New Drug Development

Chapter 1. An Introduction to the U.S. New Drug Approval Process 1

The FDA and the Food, Drug and Cosmetic Act 3
New Drug Development and Approval: A Brief Overview of the Principal Steps 4

Chapter 2. Nonclinical Drug Testing 15

Trends in Nonclinical Testing 16
FDA Guidance on Nonclinical Testing Requirements 18
Types of Nonclinical Studies 19
Pharmacology Studies 20
Toxicity Studies 22
Acute Toxicity Studies 22
Subacute or Subchronic Studies 23
Chronic Toxicity Testing 25
Carcinogenicity Studies 26
Special Toxicity Studies 28
Reproductive Toxicity Studies 29
Genotoxicity Studies 30
Toxicokinetic Studies 32
Nonclinical Testing and New Drug Excipients 32
FDA Standards for Nonclinical Testing: Good Laboratory Practice (GLP) 33

Chapter 3. The IND 37

Types of INDs 38
Investigator INDs 38
Emergency Use INDs 38
Treatment INDs 39
Screening INDs 39
The Applicability of the IND 40
IND Content and Format Requirements 41
Cover Sheet (Form FDA 1571) 43
Table of Contents 44
Introductory Statement 44
General Investigational Plan 44
Investigator�s Brochure 44
Clinical Protocols 47
Chemistry, Manufacturing, and Controls Information 54
Animal Pharmacology and Toxicology Information 58
Previous Human Experience with the Investigational Drug 59
Additional Information 59
Pharmacogenomic Data and the IND 60
Submitting the IND 61
Maintaining/Updating the IND 61
Protocol Amendments 62
IND Safety Reports 63
Annual Reports 65
Information Amendments 66

Chapter 4. CDER and the IND Review Process 69

The FDA�s Center for Drug Evaluation and Research 70
Recent and Upcoming Changes in CDER Structure 73
CDER�s Review Divisions 75
Division of Cardio-Renal Drug Products 75
Division of Oncologic Drug Products 76
Division of Neuropharmacological Drug Products 77
Division of Metabolic and Endocrine Drug Products 77
Division of Pulmonary and Allergy Drug Products 78
Division of Anesthetic, Critical Care, and Addiction Drug Products 78
Division of Reproductive and Urologic Drug Products 78
Division of Medical Imaging and Radiopharmaceutical Drug Products 79
Division of Gastrointestinal and Coagulation Drug Products 79
Division of Anti-Infective Drug Products 80
Division of Antiviral Drug Products 80
Division of Special Pathogens and Immunologic Drug Products 80
Division of Dermatologic and Dental Drug Products 81
Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products 81
Inside the FDA�s Drug Review Divisions 82
The IND Review Process 83
Initial Processing of the IND 85
The IND within the Review Division 85
Pharmacology Review 86
Chemistry Review 86
Clinical Review 86
Microbiology Review 86
The 30-Day Review Clock 87
The Clinical Hold 88
IND Status 93

Chapter 5. The Clinical Development of New Drugs 95

Clinical Trials and the FDA�s New �Critical Path� Initiative 98
The FDA�s Role in Clinical Trials 102
The Structure of Clinical Trials 104
Phase 1 Clinical Trials 106
PK/PD and Phase 1 Trials 107
Sponsor Information/Data Submissions During Clinical Trials 108
Phase 2 Clinical Trials 109
End-of-Phase 2 Meetings and Other FDA-Sponsor
Communication During Clinical Trials 111
Phase 3 Clinical Trials 114
Pivotal Clinical Studies 114
Standards for Pivotal Trials 116
Determining Adequate Study Sizes 119
Completing a Drug�s Clinical Study 124
Phase 4 Clinical Studies 126

Chapter 6. Good Clinical Practices (GCP) 129

Recent Developments in GCP 130
Responsibilities of the Sponsor 134
Selecting Investigators and Monitors 134
Informing Investigators 137
Review of Ongoing Investigations 137
Recordkeeping and Record Retention 138
Disposition of Unused Drug Supplies 138
Sponsors and Data Safety Monitoring Boards 139
Responsibilities of Investigators 140
Control of the Product 140
Recordkeeping and Record Retention 140
Investigator Reports 141
Assurance of IRB Review 141
Handling of Controlled Substances 141
The Institutional Review Board (IRB) 141
Informed Consent 143

Chapter 7. The New Drug Application (NDA) 147

The History of the NDA 148
NDA Content and Format Requirements 151
The Common Technical Document/Electronic Common Technical Document 152
The Fundamentals of NDA Submissions 158
The Archival, Review, and Field Copies of the NDA 161
Application Form 162
The Index 162
Labeling 163
The New �Content of Labeling� Section 163
The NDA Summary 164
Chemistry Section 165
The NDA�s CMC Section and CDER�s New Quality Assessment System 167
Nonclinical Pharmacology and Toxicology Section 175
Human Pharmacokinetics and Bioavailability Section 176
Microbiology Section 178
Clinical Data Section 178
Safety Update Report Section 182
Statistical Section 182
Pediatric Use Section 183
Case Report Tabulations Section 184
Case Report Forms Section 185
Patent Information 185
Patent Certification 185
Establishment Description 185
Debarment Certification 186
Field Copy Certification 186
User Fee Cover Sheet (Form FDA 3397) 186
Financial Information Section 186
Other Information 187
Other Possible Elements of the NDA: RiskMAPs and Pharmacogenomic Data 188
The NDA and Risk Minimization Action Plans 188
Pharmacogenomic Data and the NDA 189
Complete versus Partial NDA Submissions 190
The GRMPs and the Wisdom of Complete NDA Filings 190
PDUFA III and Pilot 1: The Reviewable Unit 192
Pre-NDA Meetings 193
Assembling and Submitting the NDA 195
Amending the NDA 196

Chapter 8. The NDA Review Process 197

The NDA Review Process: Post-PDUFA 197
A Profile of the NDA Review Process 202
Initial Processing of the NDA 203
Processing Within the Drug Review Division 203
The FDA�s Refuse-to-File Authorities 204
PDUFA III and Early Notification of NDA Issues 208
The Preapproval Inspection 209
The Primary Review Process 211
Clinical Review 211
Pharmacology/Toxicology Reviewer 211
Chemistry Reviewer 212
Statistical Reviewer 212
Biopharmaceutics Reviewer 212
Microbiology Reviewer 212
Bioresearch Monitoring Reviewer 212
Mid-Review CDER/Sponsor Communications 215
Emerging Elements of the NDA Review Process: RiskMAPs and
Pharmacogenomic Data 217
Reaching an Institutional Decision on the NDA 218
The Formal Action on an NDA 220
FDA Action Letters 221
Approval Letter 222
Approvable Letter 222
Not-Approvable Letter 225
Applicant Responses to Approvable or Not-Approvable Letters 225
Final Printed Labeling 226
Draft Package Labeling 227
The FDA�s Review of Draft Labeling 230
Sponsor Rights During the NDA Review Process 231
The Right to a Timely Review 231
The Right to Meetings 233
The Right to Protest and Appeal FDA Actions/Decisions 235
The Right to Confidentiality 237
Proposed Changes to NDA Confidentiality Standards 238

Chapter 9. The FDA�s Priority Review Policy 241

Therapeutic Rating 242
Assigning the Therapeutic Rating 244
Chemical Novelty Rating 244
CDER�s Prioritization Policy at Work 246
The Impact of CDER�s Priority Review Policy 247
Patterns in Priority/Standard Designations for New Drugs 248

Chapter 10. Advisory Committees and the Drug Approval Process 251

A Look at Committee Membership 256
Conflict of Interest Standards for Committee Members 257
When CDER Uses Advisory Committees 258
How Advisory Committees Function 260
Committee Meeting Scheduling and Practices 261
How Influential Are CDER�s Advisory Committees? 263
What Sponsors Should Know About Advisory Committees 264

Chapter 11. Beyond Approval: Drug Manufacturer Regulatory Responsibilities 267

General Reporting Requirements 268
Field Alert Reports 268
Annual Reports 268
Other Reports 268
Adverse Drug Experience Reporting Requirements 271 Key Definitions Relevant to Adverse Drug Experience Reporting 274
Adverse Drug Experience Reporting Requirements 275
Pending Revisions to the FDA�s Postmarketing AE Reporting Requirements 279
Current Good Manufacturing Practice (cGMP) 281
The Pharmaceutical cGMPs for the 21st Century Initiative 282
The FDA�s cGMP Standards 285
The Enforcement of cGMP 288
Phase 4 Commitments 290
Trends in Postmarketing Commitments for New Drugs 293
Post-Approval Risk Management 294

Chapter 12. The Supplemental NDA and Postapproval Changes to Marketed Drugs 295

Recent History of Regulatory Reform and sNDAs 295
When to Submit Supplemental versus Original NDAs 298
Supplemental NDA Submission Requirements 298
Postmarketing Manufacturing Changes 299
FDAMA and Postmarketing Manufacturing Changes 299
SUPAC and sNDAs for Manufacturing Changes 301
Expedited Review for NDA Chemistry Supplements 303
�Bundled� CMC Supplements 303
Labeling Changes 304
Pursuing New Indications for Approved Drugs 305
Approval Times for Efficacy Supplements 306

Chapter 13. The FDA�s Orphan Drug Development Program 307

The FDA and Orphan Drugs: A Brief History 308
The Significance of Orphan Drug Designation 308
Obtaining Orphan Drug Designation 309
A Look at Orphan Drug Incentives 311
Marketing Exclusivity 311
Tax Credits 314
Protocol Assistance 314
FDA Grants and Contracts 315
The FDA Approval Process: Advantages for Orphan Drugs? 315
What Other Recent Studies Reveal About Orphan Drug Trends 316

Chapter 14. CDER�s Bioresearch Monitoring Program 319

A Brief History of the Bioresearch Monitoring Program 322
The Clinical Investigator Compliance Program 323
Study Oriented Inspection Program 324
Investigator Oriented Inspection Program 325
Bioequivalency/Bioavailability Inspection Program 326
Post-Inspectional FDA Actions 329
The Sponsor/Monitor Compliance Program 330
The Inspection of Drug Sponsors 331

Chapter 15. Accelerated Drug Approval/Expanded Access Programs 335

The Treatment IND 339
Treatment Use for Immediately Life-Threatening Conditions 341
Treatment Use for Serious Conditions 341
Obtaining FDA Permission for Treatment Use 342
The Sale of Investigational Drugs 343
The FDA�s Accelerated Drug Development Program (Subpart E) 344
Eligibility for Accelerated Development 347
The Cornerstone of Accelerated Development: Early FDA-Sponsor Consultation 348
Restructuring Clinical Trials 348
Accelerated Drug Approval Program (Subpart H) 349
Eligibility for Accelerated Approval 351
The Parallel Track Program 353
The Oncology Initiative 353
Fast Track Initiative 355
Qualifying for Fast Track Status 356
Seeking a Fast Track Designation 358
Fast Track and the Rolling NDA 359
Assessing the Activity and Success of the Fast Track Program 360

Chapter 16. The Pediatric Studies Initiative 363

Historical Development 364
The Carrot: FDAMA Pediatric Exclusivity as Reauthorized Under
the Best Pharmaceuticals for Children Act (BPCA) 365
Modifications of the FDAMA Pediatric Exclusivity Scheme Under the BPCA 368
The Stick: The FDA�s 1998 Rule as Codified Under the Pediatric
Research Equity Act (PREA) 370
Incorporating Pediatric Studies into Drug Development Planning 374
Planning Considerations I: What Types of Studies Will Be Needed? 375
Planning Considerations II: How Often Will New Formulations be Needed? 379
Planning Considerations III: What Resources Are Available? 380
Information Sources 382
The Present 383
The Future 386