NEW DRUG APPLICATION

Learning Objectives

At the end of the session, the student will be able to

• Discuss and analyze the need for New Drug Application
• Describe the steps involved in filing an NDA
• Explain the fundamentals of NDA submission

NEW DRUG APPLICATION

• For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization.
• The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) becomes part of the NDA.
• When the Food, Drug, and Cosmetic Act (FD&C Act) was passed in 1938, NDAs were only required to contain information pertaining to the investigational drug’s safety.
• In 1962, the Kefauver-Harris Amendments to the FD&C Act required NDAs to contain evidence that a new drug was effective for its intended use as well and that the established benefits of the drug outweighed its known risks
• The NDA was again the subject of change in 1985 when the FDA completed a comprehensive revision of the regulations pertaining to NDAs.

• While this revision, commonly called the NDA Rewrite, modified content requirements, it was mainly intended to restructure the ways in which information and data are organized and presented in the NDA to easily access FDA reviews.

Fundamentals of NDA Submission

• As outlined in Form FDA-356h, Application to Market a New Drug for Human Use or as an Antibiotic Drug for Human Use, NDAs can consist of as many as 15 different sections:

1. Index
2. Summary
3. Chemistry, Manufacturing, and Control;
4. Samples, Method Validation Package, and Labeling
5. Nonclinical Pharmacology and Toxicology
6. Human Pharmacokinetics and Bioavailability
7. Microbiology (for anti-microbial drugs only);
8. Clinical Data;
9. Safety Update Report (typically submitted 120 days after the NDA’s submission);
10. Statistical;
11. Case Report Tabulations;
12. Case Report Forms;
13. Patent Information;
14. Patent Certification; and
15. Other Information.

(E.g. the marketing history of the drug (if any) outside the U.S., a concluding discussion of benefit/risk considerations and of proposed additional studies or postmarketing surveillance plans etc.)

NDA Classification

1. New Molecular Entity
2. New Salt of Previously Approved Drug (not a new molecular entity)
3. New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity)
4. New Combination of Two or More Drugs
5. Already Marketed Drug Product – Duplication (i.e., new manufacturer)
6. New Indication (claim) for Already Marketed Drug (includes switching marketing status from prescription to OTC)
7. Already Marketed Drug Product – No Previously Approved NDA

GENERAL REQUIREMENTS

• The new (present) NDA regulations require that an application be submitted in two copies:

(a) An archival copy that serves as a permanent record of the submission, and

(b) A review copy.

• The review copy is made up of a number of separate technical volumes, each tailored to the needs of the disciplines involved in the review.
• Both the archival and review copies are submitted in hard copy, the regulations permit an application to submit the archival copy as microfiche
• The NDA application form (FORM NDA 356 h) consists of twelve items (including index) that deals with the safety and efficacy features of drug product, two are concerned with patent information.

Filing an NDA

The application form is supplemented with detailed, technical guidelines to improve the quality of submissions

• The format and content of an application summary
• Formatting, assembling, and submitting new drug and antibiotic applications
• The submission in microfiche of the archival copy of an application
• The format and content of the human pharmacokinetics and Bioavailability section of an application
• The format and content of the clinical and statistical sections of an application
• The format and content of the chemistry, manufacturing, and control section of an application
• The chemistry section, because of its length, and highly detailed sections dealing with the manufacturing and control processes, is required to be submitted 90-120 days prior to the submission of the application for facilitating the identification of deficiencies in the filed NDA.
• Submission of the chemistry section earlier than 120 days and less than 90 days before the remainder of the application will not be accepted.
• The archival copy of the application should include a comprehensive index by volume and page number.
• It is recommended that additional copies of the index be prepared and included with any material submitted to the FDA for the NDA.
• This will easily locate important parts of the submission that may be needed for meetings/view by Phairnmadcyividual technical reviewers

Investigator’s Brochure

• The Investigator’s Brochure (IB) is a compilation of all relevant nonclinical and clinical data for a drug undergoing clinical investigation.
• It is an important source of information for clinical investigators, Institutional Review Boards (IRBs), Independent Ethics Committees (IECs), and regulatory agencies.
• It is a dynamic document that evolves over time to reflect an increasing body of nonclinical and clinical data as the drug progresses through the various stages of clinical development.
• The preparation and updating of the IB is a collaborative process that involves extensive interactions among individuals from various functional areas.
• Information contained in the IB enables potential investigators to evaluate the drug and determine their interest in the clinical program and their ability to conduct the proposed clinical investigation(s).
• The IB is used by IRBs, IECs, and regulatory agencies to assess whether a proposed clinical study or group of studies is acceptable from a risk/benefit standpoint and to determine whether there are adequate data to justify the dosage regimen, duration, and other aspects of the proposed clinical trial(s).
• The IB provides investigators with sufficient background information to discuss the benefits and risks of the drug with potential study subjects as part of the informed consent process.
• Finally, the IB serves as an up-to-date reference manual for investigators during the clinical study.
• The IB is included in the initial filing of an Investigational New Drug Application (IND) or Clinical Trials Exemption (CTX) and, in some countries, is the primary document required by regulatory agencies to initiate clinical studies.
• Guidelines are also provided for the use of data from various sources, including preliminary data from completed studies, data from ongoing studies, and information from postmarketing surveillance.

Drug Management Teams

• Management of overall pharmaceutical drug development programs, or specific aspects of drug development programs (e.g., an NDA), requires skilled professionals who have prior experience with these activities.
• Cross-functional product development teams need to be managed in a way that fosters strategic planning, and information flowing, & ensures that timelines & deliverables stay on track. The same applies to functional area subteams, or other teams created to achieve a particular goal or complete a particular task.

FAQ

What is a New Drug Application (NDA) in the pharmaceutical industry?

An NDA is a formal request submitted to regulatory authorities, such as the FDA in the United States, for permission to market and sell a new pharmaceutical product. It includes comprehensive data on the drug’s safety, efficacy, quality, manufacturing processes, and more.

Why is an New Drug Application necessary for new pharmaceutical products?

NDAs are required by regulatory authorities to assess the safety and effectiveness of new drugs. They ensure that the benefits of the drug outweigh potential risks for patients.

What are the key steps involved in filing an New Drug Application?

The key steps include pre-NDA activities, NDA dossier preparation, submission to regulatory authorities, and a thorough regulatory review of all data and documentation.

What kind of data and information are typically included in an New Drug Application dossier?

An NDA dossier includes data on drug development, clinical trials, pharmacology, toxicology, manufacturing processes, labeling, and other critical aspects of the drug.

How important is data integrity in the New Drug Application submission process?

Data integrity is of utmost importance. Data included in the NDA must be accurate, truthful, and supported by evidence. Any data manipulation or misrepresentation can lead to rejection.

Is the New Drug Application submission process confidential?

Yes, the NDA submission is typically confidential to protect proprietary information and trade secrets. However, once approved, certain information may become publicly accessible.

What is the role of regulatory authorities in reviewing NDAs?

Regulatory authorities review NDAs for completeness, accuracy, and compliance with regulations. This involves an in-depth evaluation of all data and documentation to ensure patient safety and drug efficacy.

Why is timely New Drug Application submission crucial in the pharmaceutical industry?

Timely NDA submission is essential to align with development milestones and market demands. Delays in submission can impact a drug’s competitive advantage and availability to patients in need.

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