TASK ORDER NO. HHSP23337007T CONTRACT NO. HHSP23320095634WC EXAMINATION OF CLINICAL TRIAL COSTS AND BARRIERS FOR DRUG DEVELOPMENT FINAL Submitted to: Hui-Hsing Wong Amber Jessup U.S. Department of Health and Human Services Assistant Secretary of Planning and Evaluation (ASPE) 200 Independence Avenue, SW Washington, DC 20201 Submitted by: Aylin Sertkaya Anna Birkenbach Ayesha Berlind John Eyraud Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421 www.erg.com July 25, 2014 FINAL JULY 25, 2014 TABLE OF CONTENTS 1 INTRODUCTION AND BACKGROUND ............................................................................... 1-1 2 CLINICAL TRIAL DECISION-MAKING MODEL ............................................................. 2-1 2.1 DATA SOURCES ...................................................................................................................... 2-2 2.1.1 Publically Available Literature ................................................................................. 2-3 2.1.2 Discussions with Experts, FDA Personnel, Drug Sponsors, Contract Research Organizations (CROs), and Academic Clinical Research Centers ........................... 2-3 2.1.3 Medidata Solutions Databases .................................................................................. 2-4 2.2 CONCEPTUAL FRAMEWORK ................................................................................................... 2-5 2.3 OPERATIONAL MODEL ........................................................................................................... 2-8 2.4 MODEL PARAMETERS ............................................................................................................. 2-8 3 ANALYSIS OF COSTS .............................................................................................................. 3-1 3.1 COSTS BY THERAPEUTIC AREA .............................................................................................. 3-2 3.2 COSTS BY TRIAL PHASE ......................................................................................................... 3-4 3.3 COSTS BY COST COMPONENT ................................................................................................. 3-5 3.4 CONCLUSIONS ......................................................................................................................... 3-7 4 BARRIERS TO CLINICAL TRIALS ...................................................................................... 4-1 4.1 HIGH FINANCIAL COST ........................................................................................................... 4-1 4.2 LENGTHY TIMELINES .............................................................................................................. 4-3 4.3 DIFFICULTIES IN RECRUITING AND RETAINING PARTICIPANTS ............................................. 4-5 4.4 INCREASING COMPETITION FOR QUALIFIED INVESTIGATORS AND SITES .............................. 4-6 4.5 REGULATORY AND ADMINISTRATIVE BARRIERS ................................................................... 4-7 4.5.1 Regulations Protecting Human Research Subjects and Their Privacy ..................... 4-8 4.5.2 Safety Reporting Requirements for Investigational New Drugs (INDs) and Biologics (21 CFR 312) ...................................................................................... 4-9 4.5.3 Regulations for Multiple Jurisdictions .................................................................... 4-11 4.5.4 Conservative Regulatory Climate ........................................................................... 4-12 4.5.5 Lack of Clear Regulatory Pathways and Guidance for Some Therapeutic Areas .. 4-13 4.5.6 Barriers Related to the Review Process .................................................................. 4-14 4.6 DRUG SPONSOR-IMPOSED BARRIERS ................................................................................... 4-16 4.6.1 Administrative ......................................................................................................... 4-16 4.6.2 Study Design ............................................................................................................ 4-16 4.6.3 Data and Site Monitoring ........................................................................................ 4-20 4.6.4 Serious Adverse Events (SAEs) Reporting for Investigational New Drugs and Biologics (INDs) (21 CFR 312) ............................................................................... 4-22 4.7 DISCONNECT BETWEEN CLINICAL RESEARCH AND MEDICAL CARE ................................... 4-22 4.8 BARRIERS AT ACADEMIC INSTITUTIONS .............................................................................. 4-23 4.9 BARRIERS RELATED TO THE GLOBALIZATION OF CLINICAL RESEARCH ............................. 4-24 5 ANALYSIS OF BARRIERS TO CLINICAL TRIALS ........................................................... 5-1 i FINAL JULY 25, 2014 5.1 USE OF ELECTRONIC HEALTH RECORDS (EHR) .................................................................... 5-3 5.2 RELAXING TRIAL ENROLLMENT RESTRICTIONS ...................................................................... 5-4 5.3 SIMPLIFIED CLINICAL TRIAL PROTOCOLS AND REDUCED AMENDMENTS ............................. 5-5 5.4 REDUCED SOURCE DATA VERIFICATION (SDV) .................................................................... 5-6 5.5 WIDER USE OF MOBILE TECHNOLOGIES SUCH AS ELECTRONIC DATA CAPTURE (EDC) ...... 5-8 5.6 WIDER USE OF LOWER-COST FACILITIES AND/OR AT-HOME TESTING ................................. 5-9 5.7 PRIORITY REVIEW/PRIORITY REVIEW VOUCHERS................................................................ 5-11 5.8 IMPROVEMENTS IN FDA REVIEW PROCESS EFFICIENCY AND MORE FREQUENT AND TIMELY INTERACTIONS WITH FDA .............................................................................. 5-11 5.9 CONCLUSIONS ....................................................................................................................... 5-12 6 REFERENCES ............................................................................................................................ 6-1 APPENDIX A: DRAFT INTERVIEW GUIDE,................................................................................... A-1 APPENDIX B: MEDIDATA DATA ELEMENT DESCRIPTIONS .................................................. B-1 APPENDIX C: FEATURES OF OPERATIONAL MODEL ............................................................. C-1 APPENDIX D: ADDITIONAL DATA CLEANING STEPS .............................................................. D-1 ii FINAL JULY 25, 2014 LIST OF TABLES AND FIGURES FIGURE 1: NEW MOLECULAR ENTITY (NME) AND NEW BIOLOGIC ENTITY (NBE) FILINGS AND APPROVALS ................................................................................................................................... 1-1 FIGURE 2: DRUG DEVELOPMENT DECISION TREE DEPICTING NET PRESENT VALUE (NPV) OF RETURNS AT EACH NODE ........................................................................................................ 2-6 FIGURE 3: CLINICAL TRIAL COSTS (IN $ MILLIONS) BY PHASE AND THERAPEUTIC AREA ....................... 3-3 FIGURE 4: AVERAGE PER-STUDY COSTS BY PHASE (IN $ MILLIONS) ACROSS THERAPEUTIC AREAS ...... 3-4 FIGURE 5: PER-STUDY COSTS ACROSS ALL THERAPEUTIC AREAS, BY COST COMPONENT AND PHASE ... 3-7 FIGURE C - 2: WELCOME SCREEN OF THE CLINICAL TRIALS MODEL ....................................................... C-1 FIGURE C - 1: IMPACT OF REMOVAL OF BARRIERS SCREEN ..................................................................... C-1 FIGURE C - 3: SELECTION OF TYPE OF TRIAL SCREEN FOR EXAMINATION OF COSTS .............................. C-2 FIGURE C - 4: GENERAL QUESTIONS SCREEN ........................................................................................... C-2 FIGURE C - 5: PARAMETER VALUE ENTRY FOR CLINICAL TRIAL STUDY PER TRIAL PHASE SCREEN ...... C-3 FIGURE C - 6: RESULTS SCREEN ................................................................................................................ C-3 TABLE 1: TOTAL PER-STUDY COSTS (IN $ MILLIONS), BY PHASE AND THERAPEUTIC AREA [A] [B] ....... 3-3 TABLE 2: CLINICAL TRIAL COSTS, BY COST COMPONENT, PHASE, AND THERAPEUTIC AREA [A] [B]...... 3-6 TABLE 3: BARRIER MITIGATION MEASURES AND ASSOCIATED MODELING APPROACH FOR ANALYSIS ...................................................................................................................................... 5-2 TABLE 4: PROJECTED IMPACTS OF EHR USE ON CLINICAL TRIAL COSTS (IN $ MILLIONS AND IN PERCENTAGES), BY THERAPEUTIC AREA AND PHASE [A] ............................................................ 5-4 TABLE 5: PROJECTED IMPACTS OF RELAXING TRIAL ENROLLMENT RESTRICTIONS ON CLINICAL TRIAL COSTS (IN $ MILLIONS AND IN PERCENTAGES), BY THERAPEUTIC AREA AND PHASE [A] ........... 5-5 TABLE 6: PROJECTED IMPACTS OF SIMPLIFIED CLINICAL TRIAL PROTOCOLS AND REDUCED AMENDMENTS ON CLINICAL TRIAL COSTS (IN $ MILLIONS AND IN PERCENTAGES), BY THERAPEUTIC AREA AND PHASE [A] ............................................................................................ 5-6 TABLE 7: PROJECTED IMPACTS OF REDUCED SOURCE DATA VERIFICATION (SDV) ON CLINICAL TRIAL COSTS (IN $ MILLIONS AND IN PERCENTAGES), BY THERAPEUTIC AREA AND PHASE [A] ........... 5-8 TABLE 8: PROJECTED IMPACTS OF WIDER USE OF MOBILE TECHNOLOGIES, SUCH AS ELECTRONIC DATA CAPTURE (EDC), ON CLINICAL TRIAL COSTS (IN $ MILLIONS AND IN PERCENTAGES), BY THERAPEUTIC AREA AND PHASE [A] ......................................................................................