New Drug Application (NDA)

The NDA includes data from the drug manufacturer that signifies the drug's safety and efficacy for its intended use. The NDA contains comprehensive information about the drug's composition, manufacturing process, proposed labeling, and results of clinical studies.

After a pharmaceutical company formulates a new drug, it performs an elaborative preclinical and clinical trial to ensure its safety and efficacy. If the new drug candidate shows desired therapeutic promise then the company submits an NDA to the FDA. If the US FDA approves the NDA, then the drug can be legally commercialized in the USA.

A new drug candidate passes through multiple stages before it reaches patients. The stages include:

• Discovery and preclinical research: Scientists develop a potential drug candidate through laboratory experiments. Preclinical research involves testing the drug's safety, efficacy, and toxicity using cell lines (in vitro) and animal subjects (in vivo).
• Investigational New Drug application (IND): The Pharmaceutical company must submit an IND application that includes the chemical composition of the drug, data from preclinical studies, manufacturing details, and proposed clinical trials.
• Clinical trials: There are three phases of clinical trials to test the efficacy of the drug: Phase 1 includes a small-scale trial on a small group of healthy volunteers; Phase 2 involves a large-scale trial on a varied group of patients; Phase 3 is an extensive trial to confirm the effectiveness of the drug.
• New Drug Application (NDA): As mentioned above, the pharmaceutical company files an NDA, and the FDA reviews the application.
• FDA review and action: The FDA reviews the NDA, approves it if satisfied, and monitors the post-market effects.

The journey of a new drug candidate from discovery to NDA approval is shown in the graphic below.

Important Regulations

The Center for Drug Evaluation and Research (CDER) body of the FDA reviews the NDA. The key regulations and guidelines related to NDAs include:

• 1. Code of Federal Regulations (CFR): Title 21 of the Code of Federal Regulations contains regulations specific to food and drugs in the United States. Part 314 of Title 21 outlines the requirements for NDAs.
• 2. FDA Guidance Documents: The FDA publishes various guidance documents to assist pharmaceutical companies in preparing and submitting NDAs. These documents provide detailed information on specific topics related to drug development, clinical trials, manufacturing, and labeling.
• 3. Food, Drug, and Cosmetic Act (FD&C Act): The FD&C Act of 1938 is the primary statute governing the regulation of drugs in the United States. It outlines the legal requirements for drug approval, safety, labeling, and marketing.
• 4. Pediatric Research Equity Act (PREA): The PREA of 2003 requires pediatric assessments of certain drug products, including the subject of NDAs. It ensures the safe and effective use of clinically tested drugs in pediatric populations.
• 5. Orphan Drug Act: This act provides incentives for the development of drugs and biologics for rare diseases or conditions. Drugs designated as orphan drugs are eligible for various benefits, including market exclusivity.
• 6. Fast Track, Breakthrough Therapy, and Priority Review Designations: These designations are not formal regulations but special programs established by the FDA to expedite the development and review of drugs for serious or life-threatening conditions. Each designation has specific regulatory implications.

It's important to note that these regulations are subject to change, and pharmaceutical companies are requested to refer to the official FDA website when preparing an NDA.

Filing a successful NDA

For a successful NDA filing, the application should contain data from specific technical viewpoints for review, including chemistry, pharmacology, medical, biopharmaceutics, and statistics. The documents essential for NDA must be submitted in eCTD format, a standard format for submitting applications, amendments, supplements, and reports to the CDER and Center for Biologics Evaluation and Research (CBER). After the submission, the team of CDER scientists, physicians, statisticians, chemists, and pharmacologists review the drug approval documents and propose labeling for pharmaceutical products.

• 1. Good Manufacturing Practices (GMP): The drug manufacturing facilities must comply with Good Manufacturing Practices, ensuring that the drugs are produced and controlled to meet consistent quality standards.
• 2. Content requirements: The FDA has specific requirements regarding the content of the NDA that include detailed information about the drug's composition, manufacturing process, labeling, preclinical and clinical trial data, pharmacology, toxicology, and proposed use indications.
• 3. Clinical trials: Pharmaceutical companies should conduct extensive clinical trials to demonstrate the safety and efficacy of the drug. These trials must be well-designed and follow the ethical guidelines.
• 4. User Fees: Pharmaceutical companies must pay user fees to the FDA when submitting an NDA. These fees help fund the FDA's drug approval process and review activities. The three types of user fees under the Prescription Drug User Fee Act (PDUFA VI) for FY2022 were:
  • Application fee requiring clinical data- $ 3,117,218
  • Application fee not requiring clinical data- $ 1,558,609
  • Program fee- $369,413
• 5. Pediatric studies: If you are filing an NDA for use in the pediatric population, the FDA requires pediatric studies to determine the safety and efficacy of the drug in pediatric populations. It is part of the Pediatric Research Equity Act (PREA) requirements.
• 6. Post-marketing surveillance: After approval, pharmaceutical companies conduct post-marketing surveillance to monitor the drug's safety and report adverse events to the FDA.
• 7. Orphan drug designation: Drugs intended to treat rare diseases or conditions can obtain orphan drug designation, providing incentives and benefits to the drug developers, including market exclusivity for a specified period.

Forms for NDA submission

Below is a list of forms necessary for filing NDA submissions:

1. Form FDA-356h: Application to market a new drug, niologic, or antibiotic drug for human use. The application form contains:

• The applicant’s name and address
• Details of the authorized US agent (for non-U.S. applicants)
• Product description including established, proprietary, and chemical names, the dosage form
• Strengths route of administration
• The proposed indication for use (orphan designation number must be provided if the drug is for a rare disease)
• Identification number of all INDs, drug master file
• Case reports forms
• Establishment description
• Labeling
• Patient data, safety update report
• Human pharmacokinetics and bioavailability sections
• Statistical sections
• Chemistry section
• Non-clinical pharmacology and toxicology section
• Patent, debarment, and field copy certification
• User fee cover sheet
• Financial disclosure information, case report tabulation

2. Form FDA-3397: User Fee Cover Sheet (PDUFA Form FDA 3397)

3. Form FDA-3331: New Drug Application Field Report; this report aims for an immediate identification of any quality defects in the marketed drugs that may cause harmful health effects. An applicant of an approved NDA needs to submit a field alert report to the FDA within 3 days of receiving the information referring to any significant quality issues in the distributed drug.

More information on the guidance documents for electronic submission is available at the Electronic Regulatory Submissions and Review Helpful Links.

Conclusion

Any pharmaceutical company must submit an NDA for FDA approval in the USA. The NDA demonstrates every detail of the new drug; providing the FDA with adequate information related to the drug. Though the course from NDA submission to approval is long, it ensures that the drug meets the mandatory safety and efficacy standards before it is available to healthcare providers and patients. The guidance documents for NDA and assistance from CDER can aid you in meeting all the requisites, and internal NDA review principles, policies, and procedures. These documents guide FDA review staff, applicants, and sponsors on regulating products. Note they are not enforceable laws or regulations, unlike the Code of Federal Regulations.