FDA's Drug Review Process and the Package Label: Strategies for Writing Successful FDA Submissions

FDA’s Drug Review Process and the Package Label

Strategies for Writing Successful FDA Submissions

Tom Brody

Table of Contents

Cover image

Title page

Copyright

Dedication

Biography

Abbreviations and Definitions

Chapter 1. Introduction to Regulated Clinical Trials

Abstract

I Introduction

II Details on FDA Submissions

III Legal Basis for Regulated Clinical Trials

IV Drafting FDA Submissions

V Distinguishing Package Labeling of Pharmaceuticals From Other Labeling Issues

Chapter 2. FDA’s Decision-Making Process When Assessing Ambiguous Data

Abstract

Chapter 3. Food Effect Studies

Abstract

I Introduction

II Food Effects Where the Drug Is Intended to Influence GI Physiology or to Influence Nutrient Processing

III Food Effect Studies With Anticancer Drugs

IV Study Design Methodology—Steady-State Concentrations

V Food Effect Studies on Drugs for Other Indications

VI FDC Drugs and Instructions for Taking Food

VII Drug–pH Interactions and Drug–Cation Interactions

VIII Drug–pH Interactions Analysis and Assessment by the BCS

IX Vitamins and Minerals

X Grapefruit Juice

XI Alcohol-Induced Dose Dumping

XII Concluding Remarks

Chapter 4. Dose Modification and Dose Titration

Abstract

I Introduction

II FDA’s Reviews Reveal the Origins of Dose Modification or Dose Titration Instructions in the Package Label

III Package Label Instructions for Dose Modification Influenced by Phenomenon of Target-Mediated Drug Disposition

IV Introduction to Renal Impairment and Hepatic Impairment

V FDA’S Analysis of Renal Impairment and Hepatic Impairment, and the Package Label

VI Concluding Remarks

Chapter 5. Contraindications

Abstract

I Introduction

II FDA’s Decision-Making Process for Arriving at Recommendation for the Contraindications Section

III Genetic Markers Used in Package Labeling

IV Concluding Remarks

Chapter 6. Animal Studies

Abstract

I Introduction

II No Observed Adverse Effect Level (NOAEL)

III Calculating the Safety Margin

IV Use in Specific Populations Section of the Package Label

V Animal Data from FDA’s Reviews Find a Corresponding Disclosure in the Package Label (Small Molecule Drugs)

VI Animal Data from FDA’s Reviews Find a Corresponding Disclosure in the Package Label (Biologics)

VII Concluding Remarks

Chapter 7. Drug–Drug Interactions: Part One (Small Molecule Drugs)

Abstract

I Introduction

II Background on Cytochrome P450 Enzymes and Drug Transporters

III P-Glycoprotein

IV Integrated Picture of P-Glycoprotein’s Influence on Drug Exposure

V Clearance of Drugs by Conjugation Catalyzed by UDP-glucuronosyltransferase

VI Metabolites of Study Drugs

VII Drug Clearance

VIII Published Clinical Studies on Drug–Drug Interactions

IX Drug–Drug Interactions in FDA’s Clinical Pharmacology Reviews

X Organic Anion Transporter Polypeptide (OATP) Data

XI A Small Molecule Drug Can Stimulate the Catabolism of Its Own Self

XII Concluding Remarks

Appendix A

Chapter 8. Drug–Drug Interactions: Part Two (Therapeutic Proteins)

Abstract

I Introduction

II Biology of Cytokines and of Th1- and Th2-Type Immune Response

III Background for Acquired Immunity Resulting in Immune Response Against Specific Antigens

IV Materialization of Antibodies Against Therapeutic Proteins, as Revealed by FDA’s Reviews

V Concluding Remarks

Chapter 9. Immunosuppression, Drug-Induced Hypersensitivity Reactions, and Drug-Induced Autoimmune Reactions

Abstract

I Introduction

II AEs Involving Acquired Immunity Illustrated by FDA’s Medical Reviews

III Drug-Induced Hypersensitivity Reactions

IV FDA’s Analysis of Hypersensitivity Reactions

V Concluding Remarks

Chapter 10. Drug Class Analysis

Abstract

I Introduction

II Off-Target Adverse Events

III Short Examples of Drug Class Analysis

IV First-in-Class and increased need for an Advisory Committee

V Drugs for Cancer

VI Drugs for Indications Other Than Cancer

VII Concluding Remarks

Chapter 11. Relatedness

Abstract

I Introduction

II Code of Federal Regulations Provides a Basis for the Relatedness Inquiry

III How to Resolve Ambiguity in the Relatedness Inquiry

IV Assessing Relatedness of AEs to the Study Drug, as Illustrated by FDA’s Medical Reviews

V Formatting Disclosures of Relatedness

VI Inconclusive Relatedness Analysis Finds a Place on the Package Label

VII Responsibility for Determining Relatedness

VIII Concluding Remarks

Chapter 12. Adjudication of Clinical Data

Abstract

I Introduction

II Account of Adjudication From FDA’s Background Package for Osteoarthritis

III Accounts of Adjudication From Medical Journals and Clinical Study Protocols

IV Tasks of the Adjudication Committee

V Accounts of Adjudication From FDA’s Medical Reviews

VI Concluding Remarks

Chapter 13. Coding

Abstract

I Introduction

II Coding Examples From FDA’s Medical Reviews

III Splitting and Lumping

IV FDA’S Medical Reviews, Examples of Splitting and Lumping

V Formatting Adverse Events

VI Concluding Remarks

Chapter 14. Pooling

Abstract

I Introduction

II Pooling Examples From FDA’s Medical Reviews

III Similar Values for Allocation Ratios, as a Condition for Appropriate Pooling

IV Summary of Coding and Pooling

Index

Copyright

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Dedication

To Dawnia and Shideh

Biography

The author received his PhD from the University of California at Berkeley in 1980, and conducted postdoctoral research at the University of Wisconsin-Madison and also at the University of California at Berkeley. The author has 15 years of pharmaceutical industry medical writing experience, acquired at Schering-Plough, Cerus Corporation, SciClone Pharmaceuticals, and Athena Neurosciences (Elan Pharmaceuticals), and has contributed to FDA submissions for the indications of multiple sclerosis, melanoma, head and neck cancer, hepatocellular carcinoma, idiopathic thrombocytopenic purpura, and hepatitis C virus. The author has published two editions of the textbook, Clinical Trials: Study Design, Endpoints and Biomarkers, Drug Safety, and FDA and ICH Guidelines.¹ This book provides background information for the topics in the present book, but the information in these two books overlaps by only 5%.

The author has 15 years of training and experience in the Code of Federal Regulations as it applies to pharmaceuticals. Shortly before entering the pharmaceutical industry, he published two editions of Nutritional Biochemistry, which describes the clinical features, diagnosis, and treatment of metabolic diseases.² The author has 20 research publications from his laboratory bench work on the enzymology and metabolism of folates and related amino acids,³,⁴,⁵,⁶,⁷,⁸,⁹,¹⁰ on the blood-clotting cascade,¹¹,¹² and on the structure of an antibody drug for multiple sclerosis (natalizumab).¹³ The author also conducted laboratory bench research in oncology, where he cloned, sequenced, and expressed an oncogene (XPE gene).¹⁴,¹⁵,¹⁶

¹Brody T. Clinical Trials study design, endpoints and biomarkers, drug safety, and FDA and ICH guidelines. 2nd ed. New York, NY: Elsevier, Inc. 2016.

²Brody T. Nutritional Biochemistry. 2nd ed. New York, NY: Elsevier, Inc. 1999.

³Brody T, Stokstad ELR. Folate oligoglutamate: amino acid transpeptidase. J. Biol. Chem. 1982;257:14271–9.

⁴Brody T, et al. Folate pentaglutamate and folate hexaglutamate mediated one-carbon metabolism. Biochemistry 1982;21:276–82.

⁵Brody T, Stokstad ELR. Nitrous oxide provokes changes in folylpenta- and hexaglutamates. J. Nutr. 1990;120:71–80.

⁶Brody T, Stokstad ELR. Incorporation of the 2-ring carbon of histidine into folylpolyglutamate coenzymes. J. Nutr. Biochem. 1991;2:492–8.

⁷Brody T, et al. Separation and identification of pteroylpolyglutamates by polyacrylamide gel chromatography. Analyt. Biochem. 1979;92:501–9.

⁸Brody T. The influence of folate binding proteins on 1-carbon metabolism. Pteridines 1989;1:159–65.

⁹Brody T, et al. Rat brain folate identification. J. Neurochem. 1976;27:409–13.

¹⁰Brody T, Shane B. Folic acid. In: Rucker RB, Suttie JW, McCormack DB, Machlin LJ, editors. Handbook of the vitamins. 3rd ed. New York, NY: Marcel Dekker, 2001. pp. 427–62.

¹¹Brody T, Suttie JW. Glutamate carboxylase: assays, occurrence, and specificity. Methods Enzymol. 1984;107:552–63.

¹²Brody T, Suttie JW. Evidence for the glycoprotein nature of vitamin K-dependent carboxylase from rat liver. Biochim. Biophys. Acta. 1987;923:1–7.

¹³Brody T. Multistep denaturation and hierarchy of disulfide bond cleavage of a monoclonal antibody. Analyt. Biochem. 1997;247:247–56.

¹⁴Brody T, et al. Human damage-specific DNA binding protein p48 subunit mRNA. GenBank Accession No. U18299; 1995.

¹⁵Keeney S, Eker AP, Brody T, et al. Correction of the DNA repair defect in xeroderma pigmentosum group E by injection of a DNA damage-binding protein. Proc. Natl Acad. Sci. 1994;91:40536.

¹⁶Dualan R, Brody T, Keeney S, et al. Chromosomal localization and cDNA cloning of the genes (DDB1 and DDB2) for the p127 and p48 subunits of a human damage-specific DNA binding protein. Genomics. 1995;29:629.

Abbreviations and Definitions

ADR adverse drug reaction

AE adverse event

agonist An agonist is a drug or naturally occurring ligand that binds to and stimulates (or activates) a receptor. The fact that a drug binds to a receptor, without more, does not imply that it is an agonist or an antagonist.

antagonist An antagonist is a drug or naturally occurring ligand that binds to and inhibits (or blocks) a receptor. The fact that a drug binds to a receptor, without more, does not imply that it is an agonist or an antagonist.

ALT alanine aminotransferase. Also called, serum glutamate pyruvate transaminase (SGPT)

AST aspartate serum transaminase. Also called, serum glutamate oxaloacetate transaminase (SGOT)

AUC area under the curve. AUC is a measure of exposure to a given drug, as determined by analysis of blood concentration over a period of hours, with a multiplicity of blood samples, taken after an oral or intravenous dose.

BCS class Biopharmaceutics Classification System. BCS class is used to designate or to predict the bioavailability of drugs that are taken orally. BCS class takes into account solubility in water and permeability to cell membranes.

BID Twice a day. From the Latin, bis in die.

BLA biologics license application

BMI body mass index

CBER Center for Biologics Evaluation and Research

CDER Center for Drug Evaluation and Research

CFR Code of Federal Regulations. The CFR provides rules, which take the form of administrative law

CLcr Creatinine clearance. See FDA. Guidance for Industry. Pharmacokinetics in Patients with Impaired Renal Function—Study Design, Data Analysis, and Impact on Dosing and Labeling; 2010.

Clinical Clinical, as used in clinical studies, clinical effect, or clinical trials, refers to use with humans, not animals

Clinical hold A Clinical Hold is a notification from FDA to the Sponsor to delay a proposed clinical trial or to suspend an ongoing clinical trial (21 CFR §312.42). Section 312.42 states, for example, When an ongoing study is placed on Clinical Hold, no new subjects may be recruited to the study … patients already in the study should be taken off therapy.

ClinPharm Review Clinical Pharmacology Review. These reviews are published on FDA’s website, together with the Approval Letter, Medical Reviews, Pharmacology Reviews, and package label, when FDA grants approval to a drug.

CAZ/AVI Ceftazidime/avibactam combination. This is a medication taking the form of a combination of two drugs.

Combination Rule (21 CFR §300.50) Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effect and the dosing of each component is such that the combination is safe and effective for a significant patient population (see U.S. Dept. Health and Human Services. FDA. CBER. Guidance for Industry. Chronic Obstructive Pulmonary Disease: Developing Drugs for Treatment, 2007).

COX-2 cyclooxygenase-2

CRDAC Cardiovascular and Renal Drugs Advisory Committee

CRF Case Report Form

CRO Contract Research Organization

CSP Clinical Study Protocol, or Protocol

CTCAE Common Terminology Criteria for Adverse Events

CTD Common Technical Document

CYP Cytochrome P-450

DAARP Division of Analgesia, Anesthesia, and Rheumatology Products. DAARP is a division in the U.S. FDA

DDI drug–drug interaction. DDI refers to the influence of the study drug on metabolism of any second drug that is coadministered, and to the influence of any second drug that is coadministered on the study drug’s metabolism.

DDI drug–disease interaction. DDI refers to the influence of a disease, such as renal impairment or hepatic impairment, on the study drug’s exposure.

DLT dose-limiting toxicity. DLT finds a basis in FDA’s Guidance for Industry. See FDA. Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers; 2005.

DRESS Drug Reaction with Eosinophilia and Systemic Symptoms. Adverse events that are hypersensitivity reactions include DRESS, rashes, anaphylactic reactions, and Stevens-Johnson syndrome (SJS).

eCTD Electronic Common Technical Document

EGFR epidermal growth factor receptor

EMA European Medicines Agency

EMDAC Endocrinologic and Metabolic Drugs Advisory Committee

ESRD end stage renal disease

Exposure In pharmacokinetics studies exposure is usually a measure of concentration of a drug in the bloodstream. Exposure is expressed in terms of, AUC, AUC0–24 hours, AUC0–infinity, Cmax, Cmin (Ctrough), tmax, and so on.

FDA U.S. Food and Drug Administration

FDC fixed dose combination. 21 CFR §300.50 states that a fixed combination drug is, Two or more drugs … combined in a single dosage form when each component makes a contribution to the claimed effects. This textbook provides an account of FDA’s approvals of these fixed dose combinations: lumacaftor/ivacaftor, ceftazidime/avibactam (AVYCAZ), sumatriptan/naproxen, canagliflozin/metformin, and elvitegravier, cobicistat, emtricitabine, tenofovir alafenamide (E/C/F/TAF).

FGF fibroblast growth factor

FPI Full Prescribing Information. FPI is part of the package label. See FDA. Guidance for Industry. Labeling for Human Prescription Drug and Biological Products—Implementing the PLR Content and Format Requirements; 2013.

GMR Geometric Mean Ratio is a unit used pharmacokinetics analysis. See Davit BM, et al. Comparing generic and innovator drugs. Ann. Pharmacother. 2009;43:1583–97.

HAHA human antihuman antibodies. In clinical studies on human subjects treated with a humanized therapeutic antibody, subjects sometimes respond by generating antibodies against the administered antibody. This issue is routinely assessed by FDA in its reviews of BLAs. A more general term is antidrug antibodies.

HBV hepatitis B virus

HCV hepatitis C virus

HED human equivalent dose

5-HT 5-hydroxytryptamine

ICAC Independent Central Adjudication Committee

ICH International Conference on Harmonization

ITP idopathic thrombocytopenia purpura

ILD interstitial lung disease

IND Investigational New Drug application

Investigator Investigator means an individual who actually conducts a clinical investigation … the investigator is the responsible leader of the team (21 CFR §312.3). The terms sponsor and investigator have different definitions in the CFR.

IR drug immediate release. IR drugs are distinguished from, for example, timed release drugs

ITT Intent to treat. ITT refers to the population of all of the subjects that were initially enrolled and randomized in a clinical trial. ITT analysis refers to the analysis of safety or efficacy results for the ITT population, without regard to whether a given subject complies with all of the requirements of the Clinical Study Protocol.

IVIVR In vitro–in vivo relationship. This is a term used in food effect studies. See Mathias N, et al. Food effect in humans: predicting the risk through in vitro dissolution and in vivo pharmacokinetic models. AAPS J. 2015;17:988–98.

LUM/IVA lumacaftor/ivacaftor combination. This is a medication taking the form of a combination of two different drugs.

MDRD Modification of Diet in Renal Disease. MDRD is an equation used to determine estimated glomerular filtration rate (eGFR) which, in turn, is a measure of renal function. See Stevens LA, et al. Measured GFR as a confirmatory test for estimated GFR. J. Am. Soc. Nephrol. 2009;20:2305–13.

MedDRA Medical Dictionary for Regulatory Activities

mITT modified intent to treat

MRSD maximum recommended starting dose

MTC medullary thyroid cancer

MTD maximum tolerable dose. The EMA provides a basis for the MTD. See European Medicines Agency. Guideline on the quality, non-clinical and clinical aspects 5 of gene therapy medicinal products; 2015.

NDA new drug application

NME new molecular entity. FDA provides a definition of NME in Lanthier M, et al. An improved approach to measuring drug innovation finds steady rates of first-in-class pharmaceuticals. Health Affairs 2013;32:1433–9.

NOAEL no observable adverse effects level. NOAEL is used in animal studies, where the goal is to arrive at an appropriate dose for humans, when initiating clinical studies on the drug.

NSAIDs nonsteroidal antiinflammatory drugs

NSCLC non-small-cell lung cancer

ONJ osteonecrosis of the jaw. ONJ is a type of adverse event, which was found with, for example, denosumab

PBMC peripheral blood mononuclear cell. PBMCs, which are acquired from samples of whole blood, include T cells, B cells, dendritic cells, and NK cells, but do not include red blood cells, platelets, neutrophils or eosinophils.

PD pharmacodynamics. PD refers to the time course of the body’s response to an administered drug, for example, in the response of gene induction.

PDGF platelet-derived growth factor

P-gp P-glycoprotein. P-gp is a membrane-bound transporter that mediates efflux of xenobiotics and drugs out of the cell

PK pharmacokinetics

PMR postmarketing requirement. PMR refers to studies that are required as a condition for FDA approval, and that sponsors conduct after approval to gather additional information about a product’s safety or efficacy. Where the PMR requires that additional studies be performed, the new data may appear on revised versions of the package label (21 CFR §314.81(2) (iii and vii))

Postmarketing Postmarketing refers, for example, to information gathered about a medication after it is approved by the FDA.

PP per rotocol. Per protocol analysis refers to an analysis of safety or efficacy results, where the analysis is conducted only on subjects that complied with all of the requirements set forth by the Clinical Study Protocol.

Preclinical Preclinical as used in preclinical studies refers to studies with animals, cultured cells, perfused organs or tissues, purified enzymes, mutagen testing with bacteria, and so on. Preclinical refers to studies conducted prior to an associated clinical trial, as well as to studies conducted once the clinical trial is under way. See FDA. Guidance for Industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals; 1997.

PT Preferred Term. PT refers to a classification of terms in the MedDRA dictionary

QD Once a day. From the Latin, quaque die

Q2W Once in every 2 weeks

RECIST Response Evaluation Criteria in Solid Tumors. RECIST, which takes into account tumor size and number, is a standard criterion for assessing drug efficacy. See Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer. 2009;45:228–47.

REMS Risk Evaluation and Mitigation Strategy. REMS is part of FDA’s drug approval process for some drugs, where the REMS imposes a set of requirements on the Sponsor during marketing of the drug, to be proactive in preventing or reducing drug toxicity

SAE serious adverse event

SEER Surveillance, Epidemiology, and End Results Database. This is a database of the National Cancer Institute. The database is sometimes used as a historic control, where the Sponsor does not have sufficient information from its own clinical trial, to assess association of tumors with the study drug. See the use of SEER data from package label for abatacept (ORENCIA (abatacept) for injection, for intravenous use). June 2017. BLA 125-118.

SMQ Standardised MedDRA Queries

SNOMED-CT Systematized Nomenclature of Medicine-Clinical Terms

SOC System Organ Class

SOF/VEL sofosbuvir/velpatasvir combination. SOF/VEL takes the form of a combination of two different drugs.

Sponsor Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator (21 CFR §312.3). The terms sponsor and investigator have different definitions in the CFR.

SSRI serotonin-specific reuptake inhibitor

Subject According to the Code of Federal Regulations, Subject means a human who participates in an investigation, either as a recipient of the investigational new drug or as a control. A subject may be a healthy human or a patient with a disease. 21 CFR §312.3. Definitions and interpretations.

SUSAR Serious Unexpected Adverse Reaction

TEAE Treatment Emergent Adverse Event

TFLs Tables, figures, and listings. TFLs are source documents that are used for drafting the Clinical Study Report.

TMDD target-mediated drug disposition

TNF tumor necrosis factor

Trough concentration trough concentration refers to the lowest concentration (Cmin) of a study drug in the bloodstream, where the drug is dosed on a periodic basis, for example, daily or weekly. Trough concentration is determined in blood withdrawn immediately before the next dosing.

ULN upper limit of normal. ULN refers to concentrations of an enzyme or metabolite in the bloodstream, for example, to activity of lactate dehydrogenase.

ULRR upper limit of the reference range

USC United States Code. The USC provides a body of statutes. Note that statutes, as provided by USC, are not the same as rules, which are provided by CFR.

USPI United States Prescribing Information

VEGF vascular endothelial growth factor

VEGFR vascular endothelial growth factor receptor

VHD valvular heart disease

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 5: When FDA grants approval, it issues an Approval Letter, where the letter approves the package label’s text, methods for manufacturing the drug, and approval for interstate commerce of the drug. The importance of the package label is revealed by an excerpt from the Approval Letter for simeprevir, "We have completed review of this application, as amended. It is approved, effective on the data of this letter, for use as recommended in the enclosed agreed-upon text.⁹"

Similarly, the Approval Letter for pembrolizumab for melanoma read, "We have approved your BLA for … pembrolizumab … effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce … [u]nder this license, you are approved to manufacture Keytruda drug substance … for use as recommended in the enclosed agreed-upon text.¹⁰"

The term package label refers to the information printed on the outside of the package, to the folded-up paper document that resides inside the package (the package insert), and also to the package label available on FDA’s website. In these excerpts from FDA's Approval Letters, the phrase agreed-upon text refers to the text of the draft package label.

The above steps are summarized by the timeline in the flow chart:

The following concerns the terminology used to refer to clinical studies that are conducted by the Sponsor. FDA appears to use the terms study and trial interchangeably. For example, FDA’s Medical Review of osimertinib, the reviewer referred to "Study 5160C00001 and also referred to, 5160C00001 … the secondary objectives of the trial included."¹¹ Further showing interchangeability of terms, FDA’s review for lenvatinib referred to, Tables of Studies/Clinical Trials and also referred to, "The application is supported by a single major efficacy trial, Study E7080-G00-303 … a randomized, placebo-controlled trial.¹² Similarly, for FDA’s Medical Review of pomalidomide, the review referred to, Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence, to certification for study CC-4047-MM-002, and to possibility of submitting clinical trials CC-4047-MM-002.¹³ FDA’s Medical Review of pomalidomide, the review referred to, Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence. The same review referred to, Clinical trial CC-4047-MM-003.¹⁴ FDA’s Manual of Policies and Procedures¹⁵ provides distinct definitions for study and trial, but these definitions are not followed in FDA’s Medical Reviews for NDAs and BLAs. This book uses the term trial when referring to a Phase I, Phase II, or Phase III trial, and uses the term study" to refer to individual studies, where a given trial comprises a plurality of studies.

II Details on FDA Submissions

a Clinical Study Protocol

The Clinical Study Protocol is the instruction manual used by investigators for conducting the clinical study. During the clinical study, data are produced on efficacy and safety. Initially, these data are memorialized on Case Report Forms (CRFs), and eventually the data are collated and analyzed, where the results of the analysis are written in the Clinical Study Report. Typically, the drug development process for any given study drug involves several different clinical studies, with the generation of several different Clinical Study Reports.

The raw data used to draft Clinical Study Reports take the form of tables, figures, and listings (TFLs), which are generated by the investigator. The medical writer then uses the TFLs, together with other documents such as the Clinical Study Protocol, Investigator’s Brochures, and medical journal articles for drafting the Clinical Study Report.¹⁶,¹⁷

b Common Technical Document

Eventually, the Sponsor may decide to format the information as an electronic Common Technical Document (eCTD), which can then be submitted to the FDA. For an FDA submission that is an NDA or BLA, the format takes the form of the eCTD.¹⁸

Fig. 1.1 shows the pyramid diagram used to illustrate the organization of the eCTD and its modules.¹⁹ Module 5 of the pyramid contains Clinical Study Reports, whereas Module 4 contains data on efficacy and toxicology from animal studies. The Clinical Study Report contains many Appendices, where the first Appendix takes the form of the Clinical Study Protocol. In other words, the Clinical Study Protocol is attached to the Clinical Study Report which, in turn, resides in Module 5, which, in turn, is part of the eCTD.

Figure 1.1 CTD. Pyramid diagram showing the CTD and its five modules. Module 1 is different from country to country and Modules 2–5 are the same for all countries.

Each Clinical Study Report may contain about 20 appendices, where the first appendix takes the form of the Clinical Study Protocol. As can be seen from the pyramid diagram, Module 4 contains data from studies on animals, cultured cells, tests for mutagens, and so on. Module 3 includes data from routine quality control work on the drug, the drug product (tablet or solution), and any excipients. Quality control work involves testing drug purity and stability with storage. The appendices for any given Clinical Study Report can include those named below in references.²⁰,²¹

c Finding Package Labels

FDA’s website provides package labels and updated package labels that are published in the years following issue of the Approval Letter. The following steps provided access to the package label, FDA’s Approval Letter, and to FDA’s Medical Reviews, FDA's Clinical Pharmacology Reviews, FDA's Pharmacology Reviews, and other reviews:

1. Access www.fda.gov

2. Click Drugs tab

3. Click Search Drugs@FDA

4. Type name of drug (chemical name or trade name)

5. Click on "Approval Date(s) and History, Letters, Labels, Reviews for NDA

Package labels can be found in the USPI. In response to a query from this author, an FDA official explained the meaning of USPI and the various sources of package labels:

The term USPI refers to US Prescribing Information (USPI)." USPI is the printed labeling that is approved by FDA and accompanies each FDA approved drug. The prescribing information is sometimes called the package insert or labeling … [m]ost labels can be found in our Drugs@FDA catalog, FDA Label Repository, and DailyMed (a National Institutes of Health managed site). Please note, Drugs@FDA only contains FDA-approved drugs, the FDA Label Repository and DailyMed searches may result in over the counter (OTC) and also unapproved drug labels.²²

d Raw Data Used for Drafting the Clinical Study Report

Raw data used for drafting Clinical Study Reports and other components of the eCTD take the form of CRFs, patient narratives, and TFLs. CRFs and listings are described in this book in Chapter 13, Coding. Patient narratives are described below, as well as in this book in the Chapter 12, Adjudication of Clinical Data, in the account of FDA’s review of alvimopan NDA 021-775.²³

According to MedEffect Canada, "The objective of the narrative is to summarize all relevant clinical and related information, including patient characteristics, therapy dates, medical history, clinical course of the event(s), diagnosis, and AR(s) including the outcome, laboratory evidence (including normal ranges), and any other information that supports or refutes an AR (e.g., rechallenge information). The narrative should serve as a comprehensive stand-alone medical story.²⁴"

International Conference on Harmonization (ICH) E3 provides an account of patient narratives.²⁵ According to ICH E3, patient narratives on deaths and serious adverse events include, the nature and intensity of event, the clinical course leading up to event, with an indication of timing relevant to test drug/investigational product administration; relevant laboratory measurements, whether the drug was stopped, and when; countermeasures; postmortem findings; investigator’s opinion on causality, and sponsor’s opinion on causality, if appropriate. In addition, the following information should be included: Patient identifier – Age and sex of patient … Disease being treated … with duration … of illness – Relevant concomitant/previous illnesses with details of occurrence/duration – Relevant concomitant/previous medication with details of dosage – Test drug/investigational product administered, drug dose, if this varied among patients, and length of time administered.²⁶

III Legal Basis for Regulated Clinical Trials

a CFR, USC, and Courtroom Opinions

The source of law most frequently encountered by medical writers and other personnel in pharmaceutical companies is Title 21 of the CFR. The CFR, which provides rules, is a form of administrative law, because it applies to one of the administrative branches of the federal government, namely, the FDA. Another source of law applying to drugs is the United States Code (USC). The USC consists of statutes, not rules. The relevant part is Title 21 of the USC. Title 21 of the USC, which concerns the Food and Drug Administration, is a codification of an act of congress. This act is the Federal Food, Drug, and Cosmetic Act.²⁷

Yet another source of law is published opinions from various courts. A large number of published cases provide guidance on the content the package label.²⁸ The issue of the adequacy of safety warnings on the package label is illustrated by the following excerpt from a courtroom opinion:

Plaintiff asserts that the warnings on Zometa’s label was inadequate to properly warn … physicians about the risks of osteonecrosis of the jaw (ONJ) when using Zometa in its intended manner … [the defendent] on the other hand, asserts that the warning was so comprehensive, no other warning would have caused Plaintiff’s doctors to make a different prescribing decision … the adequacy of warnings can become a question … where the warning is accurate, clear, and unambiguous.²⁹

b Basis for the Package Label in the CFR

Regarding the package label, 21 CFR §314.50(c)(2)(ii) and 21 CFR §601.14(b) each sets forth the same requirements for labeling:

21 CFR §314.50(c)(2)(ii) Labeling. The content of labeling required under §201.100(d)(3) of this chapter (commonly referred to as the package insert or professional labeling), including all text, tables, and figures, must be submitted to the agency in electronic format.

21 CFR §601.14 (b) Labeling. The content of labeling required under §201.100(d)(3) of this chapter (commonly referred to as the package insert or professional labeling), including all text, tables, and figures, must be submitted to the agency in electronic format.

Section 201.100(d)(3), in turn refers to Sections 201.56, 201.57, and 201.80. Section 201.57, which is reproduced in part below, is the part of the CFR that most closely resembles the material in this book. In other words, the topics covered in this book track the requirements set forth by Title 21 CFR §201.57. Shown below are excerpts from the CFR that define these sections of the label. The topics are indicated by the bulletpoints, and the excerpts are indicated by the quotation marks. One unusual instruction, for example, applies to the Contraindications section. The instruction is that, if there are not any contraindications, then the Contraindications section of the package label must read, none.

• Indications and usage

• Dosage and Administration

• Contraindications

• Warnings and Precautions

• Drug Interactions

• Use in Specific Populations

• Clinical Pharmacology

"Indications and Usage. A concise statement of each of the product’s indications … [m]ajor limitations of use (e.g., lack of effect in particular subsets of the population, or second line therapy status) must be briefly noted. If the product is a member of an established pharmacologic class, the concise statement under this heading in Highlights must identify the class in the following manner: (Drug) is a (name of class) indicated for (indication(s))."

"Dosage and Administration. (i) This section must state the recommended dose and, as appropriate: (A) The dosage range, (B) An upper limit beyond which safety and effectiveness have not been established, or beyond which increasing the dose does not result in increasing effectiveness, (C) Dosages for each indication and subpopulation, (D) The intervals recommended between doses, (E) The optimal method of titrating dosage, (F) The usual duration of treatment when treatment duration should be limited, (G) Dosing recommendations based on clinical pharmacologic data (e.g., clinically significant food effects), (H) Modification of dosage needed because of drug interactions or in special patient populations (e.g., in children, in geriatric age groups, in groups defined by genetic characteristics, or in patients with renal or hepatic disease)."

"Contraindications. This section must describe any situations in which the drug should not be used because the risk of use (e.g., certain potentially fatal adverse reactions) clearly outweighs any possible therapeutic benefit. Those situations include use of the drug in patients who, because of their particular age, sex, concomitant therapy, disease state, or other condition, have a substantial risk of being harmed by the drug and for whom no potential benefit makes the risk acceptable. Known hazards and not theoretical possibilities must be listed (e.g., if severe hypersensitivity to the drug has not been demonstrated, it should not be listed as a contraindication). If no contraindications are known, this section must state None."

"Warnings and Precautions … This section must describe clinically significant adverse reactions (including any that are potentially fatal, are serious even if infrequent, or can be prevented or mitigated through appropriate use of the drug) … limitations in use imposed by them (e.g., avoiding certain concomitant therapy), and steps that should be taken if they occur (e.g., dosage modification) … the labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established."

"Drug Interactions. (i) This section must contain a description of clinically significant interactions, either observed or predicted, with other prescription or over-the-counter drugs, classes of drugs, or foods (e.g., dietary supplements, grapefruit juice), and specific practical instructions for preventing or managing them. The mechanism(s) of the interaction, if known, must be briefly described. Interactions that are described in the Contraindications or Warnings and Precautions sections must be discussed in more detail under this section."

"Use in Specific Populations. This section must contain the following subsections … Pregnancy. This subsection of the labeling must contain the following information in the following order under the subheadings Pregnancy Exposure Registry, Risk Summary, Clinical Considerations, and Data… Risk statement based on animal data. When animal data are available, the Risk Summary must summarize the findings in animals and based on these findings, describe, for the drug, the potential risk of any adverse developmental outcome(s) in humans … Presence of drug in human milk. The Risk Summary must state whether the drug and/or its active metabolite(s) are present in human milk … Geriatric use. (A) A specific geriatric indication, if any, that is supported by adequate and well-controlled studies in the geriatric population must be described under the Indications and Usage section, and appropriate geriatric dosage must be stated under the Dosage and Administration section. The Geriatric use subsection must cite any limitations on the geriatric indication, need for specific monitoring … associated with the geriatric indication."

"Clinical Pharmacology. (i) This section must contain information relating to the human clinical pharmacology and actions of the drug in humans. Pharmacologic information based on in vitro data using human biomaterials or pharmacologic animal models, or relevant details about in vivo study designs or results (e.g., drug interaction studies), may be included in this section if essential to understand dosing or drug interaction information presented in other sections of the labeling. This section must include the following subsections: (A) 12.1 Mechanism of action … Pharmacokinetics … Pharmacodynamics …"

c FDA’s Guidance for Industry

FDA’s Guidance for Industry documents, as well as the other cited published commentaries, provide instructions for the following package label sections:

• Black Box Warning³⁰,³¹,³²

• Adverse Events section³³

• Clinical Pharmacology section³⁴

• Clinical Studies section³⁵

• Dosage and Administration section³⁶

• Drug Class section³⁷

d Clinical Study Protocol, IND, NDA, and BLA

Title 21 of the CFR sets forth various requirements for conducting clinical trials, such as requirements for the Clinical Study Protocol. Regarding the need for a Clinical Study Protocol, the CFR states:

(iii) A protocol is required to contain … a statement of the objectives and purpose of the study. (b) The name and address and a statement of the qualifications (curriculum vitae or other statement of qualifications) of each investigator … criteria for patient selection and for exclusion of patients and an estimate of the number of patients to be studied … description of the design of the study, including the kind of control group to be used, if any.³⁸

Before conducting a clinical trial, the Sponsor needs to submit an IND to the FDA. This requirement is set forth in 21 CFR §312.20, which states that:

A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug … [a] sponsor shall not begin a clinical investigation … until the investigation is subject to an IND.

Phase 1, Phase 2, and Phase 3 clinical trials are described in 21 CFR §312.22. The content of the IND, which is set forth in 21 CFR §312.23, includes FDA’s Form-1571, name of the Sponsor, names of Contract Research Organizations (CROs) (if any), data from animal studies such as data on efficacy and toxicity, and data from prior human studies, if any.

Moving ahead in the FDA submission timeline, the CFR also details procedures that are followed after the Phase 1, Phase 2, and Phase 3 clinical trials are completed, namely, the submission of an NDA or BLA. The data gathered during the animal studies and human clinical trials of an IND become part of the NDA or BLA. The NDA and BLA find a basis in 21 CFR §315.50, which sets forth the requirements that these applications include animal pharmacology and toxicology data, human pharmacokinetics data, and clinical data on efficacy and safety.

The transition between completing the clinical trials and the deciding to draft and submit an NDA or BLA has been described as, "When the sponsor of a new drug/biologic believes that enough evidence on the drug’s safety and effectiveness has been obtained to meet the FDA’s requirements for marketing approval, the sponsor submits to FDA a new drug application … [a] new drug application/biological licensure application (NDA/BLA; for the FDA) or a marketing authorization application (MAA; for the EU) is a comprehensive submission of all relevant information required for a drug to be approved for marketing.³⁹"

The length of time between the date of submission of the NDA or BLA to the FDA to the date of FDA’s approval, that is, to the date of FDA’s Approval Letter is about 7 years.⁴⁰ Regarding the request to market a drug in the European Union (EU), background on the Marketing Authorization Application is provided in References.⁴¹,⁴²,⁴³

The drug development and approval process includes designing and testing candidate drugs, such as small molecule drugs and biologicals. Testing includes nonclinical studies, such as those using cultured cells or animals, and clinical studies (human subjects). In regulated clinical trials, the term subject or study subject is used (the term patient is not used).⁴⁴

Activities coordinated with drug development and FDA submissions include the preparation and submission of publications for various journals as well as preparing and filing patent applications. Funding for a company can be facilitated by publications, by having filed a patent application, and by succeeding in winning allowance patent claims and the issue of one or more patents. The cited articles provide an introduction to patenting.⁴⁵,⁴⁶,⁴⁷,⁴⁸,⁴⁹,⁵⁰,⁵¹,⁵²

Pharmaceutical companies acquire guidance for planning and conducting clinical trials from FDA’s Guidance for Industry and from ICH Guidelines. FDA’s Guidance for Industry and ICH Guidelines take the form of over 100 documents, each of a length of about 10-50 pages. ICH is not a regulatory agency, but instead it is called an initiative.⁵³,⁵⁴ ICH uses the regulatory authorities of the United States, Europe, and Japan together with experts from the pharmaceutical industry. ICH Guidelines are available for drug safety, drug efficacy, and for quality control and manufacturing.

e Briefing Document

The Briefing Document is also called a Briefing Package and a Briefing Book. The Sponsor drafts the Briefing Document and submits it to FDA for use during meetings with the Sponsor and FDA. The Briefing Document finds a basis in FDA’s Guidance for Industry.⁵⁵ The Sponsor prepares the Briefing Document for use by FDA’s panelists during the meeting with FDA’s Advisory Committee. Information in the Briefing Document supports the messages in the sponsor’s presentation during the meeting and supports the desired labeling language.⁵⁶ The Briefing Document must be submitted 22 business days prior to the meeting.⁵⁷

Briefing Documents are quoted at later points in this book, as part of this book’s accounts of the FDA submissions for miltefosine,⁵⁸,⁵⁹ ticagrelor,⁶⁰,⁶¹ dapagliflozin,⁶² and two separate Briefing Documents for denosumab.⁶³,⁶⁴

f The Sponsor and the Investigator

This distinguishes the sponsor and the investigator.⁶⁵ According to the CFR, the sponsor is, A person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institutions, private organization, or other organization. The sponsor does not actually conduct the investigation.⁶⁶

Also, according to the CFR, an investigator is, "an individual who actually conducts a clinical investigation under whose immediate direction the drug is administered or dispensed to a subject.⁶⁷ FDA’s Guidance for Industry distinguishes between the sponsor and investigator, A sponsor takes responsibility for and initiates a clinical investigation. A sponsor can be an individual or pharmaceutical company … academic institution … or other organization. An investigator is the individual who actually conducts the investigation.⁶⁸" Also, the Sponsor may train the investigators in the conduct of the study.⁶⁹

g Legal Basis for Good Clinical Practices

FDA’s Guidance for Industry publications are only recommendations and do not have the force of the law. On the other hand, if a pharmaceutical company does not comply with the routines and activities set forth under FDA’s Guidance—Good Clinical Practice, FDA can take legal action against the pharmaceutical company by issuing a Warning Letter and by forcing the company to shut down all operations.⁷⁰

FDA’s Guidance for Industry—Good Clinical Practices⁷¹ sets forth requirements for activities such as adverse event reporting and drug accountability. Regarding adverse event reporting, Good Clinical Practice requires that, The sponsor should promptly notify … the regulatory authority of findings that could affect adversely the safety of subjects.

Regarding drug accountability, Good Clinical Practices requires that, "The sponsor … [e]nsure timely delivery of investigational product(s) to the investigator … [m]aintain records that document shipment, receipt, disposition, return, and destruction of the investigational product.⁷²"

An accurate and practice view of Good Clinical Practice is provided by the many Warning Letters that are issued by the FDA to various Sponsors. A comprehensive account of FDA’s Warning Letters, as they apply to Good Clinical Practices, has been published.⁷³

The European Medicines Agency (EMA) has published a report of Good Clinical Practices violations by region, for years 2000-12.⁷⁴ The regions covered in this report include the United States, EU, Canada, Africa, Eastern Europe, and South America. For example, regarding Eastern Europe, the report stated that, A total of 9 inspections have been carried out in this area, reporting 146 findings … [a] total of 18 critical findings were reported in this area in 4 of the inspected investigational sites in this area and hence 5 inspections did not record any critical finding. The violations in Good Clinical Practice (findings) in Eastern Europe concerned, for example, supplying and storage of the study drug, informed consent process, and compliance with the Clinical Study Protocol. EMA’s report also provided an account as to whether the violations were those of the sponsor, the investigator, the CRO, or the analytical laboratory.

IV Drafting FDA Submissions

This book addresses the need for the Director of Regulatory Affairs, the Chief Medical Officer, medical writers, and other company personnel, to obtain a working knowledge of the following topics:

• Package labels. FDA’s decision-making processes used in arriving at the final draft of the package label.

• FDA’s critiques of the Sponsor’s clinical trial design. FDA’s decision-making processes, where it criticizes the Sponsor’s clinical trial design or where it instructs the Sponsor to conduct additional studies.

• Interpreting ambiguous data. FDA’s decision-making processes in navigating through ambiguous areas, on the topics of safety, efficacy, and clinical trial design.

• Topics frequent in FDA-submissions but rare in medical journals. This book reveals topics frequently encountered in FDA submissions but not routinely encountered in medical journals. The term rest of world (ROW) is an accepted term used in FDA submissions to distinguish study sites in the United States from study sites in Europe and Asia.⁷⁵,⁷⁶,⁷⁷ But the term rest of world is not often used in medical journals.⁷⁸ The terms System Organ Class (SOC) and Preferred Term are routinely used in FDA submissions when disclosing adverse events and for dividing adverse events into various categories.⁷⁹,⁸⁰ But the System Organ Class⁸¹ and Preferred Term⁸² are not often used in medical journals. Similarly, the term treatment emergent adverse events (TEAEs) is commonly used in FDA submissions as a format for disclosing adverse events. Yet another example is⁸³ the subject of Intrinsic Factors and Extrinsic Factors.⁸⁴ However, these terms are rarely used in medical journals.⁸⁵

V Distinguishing Package Labeling of Pharmaceuticals From Other Labeling Issues

a Off-Label Uses

Once a given drug receives FDA approval, it is common for physicians to use their own clinical judgment and prescribe the drug for diseases or for subgroups of patients that deviate from the disease and patient subgroup required by the package label.⁸⁶ Off-label uses also encompass the use via routes of administration or dose amounts different from that required by the package label.⁸⁷ The most common off-label uses for anticancer drugs are for rituximab, gemcitabine, and bevacizumab.⁸⁸ Other common off-label uses are for anticonvulsants, antipsychotic drugs, and antibiotics.⁸⁹

This concerns the issue of drug expense as a source of motivation for an off-label use. To provide the example of angiogenesis blocking drugs, ranibizumab is an antibody with a structure based on that of the antibody bevacizumab. Ranibuzumab and bevacizumab each bind to vascular endothelial growth factor (VEGF), where the outcome is blocking the formation of new blood vessels (angiogenesis). Angiogenesis is part of the pathology of solid tumors and also part of the pathology of age-related macular degeneration (blindness). But bevacizumab is much less expensive than ranibizumab and, as a consequence, off-label use of bevacizumab for age-related macular degeneration has become common. According to one commentator, the lack of FDA approval of bevacizumab for treating age-related macular degeneration creates the need for heightened surveillance for systemic adverse effects when using bevacizumab for this non-FDA-approved indication.⁹⁰

This concerns the issue where existing drugs are not effective and where the physician explores an off-label use of another drug. This provides the example of drugs for systemic lupus erythematosus (SLE), an autoimmune disease. SLE results from overactivity of B cells. B cells are a type of lymphocyte that secretes antibodies into the bloodstream. Most therapies for SLE are off-label, where the relevant drugs are various immunosuppressants. Rituximab is an antibody that binds to CD20 of B cells, resulting in depletion of B cells. But rituximab has not been FDA-approved for the indication of SLE. Rituximab is used for off-label treatment of about 1% of SLE patients, and specifically, where other drugs have not worked for the patient being treated.⁹¹

Yet another source of motivation for off-label uses is where the package label does not encompass a particular patient subgroup, such as the pediatric population. Off-label uses are common in pediatric patients, where the most common deviation from the package label instructions is the dose amount.⁹²,⁹³ The relative lack of FDA-approved drugs where the label’s indication is for children is due to small number of available study subjects, low financial incentive, and ethical concerns.⁹⁴ The drugs used for off-label indications for children include dexmedetomidine, dopamine, hydromorphone, ketamine, lorazepam, methadone, milrinone, and oxycodone.⁹⁵

Pharmaceutical companies are able to recoup their investment, and sometimes earn profit, as long as they own an issued patent. However, once the term of the patent expires, companies will have lost their incentive to perform additional clinical studies for proving efficacy and safety for a new indication of the old drug. The result is that physicians are forced to use their own judgment (rather than rely on judgment of FDA reviewers) in deciding to employ an off-label use.⁹⁶

Off-label uses can best be justified where a medical journal published data showing efficacy and safety for the off-label use. This statement refers to publications reporting clinical data that had not been submitted to the FDA, that is, by way of an NDA or BLA.⁹⁷

Investigators affiliated with clinics, hospitals, or pharmaceutical companies are free to devise and conduct clinical studies for off-label uses. Mullins et al.⁹⁸ provides a guideline for clinical studies for off-label uses. The guideline for this type of study design is quite similar to the typical study design used for acquiring data on efficacy and safety for submitting to the FDA, but with a notable exception. The exception is the recommendation that clinical studies for off-label indications make use of community-based trial sites (unlike clinical studies for FDA-approval, which are generally based in academic centers).

In a communication to this author, Prof. Mullins explained that this difference is to facilitate insurance coverage of the patients who eventually need compensation for the off-label use. The explanation was that, "The issue that we were trying to address is the evidence the FDA requires v. what insurers want for their coverage decisions. Some of this is about internal v external validity. Insurers want to know about the value of drugs in broader populations, which includes those treated in community settings. However, for regulatory purposes, it is easier for drug manufacturers to focus on narrower populations and study sites.⁹⁹"

An issue with off-label uses occurs where pharmaceutical companies issue advertisements or distribute publications on those uses. This practice has been called, substituting marketing for science. This issue can arise after a company wins FDA approval of a drug for a given indication and then promotes use of the same drug but for a different indication.¹⁰⁰

National Comprehensive Cancer Network (NCCN) provides lists of off-label uses for anticancer drugs. In response to an inquiry from this author, NCCN responded that:

The NCCN Clinical Practice Guidelines contain recommendations for … therapies for a particular disease indication without reference to the indications found on the FDA label … a comparison of on- and off- label usage … [is provided by] the NCCN Drugs and Biologics Compendium. This is a resource that lists all agents recommended within NCCN guidelines, along with information about the NCCN recommended