FDA's Drug Review Process and the Package Label

Strategies for Writing Successful FDA Submissions

Tom Brody

• Publisher: Academic Press
• Year: 2017
• Print ISBN: 9780128146477
• eBook ISBN: 9780128146484
• Topic: Medicine
• Subtopic: Pharmaceutical, Biotechnology & Healthcare Industry

FDA's Drug Review Process and the Package Label provides guidance to pharmaceutical companies for writing FDA-submissions, such as the NDA, BLA, Clinical Study Reports, and Investigator's Brochures. The book provides guidance to medical writers for drafting FDA-submissions in a way more likely to persuade FDA reviewers to grant approval of the drug. In detail, the book reproduces data on efficacy and safety from one hundred different FDA-submissions (NDAs, BLAs). The book reproduces comments and complaints from FDA reviewers regarding data that are fragmentary, ambiguous, or that detract from the drug's approvability, and the book reveals how sponsors overcame FDA's concerns and how sponsors succeeded in persuading FDA to grant approval of the drug. The book uses the most reliable and comprehensive source of information available for writing FDA-submissions, namely text and data from NDAs and BLAs, as published on FDA's website. The source material for writing this book included about 80, 000 pages from FDA's Medical Reviews, FDA's Clinical Pharmacology Reviews, and FDA's Pharmacology Reviews, from one hundred different NDAs or BLAs for one hundred different drugs. Each chapter focuses on a different section of the package label, e.g., the Dosage and Administration section or the Drug Interactions section, and demonstrates how the sponsor's data supported that section of the package label.- Reveals strategies for winning FDA approval and for drafting the package label- Examples are from one hundred FDA-submissions (NDAs, BLAs) for one hundred different drugs, e.g., for oncology, metabolic diseases, autoimmune diseases, and neurological diseases- This book uses the most reliable and comprehensive source of information available for writing FDA-submissions, namely, the data from NDAs and BLAs as published on FDA's website at the time FDA grants approval to the drug

Chapter 1

Introduction to Regulated Clinical Trials

Abstract

People writing documents for clinical trials need to be aware of expectations from the US Food and Drug Administration (FDA) and from corresponding agencies in Europe (European Medicines Agency, International Conference on Harmonization) as to the format and content of these documents. These documents include the Clinical Study Protocol, Clinical Study Reports, Investigational New Drug, New Drug Application, Biological License Application, and the package label. These expectations are articulated by FDA’s Guidance for Industry documents, which are generally 10–40 pages long, as well as by rules from the Code of Federal Regulations (CFR). The part of the CFR that is relevant to FDA-regulated clinical trials is called, “Section 21.”

Keywords

Code of Federal Regulations; NDA; BLA; CTD; black box warning; indications and usage; dosage and administration; contraindications; warnings and precautions; drug interactions; off-label uses

I Introduction

This book details the Food and Drug Administration’s review process for pharmaceuticals, that is, for small molecule drugs and biologicals. The book reproduces data provided by the Sponsor, FDA’s analysis and critique of the data, and pathways of logic and reasoning that result in FDA giving recommendations for the package label, and that result in FDA's approval of the drug and of the package label. The author acquired the data that had been submitted to FDA in 100 New Drug Applications (NDAs) and Biological License Applications (BLAs). The data are available on FDA’s website in the form of various reviews. Thus, as source material for writing the book, the author read one hundred of FDA‘s Medical Reviews, one hundred of FDA's Clinical Pharmacology Reviews, and one hundred of FDA's Pharmacology Reviews. These documents are published on FDA‘s website, along with FDA’s Approval Letter, package label, and Risk Evaluation and Mitigation Strategy.

As set forth in Title 21 of the Code of Federal Regulations (CFR), the main goal of FDA-regulated clinical trials is to establish that the study drug is safe and effective in humans.¹ The goal of efficacy is set forth in the Indications and Usage section and in the Dosage and Administration section of the package label, whereas the goal of providing safety is set forth in the Black Box Warning, Contraindications section, Warnings and Precautions section, Adverse Reactions section, and Drug Interactions section of the label. The package label has three large sections: (1) Highlights of Prescribing Information, (2) Full Prescribing Information Table of Contents, and (3) Full Prescribing Information. The first large section takes the form of bullet point information. The third large section reiterates what is in the first section but in the form of detailed paragraphs. The third section also contains clinical data and animal data of a neutral nature, that is, not intended as a warning and not intended as an instruction to the physician prescribing the drug. The formatting, organization, and type font of the package label have been outlined.²

This is the first book to use FDA’s reviews as a source of information for the topics of safety, efficacy, clinical trial design, and package labeling. FDA’s reviews that were used in writing this book include:

• Medical Reviews,

• Clinical Pharmacology Reviews,

• Pharmacology Reviews,

• Cross Discipline Team Leader Reviews,

• Summary Reviews, and

• Statistical Reviews.

FDA’s recommendations for a given section of the package label are typically dispersed over these various reviews. In other words, FDA’s train of logic and reasoning, for example, for arriving at the Warnings and Precautions section, occurs in fragments where each fragment resides in a different review. For this reason, the author needed to explore all of these reviews, especially where any steps of logic were missing in any one review.

The timeline for drug development and for subsequent FDA submissions includes these steps:

Step 1: Basic research is used to characterize the mechanism of action of a given disease, where data on mechanism are acquired from human subjects, animal models of the disease, cell culture models, gene expression data, and so on.

Step 2: When sufficient information on disease mechanism is at hand, the Sponsor designs a drug that acts at one or more steps in the mechanism, where the drug is expected to ameliorate one or more features of the disease.

Step 3: The Sponsor requests permission from FDA to conduct a clinical trial on human subjects, using the preferred drug candidate. Permission is requested by way of an application called Investigational New Drug (IND). As part of the request to conduct the clinical trials, the Sponsor drafts a Clinical Study Protocol. The Clinical Study Protocol is an instruction manual for physicians and other healthcare workers, which teaches all aspects of conducting the clinical trial, such as criteria for selecting study subjects and methods of dosing the investigational drug. The textbook, Clinical Trials³
the CFR (21 CFR §312.21) describes the relationship between the Sponsor’s clinical studies and the package label:

Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects contains about three chapters devoted to each of the topics found in a typical Clinical Study Protocol. These topics include efficacy endpoints, safety endpoints, instructions for randomization and allocation, inclusion criteria, exclusion criteria, dose modification instructions, the study schema, the run-in period as a feature of study design, and nature of the control arm, for example, a placebo control or a comparator drug control.

Before conducting the Phase 3 clinical study, the Sponsor can meet with FDA and discuss, among other things, the proposed package label (21 CFR §312.47). Thus, according to Section 312.47:

the sponsor should submit background information on the sponsor’s plan for Phase 3, including summaries of the Phase 1 and 2 investigations, the specific protocols for Phase 3 clinical studies, plans for any additional nonclinical studies, plans for pediatric studies, including a time line for protocol finalization, enrollment, completion, and data analysis, or information to support any planned request for waiver or deferral of pediatric studies, and, if available, tentative labeling for the drug.

The Sponsor’s application (NDA; BLA) includes the Sponsor’s proposed package label (21 CFR §314.50). Thus, according to Section 314.50:

Content and format of an application. Applications … are required to be submitted in the form and contain the information, as appropriate for the particular submission … [a]n application for a new chemical entity will generally contain an application form, an index, a summary, five or six technical sections, case report tabulations of patient data, case report forms, drug samples, and labeling.

When submitting an NDA or BLA, the Sponsor submits the information in a format known as the Common Technical Document (CTD). The CTD includes the outcome of the conducted clinical studies, where this information is in the Sponsor’s Clinical Study Reports and other documents. The Sponsor includes a draft package label in Module 1 of the CTD. Regarding Module 1, FDA’s Guidance for Industry teaches:

For the NDA, you should provide a copy of the proposed labeling text with annotations directing reviewers to the information in the summaries and other modules that support each statement in the labeling, as described in 21 CFR §314.50(c)(2)(i). The annotated labeling text should include the content of the labeling described under 21 CFR §201.57 and all text, tables, and figures used in the package insert.⁴

FDA’s Guidance for Industry provides additional information for drafting the package label, in the additional documents cited here.^5,6,7,8

Step 4: As revealed by FDA’s Medical Reviews, Clinical Pharmacology Reviews, and Pharmacology Reviews, FDA assesses the Sponsor’s data on efficacy and safety, contemplates the Sponsor’s proposed label, and then makes recommendations and requirements regarding the information needed on the label.

Step ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Biography
• Abbreviations and Definitions
• Chapter 1. Introduction to Regulated Clinical Trials
• Chapter 2. FDA’s Decision-Making Process When Assessing Ambiguous Data
• Chapter 3. Food Effect Studies
• Chapter 4. Dose Modification and Dose Titration
• Chapter 5. Contraindications
• Chapter 6. Animal Studies
• Chapter 7. Drug–Drug Interactions: Part One (Small Molecule Drugs)
• Chapter 8. Drug–Drug Interactions: Part Two (Therapeutic Proteins)
• Chapter 9. Immunosuppression, Drug-Induced Hypersensitivity Reactions, and Drug-Induced Autoimmune Reactions
• Chapter 10. Drug Class Analysis
• Chapter 11. Relatedness
• Chapter 12. Adjudication of Clinical Data
• Chapter 13. Coding
• Chapter 14. Pooling
• Index