The New Drug Application and Its Review Cycle
The application is the point at which a development program becomes a legal claim: that adequate and well-controlled investigations show the drug does what its proposed labeling says. A review cycle ends in one of two letters.
The rule in short
Section 355 of Title 21 bars introducing a new drug into interstate commerce without an effective approval. The application must contain full reports of investigations showing safety and effectiveness, the composition and manufacturing methods, samples and proposed labeling. Approval requires substantial evidence from adequate and well-controlled investigations. Under 21 CFR Part 314 a review cycle ends in an approval letter or a complete response letter.
A new drug may not be introduced into interstate commerce without an effective approval. The application is how a sponsor obtains one. It is not a summary of the development program; it is the program itself, submitted with the data, the analyses, the manufacturing description and the labeling the sponsor proposes to use.
What the statute requires of the filing
Section 355(b) lists the contents. Full reports of investigations showing whether the drug is safe for use and whether it is effective in use. A full list of the articles used as components and a full statement of the composition. A full description of the methods used in, and the facilities and controls used for, the manufacture, processing and packing of the drug. Samples, specimens of the proposed labeling, and patent information about any patent claiming the drug or a method of using it.
The regulations expand each of those headings into technical sections that are reviewed by different disciplines and that must stand on their own. Chemistry, manufacturing and controls. Nonclinical pharmacology and toxicology. Human pharmacokinetics and bioavailability. Microbiology, where the product is an anti-infective. Clinical data, and a separate statistical section analyzing it. Case report tabulations and, for defined categories of subjects, the underlying forms accompany the analyses so that the agency can examine the data behind a conclusion rather than only the conclusion.
The statute then states the grounds for refusing approval, and each ground is worth reading as a checklist. Investigations that do not include adequate tests to show safety. Results that show the drug is unsafe or that fail to show it is safe. Manufacturing methods, facilities and controls inadequate to preserve identity, strength, quality and purity. Insufficient information to determine safety. Labeling that is false or misleading. And the absence of substantial evidence that the drug will have the effect it purports or is represented to have.
The substantial evidence standard
Substantial evidence is defined in the statute as evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate effectiveness, on the basis of which those experts could fairly and responsibly conclude that the drug will have the claimed effect.
How many such investigations are needed is a question the statute answers only by using a plural. The agency has long accepted that a single adequate and well-controlled study with confirmatory evidence can suffice in defined circumstances, and the quantum of evidence in practice depends on the seriousness of the condition, the availability of alternatives and the persuasiveness of the result. Sponsors planning a single-trial program should treat that as a matter to be agreed in advance rather than argued at the end.
Section 314.126 fills in what adequate and well-controlled means. There must be a clear statement of objectives and a design permitting a valid comparison with a control. The method of subject selection must assure suitable subjects, the method of assigning subjects must minimize bias, adequate measures must be taken to minimize bias on the part of subjects, observers and analysts, the responses assessed must be well defined and reliable, and the analysis must be adequate to assess the drug's effects. Uncontrolled studies and partially controlled studies are not accepted as the sole basis for approval, though they may support other data.
Sponsors concentrate on efficacy because that is where the science is contested. The refusal grounds are indifferent to that emphasis. An application supported by unimpeachable trials will not be approved where the chemistry section is thin, where the proposed specifications are not justified, or where a preapproval inspection of the manufacturing site produces significant findings. Facility readiness runs on its own schedule and needs to be complete when the review ends, not when the sponsor next looks at it.
The filing decision and the review cycle
Not every submitted application is reviewed. The agency may refuse to file one that is incomplete on its face, and a refusal to file is a determination that the submission does not contain enough to support a review at all. Where the application is filed, review proceeds across the technical disciplines: chemistry and manufacturing, pharmacology and toxicology, clinical pharmacology, clinical, statistical and, where applicable, microbiology.
The regulation states a review period and provides that a major amendment can extend it. Sponsors also work to user fee performance goals, which set the dates the agency aims to meet and which differ for standard and priority review. Those goals are commitments about timing rather than legal deadlines, and the distinction matters when a sponsor is deciding whether to submit data late in a cycle. Inspections of manufacturing sites and of clinical investigator sites are scheduled during the cycle, and their findings feed the action.
| Action | What it means | What the applicant does next | Effect on marketing |
|---|---|---|---|
| Refuse to file | The submission is too incomplete to review | Complete the application and resubmit, or request review of the refusal | None; no review has occurred |
| Filed | The application is under substantive review | Respond to information requests and inspection findings | None until an action issues |
| Complete response letter | The application cannot be approved in its present form | Resubmit addressing the deficiencies, withdraw, or ask for a hearing | Marketing remains prohibited |
| Approval letter | The application is approved with the accompanying labeling | Meet any postmarketing requirements and commitments | Lawful marketing may begin |
| Supplement | A change to an approved application | File for prior approval or under a changes-being-effected route | Depends on the supplement category |
After the cycle, and after approval
A complete response letter describes the deficiencies and, where the agency can identify them, recommends actions the applicant might take to place the application in condition for approval. The applicant then resubmits, withdraws, or requests an opportunity for a hearing on whether there are grounds for denying approval. A resubmission starts a new review period whose length depends on the extent of what has been submitted.
Approval is the beginning of a different regime rather than the end of the process. The approved labeling becomes the boundary of what may be claimed, a subject treated in required labeling content and how it is changed and, from the promotional side, in what may be said outside the approved labeling. The manufacturing description becomes an enforceable commitment policed through the inspections described in quality systems and inspections. And the approved product becomes the reference standard against which later applicants seek approval by the route explained in abbreviated applications and the patent certifications.
Points to carry away
- Approval requires substantial evidence from adequate and well-controlled investigations.
- Inadequate manufacturing methods, facilities or controls are an independent ground for refusal.
- The agency may refuse to file an application that is incomplete on its face.
- A review cycle ends in an approval letter or a complete response letter.
- A complete response letter describes deficiencies and, where possible, recommends actions.
- Postapproval changes to the product or its labeling are made through supplements.
Questions readers ask
Does the agency have to convene an advisory committee?
No. Advisory committees are convened at the agency's discretion, typically where a product raises a novel scientific question, a difficult risk-benefit judgment, or a matter of public significance. The committee votes and gives advice; the agency is not bound by it and has departed from committee recommendations in both directions. For a sponsor, a committee meeting is a public examination of the weakest part of the application, held on a record that competitors and plaintiffs will read. It also adds time, which is why the possibility is worth planning for rather than reacting to.
What is a major amendment and why does it matter?
It is a submission during review that contains substantial new information requiring significant additional review, such as a new clinical study, major reanalysis of submitted data, or substantial manufacturing changes. Its consequence is on the clock: a major amendment can extend the review period, because the agency is entitled to time to evaluate what has just arrived. Sponsors sometimes submit late data hoping to strengthen a marginal application and instead reset their own schedule. Whether a submission counts as major is the agency's determination, not the sponsor's.
Can a product be marketed while a complete response is being answered?
No. A complete response letter means the application is not approved, and without an effective approval the drug may not be introduced into interstate commerce. The only lawful distribution during that period is under an investigational application or an authorized expanded access arrangement, both of which carry their own conditions and neither of which permits commercial promotion. Sponsors that have built launch inventory carry it as a cost. Nothing about the pendency of a resubmission changes the marketing prohibition.
Sources
- Cornell Legal Information Institute — 21 U.S.C. 355, New DrugsThe approval requirement, the contents of an application and the grounds for refusal.
- eCFR — 21 CFR 314.50, Content and Format of an NDAThe technical sections, labeling, case report material and patent information.
- eCFR — 21 CFR 314.100, Timeframes for Reviewing Applications and SupplementsThe review period and the effect of a major amendment on it.
- eCFR — 21 CFR 314.105, Approval of an ApplicationWhat an approval letter does and the marketing status it confers.
- eCFR — 21 CFR 314.110, Complete Response Letter to the ApplicantThe deficiency letter and the applicant's options to resubmit, withdraw or request a hearing.
- eCFR — 21 CFR 314.126, Adequate and Well-Controlled StudiesThe characteristics a study must have to count toward substantial evidence.
- eCFR — 21 CFR 314.70, Supplements and Other Changes to an Approved NDAThe categories of postapproval change and which require prior approval.
Liberty Law Library is a publication, not a law firm. This article states general rules and cites its sources; it is not advice about any particular case, and the law differs by state and changes over time.
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