PHARMACEUTICAL LIFECYCLE MANAGEMENT MAKING THE MOST OF EACH AND EVERY BRAND
Tony Ellery Ellery Pharma Consulting Magden, Switzerland
Neal Hansen Datamonitor Limited London, United Kingdom
©WILEY A JOHN WILEY & SONS, INC., PUBLICATION
CONTENTS
ACKNOWLEDGMENTS
"
INTRODUCTION PART A LIFECYCLE MANAGEMENT BUSINESS ENVIRONMENT 1. Challenges Facing the Branded Drug Industry 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8
1.9
Depleted NME Pipelines/Lower R&D Efficiency Higher Development Costs Safety Concerns Tougher Environment for Pricing, Reimbursement, and Listing Increased Competition Earlier Genericization Faster Sales Erosion Following Patent Expiry Poor Image of Branded Drug Industry 1.8.1 Prosperity of the Branded Drug Industry 1.8.2 Lack of Innovation 1.8.3 Marketing Spend and Tactics 1.8.4 Safety Issues 1.8.5 Keeping Generics Off the Market Diversification
2. The Life Cycle of Industries, Technologies, and Brands 2.1 2.2 2.3
Diffusion of Innovations The Lifecycle Curve Lifecycle Phases 2.3.1 Development Phase 2.3.2 Introduction Phase 2.3.3 Growth Phase 2.3.4 Maturity Phase 2.3.5 Decline Phase
xvii xix
1 3 4 8 9. 12 16 17 18 20 21 22 22 .. 23 24 26 30 30 32 34 34 35 35 36 36 vii
viii
CONTENTS
3. The Life Cycle of a Pharmaceutical Brand 3.1
3.2
3.3
Lifecycle Curve of Pharmaceuticals 3.1.1 Slow Rate of Growth during the Growth Phase 3.1.2 Lack of a True Maturity Phase 3.1.3 Precipitous Decline Phase Factors Affecting Rate of Conversion to Generics 3.2.1 Government Policy 3.2.2 Disease 3.2.3 Size of Brand :.. 3.2.4 Hospital versus Nonhospital Drug Usage 3.2.5 Active Substance and Other Barriers to Entry The Life Cycle of a Pharmaceutical Brand
PART B LIFECYCLE MANAGEMENT REGULATORY AND LEGAL ENVIRONMENT 4. The Generic Approval Process 4.1 4.2 4.3
United States Europe Japan
5. Hatch-Waxman Legislation and Its Effects on LCM 5.1 5.2 5.3 5.4 5.5
Hatch-Waxman Act of 1984 Medicare Modernization Act of 2003 FDA Amendments Act of 2007 Ql Program Supplemental Funding Act of 2008 Discussion of Hatch-Waxman Legislation
38 41 42 43 43 44 44 44 45 45 46 46
55 57 57 59 61 62 62 64 65 66 66
6. U.S. Health-Care Reform 2010
69
7. European Sector Inquiry
72
PART C
PATENTS AND EXCLUSIVITIES
8. Patents and Other Intellectual Property Rights 8.1 8.2 8.3
Nonpatent Intellectual Property Rights What Are Patents? What Is Patentable? 8.3.1 Patentable Subject Matter 8.3.2 Novelty
77 79 79 81 83 83 84
CONTENTS
8.4 8.5 8.6 8.7 8.8 8.9 8.10
8.11 8.12
8.3.3 Inventive Step 8.3.4 Utility 8.3.5 Disclosure ., How Long Does a Patent Last? Patent Term Restoration in the United States Supplementary Protection Certificates in Europe Patent Term Extension in Japan How Are Patents Obtained? Patent Enforcement Types of Patents . 8.10.1 Composition of Matter Patent 8.10.2 Medical Use Patent 8.10.3 Formulation Patent KSR versus Teleflex—Raising the Nonobviousness Bar Patent Strategy
9. Nonpatent Exclusivities 9.1 9.2 9.3 9.4 9.5 9.6 9.7
NCE Exclusivity (United States) New Clinical Study Exclusivity (United States) Data and Marketing Exclusivity (Europe) Data Exclusivity (Japan) Orphan Drug Exclusivity Pediatric Exclusivity 180-Day Generic Product Exclusivity
IX
85 86 86 87 87 88 89 89 91 92 93 93 94 94 96 99 99 100 100 101 101 103 105
10. Patent Settlements
107
PART D
113
DEVELOPMENTAL LCM
11. Strategic Principles of Developmental LCM 11.1 11.2 11.3 11.4
Developmental LCM Goal 1: Provide a Meaningful Improvement in Clinical Profile Developmental LCM Goal 2: Increase the Potential Real-World Patient Potential for the Brand Developmental LCM Goal 3: The Ability to Generate an ROI Developmental LCM Goal 4: The Ability to Enhance Market Exclusivity of the Brand Franchise
12. Indication Expansion and Sequencing 12.1
Categories of Indication Expansion
115 116 118 120 121 123 123
X
CONTENTS
13. Patient Subpopulations and Personalized Medicine 13.1 13.2 13.3
What Does a Good Patient Selection Strategy Look Like? \ Patient Selection without Predictive Criteria: Post Hoc Approaches What about the Patients Who Are Not Selected?
14. New Dosage Strengths, New Dosage Regimens 14.1 14.2
New Dosage Strengths New Dosage Regimens
,
15. Reformulation, New Routes of Administration, and Drug Delivery
131 135 138 139 140 140 141 143
15.1
Reformulation and New Routes of Administration 15.1.1 Switch and Grow Strategy 15.1.2 Expand and Grow Strategy 15.1.3 Generic Defense
143 143 145 145
15.2
Drug Delivery Devices
149
16. Fixed-Dose Combinations (FDCs) and Co-Packaging
152
17. Second-Generation Products and Modified Chemistry 17.1 Isomerism 17.2 Polymorphism 17.3 Salts, Ethers, and Esters 17.4 Prodrugs and Metabolites
159 160 161 162 163
18. Other Developmental LCM Strategies
165
18.1 18.2 PART E
Manufacturing Strategies White Papers and Citizen Petitions COMMERCIAL LCM
19. Strategic Principles of Commercial LCM 19.1 19.2 19.3
Commercial LCM Goal 1: The Ability to Drive Widespread and Preferential Patient Access to the Brand Commercial LCM Goal 2: The Ability to Defend Market Access and Formulary Position Commercial LCM Goal 3: The Ability to Optimize Profitability of the Brand Franchise
, 165 166 167 169
170 170 171
CONTENTS
20. Geographical Expansion and Optimization 20.1 20.2
Geographic Expansion Harmonization and Rationalization
21. OTC Switching 21.1 21.2 21.3 21.4
What to Switch: Choosing the Best Approach Where to Switch: Dealing with Intermarket Variability When to Switch: Balancing the Product Life Cycle? How to Make the Switch Successful: What Corporate Support Is Required? " -
XI
172 174 175 178 179 181 183 184
22. Brand Loyalty and Service Programs
186
23. Strategic Pricing Strategies
190
23.1 23.2
Pricing Strategy and Tactics in the Launch and Growth Phases Pricing Strategy and Tactics Following Patent Expiry
24. Generic Strategies and Tactics Building a Generic Portfolio: Old versus New Thinking 25. Exit Strategies Executing the Exit Strategy
190 193 198 202 204 206
PART F BIOLOGICS AND BIOSIMILARS
207
26. Biologies and LCM
209
26.1 26.2 26.3 26.4
Emergence of Biotech Some Definitions 26.2.1 Biologies ; Uptake and Value of Biologies LCM of Biologies 26.4.1 Next-Generation Biologies 26.4.2 Reformulation 26.4.3 Indication Expansion 26.4.4 Self-Injection Devices
27. Biosimilars and Their Impact on Biologic LCM 27.1 27.2
Changing Terminology: Biogenerics, Biosimilars, and FOBs Why Are Biosimilars a Big Deal?
209 210 210 211 213 213 214 215 215 217 217 219
XN
CONTENTS
27.3 27.4
27.5
27.6 27.7
27.8 27.9
How Are Biosimilars Different? Biosimilar Approval Pathways 27.4.1 Biosimilars in Europe 27.4.2 Biosimilars in the United States 27.4.3 Biosimilars around the World Substitution of Biosimilars 27.5.1 Automatic Substitution 27.5.2 Therapeutic Substitution , Innovator Responses to Biosimilar Threats The Future for Biologies LCM - 27.7.1 Legal Strategies in the United States 27.7.2 Indication Expansion in Europe 27.7.3 Brand Loyalty Programs and Services The Emergence of the "Innovasimilar" Biopharma Company Final Words
220 220 220 221 222 223 223 224 225 226 227 228 229 229 231
PART G THE INTEGRATED BRAND LCM STRATEGY AND ITS IMPLEMENTATION
233
28. Strategic Goals of LCM Brand Plans
235
28.1 28.2 28.3
Position to Market Comparative Clinical Profile versus Gold Standard Level of Market Unmet Need
235 237 237
29. Ten Keys to Successful LCM Excellent Functional Expertise 29.1.1 Patent Attorneys 29.1.2 Regulatory Affairs 29.1.3 Clinical Development 29.1.4 Formulation Scientists 29.1.5 Marketing and Sales 29.1.6 Manufacturing 29.2 Visible Management Support 29.3 Unambiguous Ownership 29.4 An Early Start 29.5 A Robust "Broad to Bespoke" Process 29.6 Focus on "High LCM Value Brands" 29.7 Adequate Resources 29.8 Measurements and Rewards 29.9 Training and Support 29.10 Realism
238
29.1
.,. '•'!}'•';
238 239 240 240 241 242 243
244 245 246 248 249 250 250 252 252
CONTENTS
30. Organizational Structures and Systems for Ensuring Successful LCM 30.1
30.2 30.3 30.4
Organization of Project and Brand Management 30.1.1 Functional Structure 30.1.2 Project Structure 30.1.3 Matrix Structure Project and Brand LCM Structures LCM Center of Excellence Composition of the LCM CoE
31. The LCM Process: Description, Timing, and Participants 31.1 31.2 31.3
Purpose of the LCM Process Timing of the LCM Process Description of the LCM Process
XiM
254 254 255 255 257 259 263 266 268 268 269 271
PART H INTEGRATING LCM WITH PORTFOLIO MANAGEMENT
277
32. Principles of Portfolio Management
279
33. LCM Projects in the Development Portfolio
284
34 Managing Established Brand Portfolios
286
34.1 34.2 34.3
What Do You Do with a Priority Established Brand? What about the Nqnpriority Brands? Building the Ideal Established Brands Portfolio
288 289 290
CONCLUSIONS
291
APPENDK: CASE HISTORIES
294
A.I
A.2
Market and Product-Shaping Dynamics in Action Alzheimer's Disease Therapies: Aricept®, Exelon®, and Reminyl®/Razadyne® Learnings Optimizing Clinical Profile versus Gold Standards Angiotensin II Receptor Blockers (ARBs): Cozaar®, Micardis®, and Benicar® Learnings '
294 294 297 298 298 299
XiV
CONTENTS
A.3
A.4
A.5
A.6
A.7
A.8
A.9
A.10
A.11
A.12
A.13
A.14
Partnering to Ensure Reimbursement and Collection of Cost-Effectiveness Data Aricept .. Learnings Active Metabolites and Late-Listed Patents Buspar® Learnings A Fixed-Dose Combination (FDC) That Could Not Fail, or Could It? Caduet® Learnings Indication Expansion Certican®/Zortress® and Afinitor® Learnings Killing a Franchise through Over-the-Counter (OTC) Switching Claritin® Learnings Moving FDCs to the Fore in Diabetes Diabetes Therapies: Glucophage®, Avandia®, Actos®, and Januvia® Learnings FDCs and Multiple Dosage Strengths Diovan® and Tekturna®/Rasilez® Learnings Building a Compliance Support Program Enbrel® Learnings Targeting Responders with High-Price Cancer Agents Erbitux® Learnings \ Failure of a "No-Brainer" LCM Strategy Exubera® Learnings At-Risk Launches and Prodrug Patents Famvir® Learnings New Dosages, FDC, and Patent Litigation Fosamax® Learnings
299 299 301 301 301 303 303 303 304 305 305 306 307 307 308 308 308 310 310 310 312 312 312 314 314 314 315 315 315 319 320 320 321 322 322 324
CONTENTS
A. 15 High Regulatory Hurdles for Lifestyle Drugs Girosa® Learnings , A.16 Big Money from Orphan Indications Gleevec® Learnings A. 17 Not Giving Up on a Controversial Brand Iressa® Learnings A.18 Expanding a Medical Aesthetics Franchise with an Ophthalmic Drug Latisse® Learnings A.19 Patent Expiry of the Biggest Drug Brand Ever Lipitor® ^ Learnings A.20 Early Out-Licensing by Biotech: Take the Money and Run Macugen® Learnings A.21 Codevelopment and Comarketing Deals End in a Megamerger . Merck and Schering-Plough: Zetia®/Vytorin® and Claritin/Singulair® Zetia/Vytorin Claritin/Singulair ' Learnings A.22 A Hugely Successful LLCM Switch Strategy: Business Needs and Reputational Issues Collide Prilosec® and Nexium The Facts The Public Reaction Learnings A.23 Combining Production Outsourcing with Settlement with a Generic Competitor Nexium Learnings A.24 Reformulating for Success in Osteoporosis Osteoporosis Drugs: Fosamax, Actonel®, Boniva®, and Aclasta® Learnings
XV
325 325 327 327 327 329 330 330 332 332 332 334 335 335 336 336 336 338 338 338 339 342 343 344 344 344 345 347 349 349 351 351 351 353
XVi
CONTENTS
A.25
Isomerism, Polymorphism, and Settlements Plavix® Learnings A.26 Payers versus Brand for Patient Selection Plavix and Brilinta Learnings A.27 Litigation Can Delay Generic Entry in the OTC Field Too Prilosec OTC Learnings A.28 Inconsistent Court Decisions Can Hurt Both Brand and Generic Companies Protonix® Learnings Holding on to an Antipsychotic Franchise A.29 Risperdal®/Invega® Learnings A.30 LCM Creates an Almost Immortal Brand Voltaren® Learnings A.31 LCM of a Women's Health Franchise The Yasmin® Family Learnings A.32 Indication Expansion/New Dosage Strength Zometa/Reclast® (Aclasta) Learnings INDEX
354 354 355 356 356 357 358 358 359 360 360 361 362 362 363 364 364 365 366 366 368 369 369 370
371