of exposure response for pediatric approval FDA’s proactive model-based analysis alleviated the need to conduct additional clinical trial for the approval of Trileptal monotherapy in pediatrics Regulatory Issue Adjunctive Monotherapy Adults Clinical trials Clinical trials Children Clinical trial “Model Based Bridging” (4-16 years approach proposed by of age) FDA FDA/Sponsor pursued approaches to best utilize knowledge from the positive trials to assess if monotherapy in pediatrics can be approved without new controlled trials Motivation Monotherapy of anticonvulsants is important Better safety, Ease of Rx mgmt Avoid unnecessary costs Monotherapy trials are challenging Reasonable ER knowledge available Integration of knowledge across trials and populations is needed Law supports model based thinking Value of this type of analysis Modeling and simulation aided in utilizing all previous data to justify approval without additional controlled clinical trials Allowed selection of dosing guidelines in pediatrics The presented approach has a greater global impact Precedent was set Conclusions PK and Exposure-Response analysis can help select suitable dose/dosing regimen and identify optimal drug products. PK from early trials will help optimize the dosing conditions for pivotal trials. Facilitate dosing in special populations and also provide dose adjustment guidelines in the presence of intrinsic (age, gender, renal function etc.) or extrinsic factors (concomitant drugs, food etc.). Conclusions …. contd. Facilitatefindings of effectiveness as well as help resolve safety concerns. E-R frame created in the approved setting can be a powerful source for approval consideration for additional settings (e.g. pediatrics). Need/Opportunities for Innovative Methods in Drug Development Assess Decrease useful avoidable Biomarkers trial failures e.g. imaging Evaluate Individualization rational of trial dosing designs, endpoints Providing solutions for these issues calls for optimal early trials and efficient use of prior knowledge ACKNOWLEDGEMENTS Dr. Mehul Mehta Dr. Patrick Marroum Dr. Robert Kumi That’s all folks!