New Drug Application Overview

An NDA's contents are set by 21 CFR 314.50. It must include reports of every investigation of the drug product that the applicant sponsored, plus all other information relevant to evaluating the NDA that the applicant has obtained from any source. For a new chemical entity, the NDA "will generally contain" an application form, an index, a summary, five or six technical sections, case report tabulations, case report forms, drug samples and labeling, including any Medication Guide required under Part 208 ^[5]. Other NDAs, such as 505(b)(2) applications, amendments and supplements, will generally contain only some of these items, limited to what that submission needs ^[5].

Approach: I read the current eCFR text of 21 CFR 314.50, "Content and format of an NDA." Everything below comes from that section ^[5].

(a) Application form. It must be completed and signed, and it contains:

• the applicant's name and address, and the date;
• the established, proprietary, code and chemical names of the drug;
• the dosage form, strength and route of administration;
• the IND numbers, drug master files and other applications it references;
• the proposed indications;
• whether this is an original, a 505(b)(2) application, a resubmission or a supplement;
• whether the product will be prescription or over-the-counter;
• a checklist of the enclosures.

If the signer has no residence or place of business in the US, a US-based attorney, agent or official must countersign.

(b) Index. The archival copy needs a full index, by volume and page, to the summary, the technical sections and the supporting information.

(c) Summary. It should be written at roughly the level of a refereed journal article, with data in tables and graphs where possible. It is not required for supplements under § 314.70. It is "required to contain":

• the proposed labeling, annotated to the supporting data;
• the pharmacologic class, the scientific rationale and the expected clinical benefits;
• marketing history outside the US: countries where the drug is marketed, countries where it was withdrawn for safety or effectiveness reasons, and countries with applications pending;
• summaries of the CMC, nonclinical, human pharmacokinetics/bioavailability, microbiology (anti-infectives only) and clinical sections, including the statistical results;
• a closing discussion of benefits and risks, including any planned postmarketing studies or surveillance.

(d) Technical sections. Each must give enough detail for the FDA to decide whether to approve, or to refuse under section 505(d).

Section	Key required content
(1) Chemistry, manufacturing and controls (CMC)	Drug substance: its characteristics, stability, manufacturer, synthesis and purification, process controls and specifications. Drug product: all components, composition, manufacturers, manufacturing and packaging procedures, specifications, and stability data with the proposed expiry dating. For each batch used in bioavailability/bioequivalence (BA/BE) or primary stability studies: batch records and contract facilities. The master production record. An environmental assessment or a claim of categorical exclusion (Part 25). A statement that the field copy was sent to the applicant's home FDA district office. The CMC section may be submitted early, 90 to 120 days before the rest of the NDA.
(2) Nonclinical pharmacology and toxicology	Pharmacology studies. Acute, subacute and chronic toxicity and carcinogenicity studies. Reproductive and developmental studies. Animal absorption, distribution, metabolism and excretion (ADME) data. A statement of compliance with good laboratory practice (GLP, Part 58), or the reason a study did not comply.
(3) Human pharmacokinetics and bioavailability	Each BA/PK study, with its methods. Statements of compliance with the institutional review board (IRB, Part 56) and informed consent (Part 50) rules. The rationale for any bioavailability specifications. Or the information supporting a waiver under Part 320.
(4) Microbiology (anti-infectives only)	Mechanism of action on microbes, antimicrobial spectrum, known resistance mechanisms, and clinical laboratory procedures.
(5) Clinical data	Clinical pharmacology studies. Every controlled study, with its protocol and statistics, including studies that are incomplete or were stopped. Uncontrolled studies. All other relevant data from any source. An integrated summary of effectiveness. An integrated summary of safety. Abuse potential, with a scheduling proposal if relevant, and overdosage data. An integrated benefit-risk summary. IRB and informed consent statements for each study. Any obligations transferred to a contract research organization (CRO). A list of studies audited against source records.
(6) Statistical	Copies of the controlled-study analyses and the safety summary, with supporting statistical documentation.
(7) Pediatric use	An integrated summary of the pediatric safety and effectiveness data, plus the information required under § 314.55.

Effectiveness and safety data must be presented by gender, age and racial subgroups. Other subgroups, such as patients with renal failure, must also be presented when appropriate. Safety update reports must be submitted at three points: 4 months after the initial submission, in a resubmission after a complete response letter, and whenever the FDA asks.

(e) Samples and labeling

• When the FDA asks, the applicant must send four representative samples each of the drug product, the drug substance and the reference standards, enough for each test to be run three times, plus market packages if requested.
• The archival copy must include three copies of the analytical procedures and validation data.
• It must also include the labels and labeling: 4 copies if draft, 12 if final printed.

(f) Case report tabulations and forms

• Tabulations are required for each adequate and well-controlled Phase 2 and Phase 3 study, for the early Phase 1 studies, and for safety data from other studies. Tabulations the FDA agrees in advance (for example at a pre-NDA meeting) are not pertinent may be left out.
• Case report forms are required for every patient who died, or who dropped out because of an adverse event, including patients on placebo or a reference drug. The FDA may waive this.
• The FDA can request additional data. If the applicant does not respond within 30 days, the eventual submission may be treated as a major amendment.

(g) to (k) Other required content

• Earlier submissions may be incorporated by reference. Using another person's data requires their signed authorization.
• Full English translations are required for anything not in English.
• If the applicant has a right of reference, it needs a signed statement from the data owner and must give the FDA access to the raw data.
• Patent information is required under § 314.53.
• For 505(b)(2) applications only: patent certifications (Paragraph I to IV) or a "no relevant patents" statement, method-of-use statements, and licensing details.
• If exclusivity is claimed under § 314.108, it must be claimed before approval, with the supporting showing (for example, that the "new clinical investigations" are "essential to approval").
• A financial certification or disclosure statement is required under Part 54.

(l) Format. Three copies are required:

• an archival copy covering paragraphs (a) to (f), on paper or electronic under Part 11;
• a review copy, with each technical section bound separately together with the form and the summary;
• a field copy containing the CMC section, the form, the summary and a true-copy certification.

The package insert content must be submitted electronically.

Under 21 CFR Part 314, the FDA reviews an NDA in two stages. First, within 60 days of receipt, it decides whether the NDA is complete enough to file. Then, within 180 days of the filing date, it reviews the NDA on the merits and either approves it or sends a complete response letter listing every deficiency it found ^[6][7]. It approves the NDA when the drug meets the legal standards for safety and effectiveness, manufacturing and controls, and labeling, and none of the 20 grounds for refusal in § 314.125 applies ^[3].

Approach: I read the current eCFR text of 21 CFR Part 314: Subpart D (§§ 314.100 to 314.126) on FDA action on applications, plus § 314.60 on amendments and § 314.200 on hearings. Part 314 does not contain the user-fee review goals the FDA works to in practice, so those are not covered here.

1. Filing review (§ 314.101)

• Within 60 days of receipt, the FDA decides whether the NDA "may be filed." Filing means the NDA is "sufficiently complete to permit a substantive review." If it is filed, the filing date is day 60, and that date starts the 180-day "filing clock" ^[6].
• The FDA may refuse to file for any of these reasons ^[6]:
  • no completed application form;
  • not in the format § 314.50 requires;
  • on its face, missing information required by section 505(b);
  • an incomplete environmental assessment, or no support for a categorical exclusion;
  • missing English translations;
  • missing compliance statements for good laboratory practice (Part 58) or for IRB and informed consent rules (Parts 56 and 50);
  • the product is already covered by the applicant's own approval, or the applicant is only a distributor or repackager;
  • it is a 505(b)(2) application for a duplicate that is eligible for an ANDA.
• The FDA will refuse to file if the product needs a licence under the Public Health Service Act, or if submission is barred under the listed exclusivity provisions ^[6].
• If the FDA refuses on one of the "may" grounds, the applicant has 30 days to ask for an informal conference. After it, the applicant can ask the FDA to file "over protest." The filing date is then 60 days after the conference request ^[6].
• If the drug appears to have abuse potential, the FDA informs the DEA ^[8].

2. Review clock (§§ 314.100, 314.60)

• The 180-day "initial review cycle" can be changed by mutual agreement, or extended by a major amendment ^[7].
• A major amendment submitted within 3 months of the end of the cycle counts as the applicant agreeing to a 3-month extension. This can happen only once per cycle, and the FDA may instead put off reviewing the amendment until the next cycle ^[9].
• A major amendment submitted more than 3 months before the end, or any non-major amendment, does not extend the cycle ^[9].
• A major amendment "may not include data to support an indication or claim" that was not in the original NDA ^[9].
• The applicant may withdraw the NDA at any time before approval and resubmit it later ^[7].

3. Communication during review (§§ 314.102, 314.103)

• The FDA "shall communicate" with the applicant on scientific, medical and procedural issues during review ^[10].
• Reviewers "shall make every reasonable effort" to flag easily correctable deficiencies promptly, especially CMC issues, so the applicant can amend before the cycle ends. Major scientific issues are normally saved for the complete response letter ^[10].
• Ninety-day conference: about 90 days after receipt, at the applicant's option. It is available for new chemical entities and major new indications ^[10].
• End-of-review conference: offered after a complete response letter, to discuss what the applicant still needs to do before approval ^[10].
• Disputes:
  • Procedural issues go to the review division first, then to the ombudsman.
  • Scientific or medical disputes go up from Division Director to Office Director to Center Director.
  • The FDA may bring in advisory committee members or refer the issue to a standing advisory committee ^[11].

4. What the FDA judges the NDA against

• Effectiveness: "substantial evidence" from adequate and well-controlled investigations ^[12].
  • A study qualifies if it has: clear objectives and analysis methods; a valid control (placebo, dose-comparison, no treatment, active, or historical control in special cases); proper subject selection; bias-minimising assignment, usually randomisation; measures against bias such as blinding; well-defined assessment methods; and adequate analysis ^[13].
  • Uncontrolled studies "are not acceptable as the sole basis" for effectiveness claims. The CDER Director may waive the criteria ^[13].
• Grounds for refusal (§ 314.125(b)) include ^[12]:
  • inadequate manufacturing methods, facilities or controls, or non-compliance with cGMP (Parts 210 and 211);
  • inadequate safety testing, unsafe results, or not enough information to judge safety;
  • lack of substantial evidence of effectiveness;
  • false or misleading labeling, or labeling that does not comply with Part 201;
  • an untrue statement of material fact;
  • missing bioavailability or bioequivalence data;
  • an unregistered establishment, or refusal to allow inspection;
  • a GLP or IRB/informed-consent failure that undermines the study or subject protection;
  • missing patent information or certifications.
• For drugs for life-threatening or severely debilitating illnesses developed under §§ 312.80 to 312.88, the safety and effectiveness criteria are applied using the considerations in § 312.84 ^[12].
• The FDA "is required to exercise its scientific judgment" on the kind and amount of data a given drug needs, and publishes its views through guidance ^[3].

5. Possible outcomes

Outcome	What it means
Approval letter	Issued when no § 314.125 ground applies. The FDA can approve on draft labeling if the only problems are minor editorial ones, on condition that the applicant makes the changes exactly as directed and submits final printed labeling before marketing [3]
Tentative approval	The NDA meets the requirements but is blocked by exclusivity (orphan, § 314.108, pediatric or section 505E) or, for 505(b)(2) applications, by patent conditions. The product "is not an approved drug" [3]
Complete response letter (§ 314.110)	Describes all the specific deficiencies and reflects a full review of the data. If the data are inadequate, it can be issued before inspections or labeling review. Where possible, it recommends fixes [14]

6. After a complete response letter

• The applicant "must" take one of three actions ^[14]:
  • Resubmit, addressing every deficiency. A Class 1 resubmission starts a new 2-month review cycle; a Class 2 resubmission starts a new 6-month cycle.
  • Withdraw, without prejudice to submitting again later.
  • Request an opportunity for a hearing. Within 60 days of the request, the FDA either approves or refuses and issues a notice of opportunity for hearing under § 314.200.
• If the applicant does nothing within 1 year, the FDA may treat that as a request to withdraw, unless the applicant has asked for more time. After the FDA's written notice, the applicant has 30 days to respond, or the NDA "will be deemed to be withdrawn" ^[14].
• Hearing: the notice is published in the Federal Register. The applicant has 30 days to file a notice of participation and 60 days to submit the studies it relies on. Where effectiveness is in dispute, only studies meeting § 314.126 (or covered by a waiver) may be submitted, with a point-by-point analysis against each criterion ^[15].

The product "may not be marketed until the date of approval" ^[3].