New Drug Application (NDA): Unit II Regulatory Approval Process
INTRODUCTION NEW DRUG APPLICATION (NDA)
If clinical studies confirm that a new drug is relatively safe and effective, and will not pose unreasonable risks to patients, the manufacturer files a New Drug Application (NDA), the actual request to manufacture and sell the drug in the United States.
The New Drug Application is the vehicle through which the drug sponsors finally propose FDA to approve a new investigational drug for sale and marketing after Phase III A Pivot trials.
The official definition of New Drug is in Section 201(P) of Federal Drug, Food and Cosmetics Act as; “Any new drug, the composition of which is such that it is not recognized among experts qualified by scientific training as safe and effective for use under prescribed, recommended or suggested conditions”. OR “Any drug the composition of which is such that it as a result of investigations to determine safety and efficacy for use has become recognized, but which has not, otherwise in such investigations been used to a material extent”.
The following letter codes describe the review priority of the drug;
S-Standard review: For drugs similar to currently available drugs.
P-Priority review: For drugs that represent significant advances over existing treatments.
Classification of Drugs in NDA
Center of drug evaluation and Research (CDER) classifies new drug applications according to the type of drug being submitted and its intended use:
- New molecular entity.
- New salt of previously approved drug.
- New formulation of previously approved drug.
- New combination of two or more drugs.
- Already marketed drug product Duplication (i.e. new manufacturer).
- New indication (claim) for already marketed drug (includes switching marketing status from prescription to OTC).
- Already marketed drug product (no previous approved NDA).
In US following four types of applications are submitted for approval of drug for marketing depending upon the type and nature of the drug:
- New Drug Application (NDA).
- Biological License Application (BLA).
- Application u/s 505(b)(2)-Paper NDA.
- Supplemental New Drug Application (SNDA).
Format and Content of NDA
The application is required to be submitted in common technical document format with the following different sections:
- FDA Form 356h
- User Fee Cover Sheet (FDA Form 3397)
- Cover letter (Comprehensive table of contents for Modules 1 to 5)
- Chemistry, Manufacturing and Control
- Samples, Method Validation Package and Labeling
- Non-clinical Pharmacology and Toxicology
- Human Pharmacokinetics and Bioavailability
- Microbiology (For anti-microbial drugs only)
- Statistical methods and analysis of Clinical Data
- Safety Update Report (typically submitted 120 days after NDA submission)
- Statement regarding compliance to IRB and Informed Consent requirements
- Case Report Tabulations
- Case Report Forms
- Patent information and certification
- Other information
General Requirements for Filling of NDA
The new NDA regulations require the application to be submitted in two copies:
A. An Archival Copy
It is a complete copy of application submission that serves as its permanent record.
B. A Review Copy:
It is divided into 6 technical sections:
- Chemistry, Manufacturing and Controls (CMC).
- Non-clinical Pharmacology and Toxicology.
- Human Pharmacokinetics and Bioavailability.
- Microbiology (if required).
- Clinical data.
On receipt of NDA, the CDER stamps with a receipt date to enable FDA to forward action within 180 days called Review Clock under Review Time Frames (21CFR 314.100). The FDA assigns the application for review.
The FDA has to intimate the applicant if it is incomplete within 60 days according to Filing Time Frames (21CFR 314.101). FDA notifies the sponsor of its completion/ incompletion and if complete send it for secondary review process.
FDA inspects the manufacturing facilities for the drug. It may also inspect sample of clinical trial locations to verify the accuracy of data submitted.
Throughout the process, FDA and sponsor communicate through in person meetings telephone conferences, fax, etc to seek clarification if necessary.
Once all reviews are complete; the Divisional Director evaluates the reviews and makes FDA’s decision.
The FDA may:
- Approve the drug for marketing. Approve the drug with condition when problem exist with the application that needs to be addressed before approval.
- Refuse to approve the drug, when it may require additional research or reformulation of the drug product.
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