Editors

Douglas J. Pisano is a professor of social and administrative sciences at the Massachusetts College of Pharmacy and Health Sciences (MCPHS) University. He began his career at the University in the Fall of 1984 and has maintained a full-time faculty appointment and is a member of the graduate faculty. In 1998, he became the founder and director of the master of science degree in regulatory affairs and health policy and served in that role until 2010. In the year 2000, he became the dean of the newly established School of Pharmacy—Worcester. Its cutting-edge accelerated Doctor of Pharmacy program was instrumental in establishing a companion program using distance education technology at the college’s Manchester campus. In June 2005, Dr. Pisano became the associate provost for Pharmacy Education and dean of the School of Pharmacy at Boston where he was charged with blending, coordinating, and overseeing many of the aspects of the college’s three distinct and accredited Doctor of Pharmacy programs, which extend over three campuses into a single face of pharmacy for the college overall. His pharmacy deanship also included the oversight of the 12 programs in the School of Graduate Studies and the Office of Pharmacy Experiential Education. He has also served as interim dean for the School of Medical Imaging

and Therapeutics and Physician Assistant Studies. Dr. Pisano currently serves as vice president of academic affairs and provost for the university.

This book contains following chapter 

1.0 Overview of FDA and Drug Development

CONTENTS

Introduction

The Evolution of the FDA—A Century of Laws and Policies

The History (1848–1979)

1980 to the Present: AIDS, Orphans, Terrorism, Economic Incentives,and the Food and Drug Administration Safety and Innovation Act

Biologics Price Competition and Innovation Act of 2009

FDASIA 

Summary

Agency Role and Organization

New Drug Development and Approval Summary

Preclinical Investigation

Investigational New Drug Application

Phase I 

Phase II 

Phase III 

New Drug Application

Fast Track, Accelerated Approval, Priority Review, and “Breakthrough Therapy” Designations

Phase IV and Postmarketing Surveillance

Orphan Drugs

Abbreviated New Drug Applications

OTC Regulations

Biologics

Devices

Regulating Drug and Device Marketing

Violations and Enforcement

Conclusion

Notes

References

2.0 What Is an IND?

CONTENTS

What Is an IND?

When Do I Need an IND?

When Don’t I Need an IND?

Pre-IND Meeting

The Content and Format of an IND Application

Cover Sheet—Section 312.23(a)(1) Form FDA 1571—IND

Table of Contents—Section 312.23(a)(2)

Introductory Statement and General Investigational Plan— Section 312.23(a)(3)

Investigator’s Brochure—Section 312.23(a)(5)

Clinical Protocol—Section 312.23(a)(6)

CMC Information—Section 312.23(a)(7)

Pharmacology and Toxicology Information—Section 312.23(a)(8)

Previous Human Experience—Section 312.23(a)(9)

Additional Information—Section 312.23(a)(10)

Relevant Information—Section 312.23(a)(11)

Other Important Information about the Submission of an IND

Electronic Submissions

FDA Review of the IND

Maintaining an IND—IND Amendments and Other Required Reports

The IND Safety Report

The Protocol Amendment

Information Amendments

IND Annual Reports

Other Types of INDs

Promotion and Charging for Investigational Drugs

Promotion of Investigational Drug Products

Charging for Investigational Drugs

More Information about INDs

The FDA Websites

Other Websites

References

3.0 The New Drug Application

CONTENTS

Overview

Laws, Regulations, and Guidances

Development of the NDA

Format and Content of the NDA. 

Module 1: Administrative and Prescribing Information 

Section 1.1: Forms—Application Form [21 CFR 314.50(a)] 

Section 1.1: Forms [User Fee Cover Sheet (Form FDA 3397)]

Section 1.2: Cover Letter/Index [21 CFR 314.50(b)]

Section 1.3.2: Field Copy Certification [21 CFR 314.50(d)(1)(v)] 

Section 1.3.3: Debarment Certification [FD&C Act 306(k)(1)]

Section 1.3.4: Financial Certification and Disclosure [21 CFR Part 54] 

Section 1.3.5.1: Patent Information [21 CFR 314.50(h) and 314.53]

Section 1.3.5.2: Patent Certification [21 CFR 314.50(i) and 314.52]

Section 1.12: Other Information [21 CFR 314.50(g)] 

Section 1.14: Labeling [21 CFR 314.50(e)]

Module 2: Common Technical Document–Summary (21 CFR 314.50) 

Section 2.2: Introduction to the Summary Documents 

Section 2.3: Quality Overall Summary

Section 2.4: Nonclinical Overview 

Section 2.5: Clinical Overview. 

Section 2.6: Nonclinical Written and Tabulated Summaries 

Section 2.7: Clinical Summary 

Module 3: Quality 

Module 4: Nonclinical Study Reports 

Module 5: Clinical Study Reports 

Mapping the Content of the NDA to the CTD Format 

Submission and Review of the NDA 

Step 1: Ensure Readiness for Application through Presubmission

Activities  

Step 2: Process Submission 

Step 3: Plan Review of the Application 

Step 4: Conduct Scientific/Regulatory Review of the Application 

Step 5: Take Official Action on the Application

Step 6: Provide Postaction Feedback to the Applicant

Maintenance of the NDA

Postmarketing 15-Day Alert Reports

Postmarketing 15-Day Alert Reports Follow-Up

Periodic ADE Reports101

NDA Annual Report

Conclusion

Notes1

4.0 Meetings with the FDA

CONTENTS

Introduction

Types of FDA Meetings

Pre-IND Meetings

End-of-Phase II Meetings

Special Protocol Assessment and Ad Hoc Technical Meetings

Pre-NDA/BLA Meetings

Advisory Committee Meetings

Late Cycle Meetings

Labeling Meetings

Postmarketing Requirement/Postmarketing Commitment, and Risk,Evaluation and Mitigation Strategy Meetings

Postaction Meetings

Biosimilar Biological Product Development Meetings

FDA Expectations

Preparing for FDA Meetings

Conduct at FDA Meetings

Avoiding the Pitfalls

Open-Ended Questions

Reasoned Proposals

Specific Meeting Objectives

Pre-IND Meetings

End-of-Phase II Meetings

Special Protocol Assessment Meetings

Pre-NDA/BLA Meetings

Advisory Committee Meetings

Late-Cycle Meetings

Labeling Meetings

PMR/PMC and REMS Meetings

Postaction Meetings

BPD Meetings 

Conclusion.

Reference

5.0 FDA Medical Device Regulation

Introduction

Is It a Device?

Product Jurisdiction

Types of Medical Devices

Medical Device Classification

Determining Device Classification

Reclassification

An Introduction to the Medical Device Approval Process

Strategic Choices

Modification of Marketed Devices

Design Controls

The Difference between Research and Development

Design Control Components

Medical Device Clinical Research

Exempted Studies

Nonsignificant Risk Studies

Significant Risk Studies

The Investigational Device Exemption

Unique Aspects of Medical Device Studies

The 510(k) Premarket Notification

Substantial Equivalence

Types of 510(k)s

Traditional 510(k)

Abbreviated 510(k)

Special 510(k) 

De Novo 510(k) 

510(k) Components

The Cover Sheet (Form FDA 3514)

The Cover Letter

The Table of Contents.

User Fee Information

Form FDA 3654

Statement of Substantial Equivalence

Labeling 

Advertising and Promotional Material

Comparative Information

Biocompatability Assessment (If Necessary)

Truthful and Accurate Statement

Clinical Data 

Shelf Life (If Necessary)

Indication for Use Form

510(k) Summary

Practical Aspects for 510(k)s

Postsubmission Considerations for 510(k)s

The PMA Application

Introduction to the PMA

The PMA Process

User Fee 

Advisory Panels

Clinical Data

Use of International Data

Components of the PMA

The Quality System Regulation

Design Controls

Management Controls

Corrective and Preventive Action

Production and Process Controls

Postmarketing Issues

Registration and Listing

Medical Device Modifications

Modifications to 510(k) Devices

Modifications to PMA Devices

Medical Device Reporting

Unique Device Identification

Advertising and Promotion

References

6.0 A Primer of Drug/Device Law: What Is the Law and How Do I Find It?

Introduction

What Is a “Law”?

Who Makes Laws?

Who Interprets Laws?

Who Enforces Laws?

What Is the Difference between a Federal Law and a State Law?

Which Laws Are More Important—The State or the Federal? What Is“Preemption”?

Are There Any Times When State Laws Control Medical Products?

Where Do I Find Laws?

How Do I Find Current Laws?

What Do All These Numbers Mean? What Is a Citation?

What Is the Difference between the USC and the Public Laws? How Are Laws  Published?

What Is the Difference between the FDCA and the USC?

What Is an “Amendment”?

Why Can’t I Find Section 510(k) in the USC?

Where Is the Biologics/Biosimilars Law? I Can’t Find It in 21 USC Anywhere

What Is a “Regulation”?

What Is the Difference between a Law and a Regulation?

Which Is More Important—A Law or a Regulation?

What Is the Difference between the USC and the CFR?

How Do I Find a Current Regulation?

How Do I Find Older Regulations?

What Is “Guidance”?

Conclusion

7.0 The Development of Orphan Drugs

Introduction

The Orphan Drug Act of 1983 and Its Amendments

Incentives for Orphan Drug Development

Orphan Drug Exclusive Approval

Tax Credit for Clinical Development

Orphan Products Grants

Exemption from Marketing Application Fee

Written Recommendations for Orphan Drug Development

Orphan Drug Designation

Patient Population Determination

Orphan Subsets of Nonrare Diseases or Conditions

Medically Plausible Basis of Effectiveness

Determination of Orphan Drug Sameness

Clinically Superior Orphan Drugs

Orphan Drug Experience in the United States

Conclusion

Acknowledgments

References

8.0 CMC Sections of Regulatory Filings and CMC Regulatory Compliance during Investigational and Postapproval Stages

Introduction

Pharmaceutical Quality

Drug Substance

Manufacture

Characterization (Structure Elucidation)

Control of Drug Substance (Specifications)

Reference Standards or Materials

Container Closure System

Stability 

Drug Product

Description and Composition of the Drug Product

Pharmaceutical Development

Components of the Drug Product

Drug Product Development

Manufacture (Manufacturer(s)/Method of Manufacture)

Control of Excipients (Specifications)

Control of Drug Product (Specifications)

Justification of Specification(s)

Reference Standards or Materials

Container Closure System

Stability 

Additional Information for Biotechnology Products

Additional Information for Combination Products

CMC Regulatory Compliance

Managing CMC Changes and Maintaining Regulatory Compliance

Managing Changes during IND Stages

Managing Changes during Postapproval Stages

CMC-Specific Meetings with the FDA

Pre-IND Meeting

EOP2 Meeting

Pre-NDA Meeting

Other Meetings (Type C)

FDA Initiative on “Pharmaceutical cGMP for the 21st Century—A Risk-Based Approach” and Its Impact on CMC Drug Development and Change Management

Conclusion

References

9.0 Overview of the GxPs for the Regulatory Professional

Introduction to the GxPs

Introduction to the GLPs

History of the GLPs

GLPs Today?

US GLP Regulations

GLP Guidance Documents

Organization and Personnel

Facilities and Equipment

Testing Facility Operations

Test and Control Article

Protocols, Records, and Reports

Compliance with GLPs

Introduction to Current GMPs

History of the cGMPs

cGMPs Today

GMP Regulations and Guidance

Compliance with cGMPs

GMP Inspections and Consequences

cGMP References

Introduction to the GCPs

History of the GCPs

GCPs Today

US GCP Regulations

GCP Guidance Documents

Who Is a Sponsor and How Do They Meet Their Obligations?

RB Responsibilities

Investigator Responsibilities

Sponsor Responsibilities and Oversight of Clinical Trials

Compliance with GCPs

Sponsor Audits

Summary

Internet Resources

GxP References

GLP References

GMP References

International GMP References

References

10.0 FDA Regulation of the Advertising and Promotion of Prescription Drugs, Biologics, and Medical Devices

Introduction

Regulation of the Advertising and Promotion of Prescription Drugs

Promoting Prescription Drugs—General Policies

Prior Approval and Preclearance of Promotional Materials

When Is Preclearance Required?

The “Fair Balance” Requirement

The Brief Summary Requirement for Prescription Drug Advertisements

Directed to Physicians

Advertisements Exempt from the Brief Summary Requirement

Product Name and Placement

Submission of Promotional Materials to OPDP

Product Claims for Prescription Drugs

Unapproved Products and Unapproved Uses for Approved Products

Accelerated Approvals—Relationship to Advertising and Promotion

Off-Label Promotion

Public Request/Response

Private Request/Response

Comparative and Superiority Claims

Pharmacoeconomic Claims

Quality-of-Life Claims

“New” and “Now-Available” Claims

Promotion to Health-Care Professionals

Drug Detailing 

Medical Conferences and Exhibits

Exchange of Scientific Information

Single-Sponsor Publications

Use of Spokespersons

DTC Advertising

Broadcast and Print Media.

Press Releases, Video News Releases, and Materials for the Financial Community

Industry Organizations

Regulation of the Advertising and Promotion of Biologic Products

General Policies

Regulation of the Advertising and Promotion of Medical Devices

Differences between Policies for Drugs and Devices

General Promotion of Devices

PE Promotion

Investigational Device Advertising

DTC Promotion of Medical Devices

Similarities between CDER Policies and CDRH Policies on Advertising and Promotion

FDA Enforcement—Violation of the FD&C Act or FDA Regulations for Advertising and Promotion of Prescription Drugs, Biologics, and Medical Devices

Primary Enforcement Tools

Untitled Letters 

Warning Letters 

Remedies for Warning Letters

Conclusion

References

11.0 The Practice of Regulatory Affairs

Introduction

What is “Regulatory Affairs”?

Background and Training

Is There a Degree That Matters?

The Importance of Self-Education

Attitude and Approach

Regulatory as Navigator and Architect

Zealotry 

Information

What Information Matters?

Gathering Information

Communicating Information

Documentation

The Memo

Managing Documents

Practical Example: Documenting an FDA Contact..

Submissions

Who Writes These Documents, Anyway?

Regulatory Review: Continuity and Connections

Presenting Data in Submissions

The Art of Handling Large Documents

Conclusions

Notes

12.0 FDA Advisory Committees

Introduction

Historical and Regulatory Framework

Structure

Composition

Membership Type

Qualification Requirements

Appointment Process

Membership Training

Conflicts of Interest

Conflict of Interest Waivers

FDA-Initiated Conflict of Interest Studies

Operation

Industry Perspective.

Affecting FDA’s Decision to Call a Meeting

Preparing for the Advisory Committee Meetings

Success Criteria: Dedicated Team

Success Criteria: External Expertise

Success Criteria: Rehearsal.

After the Advisory Committee Meetings

Conclusion

References

13.0 Biologics

Introduction.

Current FDA Oversight

Biologics Development

Design 

Process Development and Manufacturing

Analytical Development

Nonclinical Evaluation

Clinical Development

Biologics Approval Process

References

14.0 Regulation of Combination Products in the United States

Introduction

Combination Product Classification and Assignment

Classification: Is the Product a Combination Product?

Assignment: Which Center Has the Lead for a Combination Product?

Obtaining an Agency Classification or Assignment Determination

Regulation of Combination Products

Premarket Regulation: Marketing Authorization Requirements and

Processes 

Investigational and Marketing Submissions

Marketing Authorization Standards for Combination Products

Intercenter Coordination and Sponsor–FDA Interaction for Premarket Review of Combination Products

Postmarket Regulation of Combination Products

What Is OCP and What Does It Do?...

Recent and Upcoming Developments...

Acknowledgments.

Notes.