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    H E A L T H C A R E

    Drug Approval Trends at the FDA andEMEAProcess improvements, heightened scrutiny and industry

    response

    By Alison Sahoo

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    Alison Sahoo

    Alison Sahoo is a pharmaceutical industry analyst with more than 10 years of

    experience researching the development of medicines and medical devices. She holds a

    B.S. in Physics from McGill University and an M.B.A. in International Business from

    Rutgers University.

    Copyright 2008 Business Insights LtdThis Management Report is published by Business Insights Ltd. All rights reserved.Reproduction or redistribution of this Management Report in any form for anypurpose is expressly prohibited without the prior consent of Business Insights Ltd.

    The views expressed in this Management Report are those of the publisher, not ofBusiness Insights. Business Insights Ltd accepts no liability for the accuracy orcompleteness of the information, advice or comment contained in this ManagementReport nor for any actions taken in reliance thereon.

    While information, advice or comment is believed to be correct at the time ofpublication, no responsibility can be accepted by Business Insights Ltd for itscompleteness or accuracy.

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    Table of Contents

    Drug Approval Trends at the FDA, EMEA

    Executive Summary 10

    The shifting regulatory landscape 10

    Drug approval trends at FDA 11

    Drug approval trends at EMEA 12

    Industry response 13

    Global drug approval trends through 2012 14

    Chapter 1 The shifting regulatory landscape 18

    Summary 18

    Drug usage in the U.S. and Europe 19

    New molecular entities 20

    Generic drugs 21Rising usage of generics 21Generic drug application trends 22

    Indication expansions 23

    Drug approval issues 26

    Ensuring drug safety 27

    Safety shortfalls: rising adverse drug reactions 29Safety failures: drug withdrawals 30

    The importance of time to market 31Impact of cost constraints 34

    Conclusion 35

    Chapter 2 Drug approval trends at the FDA 38

    Summary 38

    Drug approval process 39Pressure to approve drug candidates 42

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    Future directions in the FDA drug approval process 43Ensuring drug safety 44Evolution of drug safety testing 44Pediatric safety testing 48

    Future directions in drug safety reviews 49Reducing time to market 50Fast track approvals 52Orphan drug approvals 53Decreasing FDA drug approvals 54

    Future directions in speeding drug approvals 56

    Delaying risky applications 58Rising data requirements 58

    Case study: hormone replacement therapy 59Case study: Galvus 60

    The future for risky drug applications 62

    Biosimilars 62

    The future of biosimilar approvals 62Canadian biosimilars legislation 63

    Rx-to-OTC switches 64New OTC drug categories 66

    Antihistamines 67Emergency contraceptives 69Hyperosmotic laxatives 71Ophthalmic allergy medications 72Proton pump inhibitors 73Weight loss medications 75

    Switch rejections 76Statins 77

    Future directions in nonprescription drug approvals 78Creation of a pharmacist dispensed class 79

    Marketing withdrawals 80

    Application withdrawals 81Future directions in marketing and application withdrawals 82

    Conclusion 82

    Chapter 3 Drug approval trends at theEMEA 86

    Summary 86

    Drug approval process 87History of European drug regulation 87The formation of the EMEA and the MRP 88

    The EMEA 89

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    The Mutual Recognition Procedure (MRP) 91The National Competent Authorities 93The Common Technical Document 93Ensuring drug safety 96

    Creation of Scientific Advisory Groups 97Future directions in drug safety testing 98Reducing time to market 98Accelerated opinions 100Pediatric testing exemptions 101Decreasing EMEA approvals vs. FDA approvals 101Current EMEA approval levels 104Future directions in speeding drug approvals 104

    Delaying risky applications 105The future for risky drug applications 106

    Biosimilars 107New biosimilar guidelines 107Future directions in biosimilar approvals 108

    Rx-to-OTC switches 109Future directions in nonprescription drug approvals 110

    Marketing withdrawals 110

    Application withdrawals 110Future directions in marketing and application withdrawals 112

    Conclusion 112

    Chapter 4 Industry response 114

    Summary 114

    Background 115

    Improving safety testing 115Genomics 116Stem cell approaches 117Future drug safety testing improvements 118

    Raising investment in R&D 118Improving R&D productivity 119

    Contract research organizations 119Repositioning 121

    Future directions in R&D investment 122

    Public reporting of clinical study results 123United States 123Europe 124Association of the British Pharmaceutical Industry 125

    Future directions in clinical data reporting 126Strengthening regulatory processes 126

    Coalition for a Stronger FDA 126

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    Future directions in regulatory support 127

    Conclusion 128

    Chapter 5 Global drug approval trends to2012 130

    Summary 130

    Background 131

    Trends at the FDA 132Focus on drug safety 132

    New technology-based standards for drug application review 133

    Decreasing application review times 135Boosting integrity and accountability 136

    Trends at the EMEA 137Focus on drug safety 138Product Information Management (PIM) Project 139Cooperation with other regulators 140Incentives for small drug developers 140

    Convergence of regulatory approaches 141

    Orphan drug approvals 143

    Conclusion 144

    Chapter 6 Appendix 146

    Index 146

    List of FiguresFigure 1.1: Drug safety risk spectrum 28Figure 1.2: Growth in U.S. reported adverse drug reactions, 1995 - 2007 30Figure 1.3: U.S. R&D spending versus new drug approvals, 1995 2007 36Figure 2.4: U.S. drug approvals, 1995 - 2007 55Figure 3.5: Average number of days for centralized procedure positive opinions, 2004 - 2006 99Figure 3.6: Average number of days for orphan drug designation opinions, 2004 - 2006 100Figure 3.7: EMEA marketing withdrawals, 2000 - 2007 111

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    List of TablesTable 1.1: Selected indication expansions for U.S. commercialized drugs, 2002 - 2007 25Table 1.2: Potential safety risks of popular drug classes 29Table 1.3: Significant drug discontinuations and affected patient groups, 1997 - 2007 33Table 2.4: Timeline of key FDA legislations 45Table 2.5: CDER Advisory Committees, 2008 48Table 2.6: U.S. New Molecular Entity (NME) Approvals, 2000 - 2007 56Table 2.7: Key U.S. Rx-to-OTC switches, 1997 - 2007 66Table 2.8: Key events in the approval of OTC nonsedating antihistamines 69Table 2.9: Recent withdrawals of U.S. marketing applications, 2002 - 2007 82Table 3.10: Leading European National Competent Authorities, 2008 94Table 4.11: U.S. Clinical trials and R&D spending, 2000 - 2007 118Table 4.12: Selected repositioning specialists 122

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    Executive Summary

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    Executive Summary

    The shifting regulatory landscape

    In both the U.S. and Europe, the utilization of Rx medicines, including both generic

    drugs and new molecular entities, is rising strongly.

    Increasing use of medications carries safety risk. Inherent drug risks are generally

    related to toxicity and the pharmacokinetic properties of the drug itself.

    Drug safety risks run the gamut from minor discomforts such as the nausea

    associated with many classes of medications to life-threatening conditions like

    increased risk of liver toxicity caused by cholesterol-reducing statins.

    Over the past five years, the incidence of adverse drug reactions reported in both

    the U.S. and Europe has risen sharply.

    Marketing withdrawals may be required for drugs that have been associated with a

    significant level of extremely adverse effects. The most significant market

    withdrawal to date has been Mercks Vioxx, which was recalled in September 2004

    after more than 80m prescriptions had been written for the drug worldwide. The

    drug was linked to an increased risk of cardiovascular effects, with one study

    showing that patients taking Vioxx were twice as likely to have a heart attack as

    those taking naproxen.

    Mercks withdrawal of Vioxx has galvanized public scrutiny of drug approval

    processes, causing regulators, particularly the FDA, to exercise more caution in

    approvals.

    As more blockbuster drugs lose patent protection and R&D productivity continues

    to decline, minimizing time to market for new drugs is becoming increasingly

    important. However, approval delays can lengthen time to market.

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    While both the FDA and EMEA are attempting to reduce approval times, largely

    through expansion of fast track programs, delays remain common, as regulators

    attempt to verify the safety of increasingly complex products.

    Expanding R&D activities to ensure that compou