Formatting, Assembling, And Submitting The New Drug Application

Formatting, Assembling, and Submitting the New Drug Application (NDA) Agnimitra Dinda School of Pharmaceutical Sciences Bhubaneswar INDIA

Introduction: • The new drug application (NDA) is a critical component in the drug approval process. The U.S. Food and Drug Administration (FDA) requires drug sponsors to submit an NDA for review before a new pharmaceutical can be approved for marketing and sale in the U.S. • The NDA contains clinical and nonclinical test data and analyses, drug chemistry information, and descriptions of manufacturing

FDA Guidelines: • NDA shares many common elements with the Common Technical Document (CTD) developed by the International Conference on Harmonization (ICH) in order to streamline submissions for registration in all three ICH regions: the U.S., the European Union, and Japan.

A list of the current FDA guidelines: • Guideline on Formatting, Assembling, and Submitting New Drug and Antibiotic Applications • Guideline for the Format and Content of the Summary for New Drug and Antibiotic Applications • Guideline for the Format and Content of the Nonclinical/Pharmacology/Toxicology Section of an Application • Guideline for the Format and Content of the Human Pharmacokinetics and Bioavailability Section of an Application • Guideline for the Format and Content of the Microbiology Section of an Application

• Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications • Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application • Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances • Guideline for Submitting Samples and Analytical Data for Methods Validation • Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics • Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics.

NDA Contents:

1. 2. 3. 4. 5. 6.

Index Labeling (±) Application Summary CMC and Methods Validation Package Nonclinical Pharmacology andToxicology Human Pharmacokinetics and Bioavailability 7. Microbiology 8. Clinical data 9. Safety Updates 10. Statistical information 11. Case Report Tabulation 12. Case Report Forms

13: Patent Information 14: Patent Certification 15: Establishment Description (if applicable) 16: Debarment Certification 17: Field Copy Certification 18: User Fee Cover Sheet (Form FDA3397) 19: Financial Disclosure (Form FDA3454, Form FDA-3455) 20: Other/Pediatric Use

NDA Section 1: Index : • The NDA index is a comprehensive table of contents that enables the reviewers to find specific information in this massive document quickly. The NDA index should follow immediately after the Form FDA-356h and the administrative items. It must show the location of every section in the archival NDA by volume and by page number

NDA Section 2: Labeling • The labeling section must include all draft labeling that is intended for use on the product container, cartons or packages, including the proposed package insert. • One copy should be bound into the archival copy. Copies should also be placed in the review copies of the clinical, chemistry, and

NDA Section 3: Application Summary

• • • • • • • • • • •

The application summary is an abbreviated version of the entire application. This overview is one of the few elements of the application that all reviewers receive, and it should give them a clear idea of the drug and its application. 1. Description 2. Clinical Pharmacology 3. Indications and Usage 4. Contraindications 5. Warnings 6. Precautions 7. Adverse Reactions 8. Drug Abuse and Dependence 9. Overdosage 10. Dosage and Administration 11. How Supplied

NDA Section 4: Chemistry, Manufacturing, and Controls (CMC):

• It includes information on the composition, manufacture, and specifications of the drug substance and the drug product. • The three main elements are (1) chemistry, manufacturing and controls information, (2) samples and, (3) methods validation package. Deficiencies in this section are common.

NDA Section 5: Nonclinical Pharmacology and Toxicology:

• The second technical section of the NDA provides a description or summary of all animal and in vitro studies with the drug. • The table of contents should clearly identify all studies not previously submitted to the IND.

It includes: 1. Effects related to the therapeutic indication, such as the pharmacodynamic ED 50 in doseranging studies and the mechanism of action (if known) 2. Secondary pharmacological actions in order of clinical importance as possible adverse effects or as ancillary therapeutic effects 3. Interactions with other drugs (or crossreference the location of the information in any of the above

For acute toxicity studies, present the animal study data in the following order:

1. 2. 3. 4. 5. 6. 7. 8. 9.

Mouse Rat Hamster Other rodent(s) Rabbit Dog Monkey Other nonrodent mammal(s) Nonmammals

Present the ADME data in the following order:

1. Absorption 2. Distribution (protein binding, tissue distribution, accumulation) 3. Metabolism (enzyme induction or inhibition) 4. Excretion (serum half-life)

NDA Section 6: Human Pharmacokinetics and Bioavailability:

• The first element in this section is a tabulated summary of studies showing all in vivo biopharmaceutic studies performed. Include a summary of data and overall conclusions. • Peak concentration (Cmax) • Area under the curve (AUC) • Time to reach peak concentration (tmax) • Elimination constant • Distribution volume (Vd) • Plasma and renal clearance • Urinary excretion

NDA Section 7: Microbiology: • Antimicrobial drugs differ from other classes of drugs in that they are designed to affect microbial physiology rather than patient physiology. In vitro and in vivo studies on the effects of the antimicrobial drug on the microorganism are critical in establishing the new drug’s effectiveness.

NDA Section 8: Clinical Data: 1. A table of all studies 2. Full clinical trial reports of all controlled studies in the following order: • a. Completed studies (U.S. studies followed by non-U.S. studies and any published trials) • b. Ongoing studies with interim results (same order as above) • c. Incomplete or discontinued studies (same order as above) 3. Full reports of dose-comparison concurrent control studies, followed by those for “notreatment” concurrent control, active control studies, and historical control studies

NDA Section 9: Safety Update Reports:

• A pending application must be updated when new safety data becomes available that could affect any of the following: • Statements in draft labeling • Contraindications • Warnings • Precautions • Adverse events

NDA Section 10: Statistics:

• This technical section includes descriptions and documentation of the statistical analyses performed to evaluation the controlled clinical trials and other safety information. It must include copies of: • All controlled clinical trial reports • Integrated efficacy and safety summaries • Integrated summary of risks and

NDA Section 11: Case Report Form Tabulations

• Include complete tabulations for each patient from every adequately or well-controlled Phase II and Phase III efficacy study, and from every Phase I clinical pharmacology study.

NDA Section 12: Case Report Forms (CRFs)

• It is necessary to include the complete CRF for each patient who died during a clinical study and for any patients who were dropped from the study due to an adverse event, regardless of whether the AE is considered to be related to the study drug, even if the patient was receiving a placebo or comparative drug.

The Common Technical Document developed by ICH is organized into well-defined modules.

As noted above, ICH has developed a Common Technical Document to streamline regulatory submissions in Europe, the U.S. and Japan. CTD is an information format that contains clinical, nonclinical, and manufacturing technical data required to get the NEW DRUG APPROVAL

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