New drug approval process 5th Edition by Richard Guarino 1420088491 9781420088496

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ISBN 10: 1420088491

ISBN 13: 9781420088496

Author: Richard A. Guarino

The thoroughly revised Fifth Edition of New Drug Approval Process supplies readers with the latest global changes that affect pharmaceutical product approval and influence how new products are researched and marketed.Updated chapters include:advances in international regulatory requirements, including ICH guidelines and harmonizationa step-by-step

New drug approval process 5th Table of contents:

1 Drug Development Teams

Introduction

Drug Discovery Project Team

Preclinical Drug Development Project Team

Clinical Drug Development Project Team

Drug Development Logic Plan

Conclusion

2 FDA Approvable Indications and Other Considerations

Introduction

Background

Considerations for Patient Benefit of Product

Surrogate Endpoints

Product Development

Precedents

FDA Advisory Panels

Special Protocol Assessment (SPA)

Conclusion

3 Data Presentation for Global Submissions: Text and Tabular Exposition—CTD Format

Introduction

Text Exposition

Content

Tone

Conciseness

Correctness

Consistency

Clarity

Outline of Sections and Subsections

Indenting

Global to Specific

Tabular Presentation

Title

Data Source

Footnotes

Orientation

Order of Data Presentation

Present Meaningful Data Together

Conclusion

References

4 Technology Change—Enabling Clinical Research and Drug Development Processes

Introduction

People, Process—and Then Technology

Technology Adoption Life Cycle

The Interent

Intranets and Extranets

The Software As a Service (SaaS) Business Model

Security

Hardware

Software

General Software Applications

Data Standards

eDiscovery Software

ePreclinical Software

eClinical Software

Electronic Data Capture (EDC) and Electronic Patient Reported Outcomes (ePRO)

Clinical Trials Management Systems (CTMS)

Collaboration Software

Database Management Systems (DBMS)

Document Management Systems

Portals and Data Warehouses

Conclusion

5 Working with a Contract Research Organization (CRO)

Part I Contract Research Organizations

Introduction

Nonclinical Contract Research Organizations

CRO Identification and Selection

Virtual Company Strategy

Preselected Strategy

Special Study Strategy

CRO Monitoring

Conclusion

Part II Clinical Contract Research Organizations

Introduction

Defining the Scope and Choosing a Clinical CRO

Working with the CRO

Conclusion

6 Industry and FDA Liaison

Introduction

Inspections and Legal Sanctions

Scientific Expertise

Product Safety

FDA’S Major Program Centers

The Center for Drug Evaluation and Research (CDER)

Contacts and Communications with FDA

Consumer/Industry Inquiries

Industry/FDA Meetings

Meeting Requests

FDA/Industry Meetings

Pre-IND/Preclinical Meetings

End-of-Phase 2 Meeting (EOP2)

Preparing for an End-of-Phase 2 Meeting

End-of-Phase 2 Conference—Summary

Pre-NDA/BLA/CTD Meetings

Advisory Committee Meetings

FDA Initiatives to Speed Drug Approval

Accelerated Development/Review Program

Treatment IND

FDA Guidance Documents/Guidelines

Freedom of Information ACT (FOIA)

Obtaining Public Information

Obtaining Information Through FOI

How to Make a FOI Request

Fees

Summary

7 Nonclinical Drug Development: Pharmacology, Drug Metabolism, and Toxicology

Introduction

Overview of Drug Discovery and Development

Pharmacology

Developability Assessment

Pharmacology

Bioanalytical Chemistry Method Development

Early Nonclinical Formulation Development and Delivery

Preliminary Animal Pharmacokinetics

Preliminary Drug Metabolism

Acute Toxicology Studies

In Vitro Toxicology Assessments

Acute or Single-Dose Tolerability Studies

Dose-Range-Finding Studies

Pilot, 14-Day Studies

Safety Pharmacology and Genotoxicity

Drug Development Candidate Selection

Preclinical Drug Development

Good Laboratory Practice

Bioanalytical Chemistry

Pharmacokinetic and Bioavailability Experiments

Drug Metabolism

Toxicology

Local Tolerance

Genotoxicity

Safety Pharmacology

Subchronic Toxicology

Formulation Analyses

Toxicokinetics

Hematology, Clinical Chemistry, and Histopathology

Immunogenicity

Nonclinical Drug Development

Pharmacokinetics

Drug Metabolism

Toxicology

Chronic Studies

Reproductive and Developmental Toxicology

Carcinogenicity

Conclusion

References

8 The Investigational New Drug Application (IND), the Investigational Medicinal Product Dossier (IMPD) and the Investigator’s Brochure (IB)

Overview

The Investigational New Drug Application

Introduction

General Information Regarding INDs

Exemptions

Labeling Requirements for an Investigational New Drug

Waivers

Preconsultation Program

Binders for IND Submissions

Address for IND Submissions

Availability for Public Disclosure of IND Data

Phases of Clinical Investigations

Phase 1

INDs for Phase 1 Trials

Requirements for Protocols

Requirements for CMC Information

Pharmacology and Toxicology Information

IND Submissions Assessments

Form FDA 1571

IND Content and Format

Protocol and Information Amendments

IND Safety Reports

Annual Reports

Clinical Holds and Withdrawal of an IND

The Investigator’s Brochure

Introduction

The Investigational Medicinal Product Dossier (IMPD) and Required Documentation to Conduct Clinical Research in the EU

Introduction

Overall Content of the IMPD

Simplified IMPD

Conclusions

9 New Product Applications for Global Pharmaceutical Product Approvals: U.S. NDA Vs. Global CTD Formats

Introduction

General Overview of New Drug Applications

Retrospective Overview of the NDA in the United States (Review and Archival Copies)

The Paper NDA—Required Information

General Format

Contents of the Archival Copy

Contents Review Copy

Other NDA Submission Requirements

Pagination/Volume Size/Identification

Packing Cartons

Overall Comments

U.S. NDA VS. CTD Format

Region Specific Documentation

Formats for New Product Applications

Overall Comments Between an NDA and CTD Format

Listing of IND and NDA Investigators

Background/Overview of Clinical Investigations

Clinical Pharmacology

Controlled Clinical Studies

Study Reports

Safety Information

Uncontrolled Clinical Studies

Other Studies and Information

Organizing Common Technical Documents Summaries

Quality

Safety (Nonclinical Pharmacology, Pharmacokinetics, and Toxicology) Summary

Human Pharmacokinetics and Bioavailability Summary

Microbiology Summary

Clinical Data Summary and Results of Statistical Analysis (Module 2)

Clinical Pharmacology

Overview of Clinical Studies

Controlled Clinical Studies

Uncontrolled Clinical Studies

Other Studies and Information

Safety Summary—General Safety Conclusions

Discussion of Benefit/Risk Relationship and Proposed Postmarketing Studies

Summary and Critique

CTD Review Guide

References

10 Abbreviated and Supplemental New Drug Applications (ANDAs and SNDAs)

Abbreviated New Drug Application

Background History

Anda Content

General

Legal Requirements and Guidance Documents

ANDA CHECKLIST for CTD or eCTD FORMAT FOR COMPLETENESS and ACCEPTABILITY of an APPLICATION FOR FILING

Additional Comments Regarding the ANDA

Amendments to an Unapproved ANDA

Postmarketing Reports

Summary

Supplemental New Drug Applications

SNDA/SANDA Checklist

Summary

Bibliography

11 The CTD and eCTD for the Registration of Pharmaceuticals for Human Use

Introduction

CTD Overview

Module 2 Common Technical Document Summaries

Quality Overall Summary

Nonclinical Overview

Clinical Overview

Nonclinical Written and Tabulated Summaries

Clinical Summary

Module 3 Quality

Module 4 Nonclinical Study Reports

Module 5 Clinical Study Reports

eCTD

Conclusions

References

12 The Biologic License Application

Introduction

A Short History of the Licensing Process for Biologicals

Introduction to BLAs: Content and Formating Requirements

The Contents of the BLA

Cover Letter

Application Form FDA 356(h)

Item 1 Index

Item 2 Labeling Section

Item 3 Summary Section

Item 4 Chemistry Section

Chemistry, Manufacturing, and Controls Information

Drug Substance

Drug Product

Investigational Product/Formulation

Environmental Assessment

Method Validation

Samples

Methods Validation Package

Item 5 Nonclinical Pharmacology and Toxicology Section

Item 6 Human Pharmacokinetics and Bioavailability Section

Item 7 Clinical Microbiology

Item 8 Clinical Data Section

Item 9 Safety Update Report

Item 10 Statistical Section

Item 11 Case Report Tabulations Section

Item 12 Case Report Forms (CRFs) Section

Item 13 Patent Information Section

Item 14 Patent Certification Section

Item 15 Establishment Description Section

General Information

Specific Systems

Contamination/Cross-Contamination Issues

Item 16 Debarment Certification Section

Item 17 Field Copy Certification Section

Item 18 User Fee Cover Sheet Section (Form FDA 3397)

Item 19 Financial Information Section

Item 20 Other

Amending the License Application

Supplement to the Original BLA

Assembling and Submitting the BLA

13 Chemistry, Manufacturing, and Control (ICH Quality Guidelines)

Introduction

The NDA Summary

The Drug Substance

Names

Physical and Chemical Properties

Stability

Manufacture

Method of Manufacture

Process Controls

Specifications and Analytical Methods

Container/Closure System

The Drug Product

Composition of the Dosage Form

Manufacturer

Method of Manufacture

Specifications and Analytical Methods

Container/Closure System

Stability

Test Formulations

Chemistry, Manufacturing, and Controls Information

The Drug Substance

Names

Structural Formula and Chemical Name(s)

Physical and Chemical Properties

Proof of Structure

Stability

Manufacturer

Method of Manufacture

Starting Materials—Specifications and Tests

Solvents, Reagents, and Auxiliary Materials

Drug Substance Synthesis

Antibiotics and Other Products Obtained by Fermentation Processes

Drug Substances Isolated from Plant or Animal Sources

Process Controls

Reprocessing

Reference Standard Preparation

Specifications and Analytical Methods

Container/Closure System

Drug Product

Components

Composition

Specifications and Analytical Methods for Inactive Components

Manufacturer

Method of Manufacture, Packaging Procedure, and In-Process Control

Regulatory Specifications and Analytical Methods for Drug Product

Container/Closure System(s)

Stability

Environmental Assessment

Samples

Methods Validation Package

Test Methods and Specifications

Supporting Data

Test Results

Abbreviated New Drug Application

Summary

Drug Substance Sources

Specifications

Drug Product Requirements

ANDA Expiration Dates

Conclusion

Bibliography

14 New Medical Device Approval Process in the United States

Background and History

Premarket Notification (510k)

Clinical Data

Investigational Device Exemptions

An IDE Submission

Submitting an IDE

FDA Action on Applications

Responsibilities of Sponsors

Retention Period

Inspection

Responsibilities of Investigators and IRBS

IDE Guidance

Labeling

Prohibition of Promotion and Other Practices

Import and Export Requirements

PMA

The PMA Submission

Format

PMA Filing Review

Presubmission Interaction

FDA Action on a PMA

FDA Steps in the PMA Application Process

Panel Review

Conditions of Approval

Availability of Safety and Effectiveness Summaries for PMAS

References

15 Orphan Drugs

Introduction

Benefits for Developing Orphan Drugs in the United States

How to Obtain Orphan Product Designation

Orphan Drug Application

Background and Significance

Content and Format of a Request for Written Recommendations of Orphan Drugs (21 CFR Subpart B 316.10)

Recommendations for Submission of an Orphan Drug Designation

Clinical Studies of Safety and Effectiveness of Orphan Products

Orphan Drug Grant Requests

Scientific/Technical Review Criteria

FDA Review and Actions

Annual Reports

Summary

References

16 Clinical Research Protocols

Introduction

Trail Objective

General Considerations in Protocol Design

Different Trail Designs

Controlled Trails

Blinding Techniques

Uncontrolled Trials

Parallel and Crossover Trial Designs

A Guideline for Elements of a Protocol: A Checklist

Title Page

A Phase 2 Double-Blind Parallel Trial of Dose Tolerance, Safety, and Efficacy Comparing Drug a to Placebo in Controlling Symptoms of Mild to Moderate Hypertension

Table of Contents

Introduction/Background

Bibliography

Objective

General

Risks

Confidentiality

Materials and Methods

Subject Sample

Age Range

Gender

Subject Inclusion and Exclusion Criteria

Trial Procedures

Trial Drugs

Assignment of Trial Products

Dosage Range (if any)

Dosage Schedule

Administration of Trial Medication

Labeling of Trial Medications

Medication Accountability

Duration of Drug Treatment

Concomitant Medications

Case Report Forms (CRFs)

Content of the Case Report Form

Laboratory Assessments

Adverse Experiences

Data Entry and Statistical Methodology of Data

Overall Duration of the Trial

Institutional Review Board (IRB) Independent Ethics Committee (IEC)

Informed Consent (IC)

Monitoring

Location of Trial

Location of Laboratory Testing Facilities

Investigator’s Obligations

Signature Page

Amendments and Addenda

Amendments

Addenda

Summary

Bibliography

17 Institutional Review Board/Independent Ethics Committee and Informed Consent: Protecting Research Subjects in the U.S. and Foreign Clinical Trials

Introduction

Background

IRB Duties

IRB Membership and Responsibilities

IRB Documentation and Operations

Information Required for IRB Review

Initial Approval and Continuing Review

Expedited Reviews

The Informed Consent Form

Basic Elements of the Informed Consent (21 CFR 50.25)

Additional Elements of the Informed Consent [21 CFR 50.25(B)]

Oral Consent

Emergency Use of Investigational Drug/Biologics

Informed Consent During Emergency Use

Health Insurance Portability and Accountability Act (HIPAA)

Assuring That Regulatory Obligations are Adequately Implemented

Audits Versus Inspections

Common Auditing/Inspectional Findings: IRBS

Common Auditing/Inspectional Findings: Informed Consent

Safety and Welfare Considerations for Subjects in Foreign Trials

Bibliography

18 HIPAA: A New Requirement to the Clinical Study Process

Introduction

HIPAA Basics

Who are the covered entities?

Who are not covered entities?

Section 164.308—Administrative Safeguards

Section 164.310—Physical Safeguards

HIPAAs Impact on Clinical Research

Covered and Not Covered Entities

Who are the covered entities?

Who are not covered entities?

Applicability

HIPAA Syntax

PHI Authorization for Clinical Trials

Background

Enforcement of HIPAA

Authorization for Clinical Trials

Relationship to IC

IRBs

Privacy Boards

IRB or Privacy Waivers of Authorization

Waiver of a Research Database

Study Recruitment

Limited Data Sets

References

Bibliography

19 Adverse Events and Reactions: Etiology, Drug Interactions, Collection, and Reporting

Introduction

Classification of Adverse Drug Reactions

Dose-Dependent AEs

Precautions of Drug Use in Pregnant Women

Antibacterial and Antibiotic Drugs

Anticoagulants

Antithyroid Drugs

Oral Hypoglycemia Drugs

Cardiovascular Drugs

Anesthetics, Analgesics, and Hypnotics

Nursing Women

Women of Childbearing Potential

Geriatric Population

Pediatric Population

Enzyme Abnormalities

Inherited Enzyme Abnormalities

Liver Diseases and Functions

Renal Function

Dose-Independent AEs

Drug Interactions

Mechanisms of Drug Interactions

Pharmacokinetic Pathways and Drug Interactions

Absorption

Distribution Competition for Transport Sites

Interference with Drug Metabolism

Modification of Drug Event at Sites of Action

Excretion

The Beneficial Effects of Drug Interactions

Collection, Evaluation, and Reporting of Adverse Events to Drugs

Overview

Collecting AEs—Legal Responsibilities

Investigational Drugs

Reporting AEs from Study Subjects During Clinical Investigations

Postmarketing Reporting

The Marketing Authorized Holder (MAH)

Regulatory Agencies Globally

Professional (Physicians and Pharmacists) and Consumers

Literature

Postmarketing Surveillance

Evaluation of AEs

Investigational Drugs

Completed Clinical Trials

Postmarketing Surveillance

Spontaneous Reports

Observational Studies

Registries

Reporting Adverse Reactions

Investigational Stage

Postmarketing Stage

Assessment of Adverse Reactions

ICH Guidelines

Adverse Event Disclaimers

General

European Guidelines on Collection and Verification of Adverse Reactions

Summary and Conclusion

References

20 Biostatistics in Pharmaceutical Product Development Facts, Recommendations, and Solutions

Introduction: The Role of Biostatistics in Late-Stage Pharmaceutical Development

Alpha = 0.05

The Price of Power

Safety by Design

Signal Detection and EDA (Exploratory Data Analysis)

Sources of Bias

Sampling

Data Refinement

Regulatory Oversight

Experimental Design in Clinical Trials: Theory and Practice

Sample Size and Experimental Design

Sensitivity and Cost

Recommendations

Random Sampling

Recommendations

Data Refinement

Safety Signal Detection and EDA

Recommendations

Summary

21 CFR/ICH/EU GCP Obligations of Investigators, Sponsors, and Monitors

Introduction

Investigator Obligations

Other Investigator Responsibilities

Investigator Penalties

Sponsor Obligations

Sponsor and Monitor Obligations

22 Quality Assurance

Introduction

Challenges of QA

QA and Legislation

Definition of QA

QA Function

QA Department

QA Activities

QA Tools and Techniques

QA During the Product Life Cycle

Regulatory Inspections

Future Value of QA

References

23 Managing and Monitoring Clinical Trials

Overview

Regulations and Guidelines

Clinical Trial Management

Investigator Selection

Clinical Monitors

PISV

Investigator Meetings

SIV

Periodic Monitoring of a Clinical Trial

Trial Conduct/Execution

Subject Recruitment

Product Accountability

Financial Disclosure—U.S. Requirement Only

Record Retention

Study Closure Visit (SCV)

Summary

References

24 European CT Directive: Implementation and Update

Glossary

Background

Purpose

Scope

Definitions

Principal Elements of Directive Articles, Detailed Guidelines, and Guidance Documents

Protection of Clinical Trial Subjects, Minors, and Incapacitated Adults

Ethics Committee, Single Opinion, and Detailed Guidance

Commencement of a Clinical Trial

Conduct of a Clinical Trial

Exchange of Information, Suspension or Infringements, European Clinical Trials EUDRACT Database

Manufacture, Import, and Labeling of Investigational Medical Products

Inspections, Verification of Compliance of Investigational Medical Products with Good Clinical Practice and Good Manufacturing Practice

Adverse Experiences (AEs) and Serious Adverse Reactions (SARs) Notification, Collection, Verification, Presentation and Reporting, SUSAR Database, Eudravigilance Clinical Trial Module Database

General Provisions, Adaptation to Scientific and Technical Progress, Committee Procedure, Application, Entry into Force, and Addressees

Implementation

Implications for Future Research

References

25 Combination Products

Clinical Investigation and Premarket Review Requirements for Drugs and Medical Devices

User Fees

Nonclinical Recommendations for Successful Characterization and Development of Combination Drug Products

Clinical Pharmacology and Clinical Development of Combination Products

Regulatory Strategy Considerations for CMC

References

26 The Current State of GXP in China

Good Clinical Certificate Practice in Clinical Trials in China

Introduction

SFDA Structure and Regulatory Responsibilities

Establishment of a GCCP System in China

Administration Office at Clinical Institution

Independent Ethics Committee

Certified Clinical Institution

Institution Qualifications

Auditing Clinical Institution

Certification Requirements for Trial Drugs

Certification Requirements for Preclinical Data

Implementation of GCCP in China

Conclusion

The NDA Registration Process and Critical Tips in the Conduct of Clinical Trials in China

Background

Basics of an NDA Application in China

Law and Regulation

Health Authority

Qualification of the Foreign Applicant

Types and Materials of an NDA Application to SFDA

Type of the Application and New Application Category

Dossier Requirements

NDA Application Process in China

Logistical Requirements of the NDA Registration in China

Clinical Trial Requirement

Specific Review and Approval Process

NDA Application Fee

NDA Reviewing Timeline

Critical Tips in the Conduction of Clinical Trials in China

Legal and Regulatory Basis for Drug Researches

Characteristics of Clinical Trials Conductions in China

Major Provisions to Run a Clinical Trial in China

Before Clinical Trials

During Clinical Trials

At the End of Clinical Trials

Preparation of Investigational Drugs

Time Demand of Starting Trial

International Multicenter Clinical Study

Conclusion

Medical Devices and Clinical Research in China

Background

Legal Basis for Medical Devices Supervision

Regulations Basis

Regulatory Body System

Authorization Requirements on Device Registration for Foreign Companies in China

Types and Materials of a Medical Device Registration Application to SFDA

Process of the New and Renewal Application for Medical Devices Registration

Dossiers Requirements for the Medical Device Registration in China

Logistical Requirements of Medical Device Clinical Trials in China

Prerequisites of Clinical Trial Waiver

For the Device Product Manufactured Overseas

For Device Products Locally Manufactured

Special Attentions to be Paid in the Medical Device Registration in China

Conclusion

Registration Information Requirements of Natural Drugs in China

Introduction

Registration Categories and Notes

Registration Categories

Notes

Application Content Items and Notes

Application Content Items

Notes to Application Content Items

Special Attentions on Application Dossiers of the Natural Drug Registration

Conclusion

References

Acronyms and Initialisms

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