21 CFR Part 314 (Applications for FDA Approval to Market a New Drug)

21 CFR Part 314 is the parent regulation establishing the New Drug Application (NDA) and Abbreviated NDA (ANDA) framework: what an application must contain, how FDA reviews and approves it, and the obligations that follow approval. Two of its sections have dedicated entries — 21 CFR 314.70 (post-approval changes) and 21 CFR 314.80 (postmarketing reporting) — this entry covers the Part overall.

How Part 314 relates to Part 312 (IND)

Part 314 picks up where 21 CFR Part 312 (Investigational New Drug) leaves off. Part 312 governs a drug during clinical investigation, before it is legally marketable — it is the regulation under which a sponsor conducts Phase 1 through Phase 3 trials. Part 314 governs the application a sponsor files once it believes it has enough evidence from that IND-stage investigation to support marketing the drug: the NDA (for a novel drug) or the ANDA (for a generic duplicating an already-approved “reference listed drug”). A sponsor cannot file an NDA/ANDA without having conducted the underlying investigation under an IND (or, for an ANDA, relying on the reference drug’s own prior approval); the two regulations describe sequential, not overlapping, phases of the same drug’s regulatory lifecycle. The biologics counterpart — a Biologics License Application (BLA) under the Public Health Service Act — follows an analogous but separately codified framework at 21 CFR Part 601, not Part 314.

The subparts of Part 314

Part 314 is organized into nine subparts (Subpart F is reserved and contains no active sections):

• Subpart A — General Provisions (314.1-314.3). Scope and definitions applicable to the rest of the Part.
• Subpart B — Applications (314.50-314.90). The core content-and-format requirements for an NDA, plus post-approval obligations. This is where 314.50 (NDA content and format), 314.70 (changes to an approved NDA), 314.71 (amendments to an unapproved application), 314.72 (change in ownership), 314.80 (postmarketing adverse drug experience reporting), and 314.81 (other postmarketing reports, including annual reports) all sit.
• Subpart C — Abbreviated Applications (314.92-314.99). The ANDA pathway: what an ANDA must contain to rely on FDA’s prior finding that a reference listed drug is safe and effective, bioequivalence requirements, and (via 314.97) the requirement that ANDA holders follow 314.70’s same post-approval change categories.
• Subpart D — FDA Action on Applications and Abbreviated Applications (314.100-314.170). FDA’s internal review process: the filing decision, communication with the applicant during review, approval and the grounds for refusing to approve, and marketing exclusivity determinations. 314.101, 314.105, and 314.110 (described below) are in this subpart.
• Subpart E — Hearing Procedures for New Drugs (314.200-314.235). The administrative hearing process available when FDA proposes to withdraw approval or refuses to approve an application, separate from the informal dispute-resolution meetings FDA also offers during review.
• Subpart G — Miscellaneous Provisions (314.410-314.445). Confidentiality of data and information in an application, and related administrative matters.
• Subpart H — Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses (314.500-314.560). The pathway allowing approval based on a surrogate or intermediate clinical endpoint reasonably likely to predict clinical benefit, subject to a post-approval confirmatory trial.
• Subpart I — Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible (314.600-314.650). The “Animal Rule,” used when efficacy cannot ethically be tested in humans (chiefly for medical countermeasures against chemical, biological, radiological, or nuclear threats).

What an NDA/ANDA must contain

21 CFR 314.50 sets out the content and format of an NDA in a series of technical sections: chemistry, manufacturing, and controls (see CASRAI’s Chemistry, Manufacturing, and Controls (CMC) entry); nonclinical pharmacology and toxicology; human pharmacokinetics and bioavailability; microbiology (for anti-infective drugs); clinical data supporting safety and effectiveness; a statistical section; and samples and proposed labeling, together with an index and summary. FDA’s standardized cover form for this submission — and for an ANDA or BLA — is FDA Form 356h. An ANDA, under 314.94, follows the same 314.50 structure but substitutes bioequivalence data and patent certifications for the full independent safety/efficacy dataset, since it relies on FDA’s existing finding for the reference listed drug.

FDA’s review process and timelines

Once submitted, an application moves through several defined stages under Subpart D:

• Filing decision (314.101). FDA has 60 days from receipt to decide whether the application is sufficiently complete to permit a substantive review (“filed”) or whether it will refuse to file it as incomplete. A refuse-to-file decision is issued before any substantive review of the evidence begins, and is distinct from a later decision not to approve a completed review.
• Substantive review. FDA reviews the technical sections against the standard for approval in 314.105 — for an NDA, that the drug is safe and effective for its proposed use(s) based on substantial evidence, and that the proposed labeling is accurate and adequate. Review-time performance goals (not legal deadlines) are negotiated through the Prescription Drug User Fee Act (PDUFA): a 10-month goal for a Standard Review application and a 6-month goal for a Priority Review application, both measured from the filing date.
• Approval or Complete Response Letter. At the end of a review cycle, FDA either approves the application or, if it cannot approve it in its current form, issues a Complete Response Letter (CRL) under 314.110 describing the deficiencies that must be resolved — distinct from a refuse-to-file decision, which happens before review, and from the formal grounds for refusing to approve set out in 314.125 (NDA) and 314.127 (ANDA).
• Exclusivity determinations. Subpart D also governs statutory marketing exclusivity periods (for example, new chemical entity exclusivity) that can run independently of any patent protection and affect when a competing ANDA may be approved.

See CASRAI’s Clinical Trial Phases guide for where NDA/ANDA submission sits relative to Phase 1-3 investigation, and the Prescription Drug User Fee Act (PDUFA) and FDA Priority Review entries for how the review-timeline goals themselves are set and earned.

Worked examples

• New molecular entity NDA: A sponsor completes Phase 3 trials of a novel drug under an IND (21 CFR Part 312), assembles the CMC, nonclinical, clinical, and statistical sections required by 314.50, and submits an NDA. FDA accepts it for filing within 60 days, reviews it against the 314.105 approval standard on a Standard or Priority Review timeline, and either approves it or issues a Complete Response Letter under 314.110.
• Generic ANDA: A generic manufacturer submits an ANDA under Subpart C relying on bioequivalence data to an already-approved reference listed drug, rather than independent safety/efficacy trials of its own; the same 314.100-series filing and review framework applies, and once approved, the ANDA holder is subject to 314.70’s post-approval change categories via 314.97, exactly as an NDA holder is.

Counter-example

A sponsor’s IND application to begin a Phase 1 trial is not a Part 314 event — it is governed entirely by 21 CFR Part 312, since no marketing application has been filed yet. Part 314 applies only once a sponsor is seeking (or holds) FDA marketing approval; investigational-stage activity, however extensive, stays under Part 312 until an NDA or ANDA is actually submitted.

Related CASRAI content

See also 21 CFR 314.70 (Changes to an Approved NDA or ANDA) and 21 CFR 314.80 (Postmarketing Reporting of Adverse Drug Experiences) for the two Part 314 sections with their own dedicated entries; Complete Response Letter (CRL) for what happens when FDA cannot approve an application as submitted; Investigational New Drug (IND) for the Part 312 pathway that precedes every NDA/ANDA; the FDA Expedited Programs guide for how Priority Review, Accelerated Approval, Breakthrough Therapy, and Fast Track interact with the Part 314 review process; and the Clinical Research Administration pillar for the broader regulatory-compliance context.