FDA approval process: IND, NDA and BLA, priority review, CRLs and accelerated approval
A new drug needs an IND to start human trials and an approved NDA or BLA to be sold. Learn each FDA step, review timelines, expedited programs and what a CRL means.
Key takeaways
- A drug sponsor must file an Investigational New Drug (IND) application before human testing, and can begin trials 30 days after FDA receives it unless the FDA places a clinical hold.
- Marketing approval requires a New Drug Application (NDA) for most small-molecule drugs or a Biologics License Application (BLA) for biologics such as antibodies, vaccines and gene therapies.
- For new molecular entities and original BLAs, FDA's goal is to act within 10 months of the 60-day filing date for standard review and 6 months for priority review, roughly 12 and 8 months from submission.
- The FDA ends a review cycle with either an approval or a complete response letter (CRL), which lists the deficiencies that must be fixed before approval.
- Expedited programs include fast track, breakthrough therapy, priority review and accelerated approval, which allows approval based on a surrogate endpoint but requires confirmatory trials.
The FDA approval process for a new drug runs from preclinical testing, through an Investigational New Drug (IND) application that permits human trials, through three phases of clinical studies, to a marketing application (an NDA or BLA) that the FDA reviews and either approves or rejects with a complete response letter. For most new drugs the whole path takes many years, and the final review alone is targeted at about 12 months from submission under standard review or 8 months under priority review. Each step generates disclosures that can move a biotech stock sharply.
The FDA approval pathway step by step
| Stage | What happens | Typical timing | Common public disclosure |
|---|---|---|---|
| Preclinical | Lab and animal studies of safety and pharmacology | Years | Scientific presentations |
| IND submission | Sponsor asks to begin human testing | FDA has 30 days to object | "IND cleared" press release |
| Phase 1 | Safety and dosing in a small group | Months to a couple of years | First patient dosed, safety data |
| Phase 2 | Efficacy signals and dose selection | Often 1 to 3 years | Topline data, end-of-phase 2 meeting |
| Phase 3 | Large confirmatory trials | Often 1 to 4 years | Topline pivotal data |
| NDA or BLA submission | Full data package filed | Often several months after Phase 3 data | "Submitted" press release |
| Filing decision | FDA decides whether the application is complete enough to review | Within 60 days | "Accepted for review" with PDUFA date |
| Review | Clinical, statistical, manufacturing and labeling review; possible advisory committee | 10 or 6 months after filing for NMEs | AdComm vote, review extension |
| Action | Approval letter or complete response letter | On or before the PDUFA goal date | Approval or CRL press release |
| Post-marketing | Safety monitoring, Phase 4 studies, label changes | Ongoing | Label updates, safety communications |
The clinical phases are covered in more depth in the clinical trial phases guide, and the review deadline in PDUFA dates explained.
What is an IND?
An Investigational New Drug application is the request a sponsor files with the FDA before testing an unapproved drug in humans. It includes preclinical data, manufacturing information and the clinical protocol. Under FDA regulations (21 CFR Part 312), a trial may begin 30 days after the FDA receives the IND unless the agency imposes a clinical hold, an order that delays or suspends the study. Clinical holds can also be imposed later, for example after a serious adverse event. A clinical hold announcement is often a significant negative catalyst, and its lifting is a common positive one.
NDA vs BLA vs ANDA
| Application | Used for | Legal basis | Example products |
|---|---|---|---|
| NDA (New Drug Application) | New small-molecule drugs and some peptides | Federal Food, Drug, and Cosmetic Act section 505(b) | Tablets, capsules, injectables made by chemical synthesis |
| 505(b)(2) NDA | New version of an approved drug relying partly on existing data | Section 505(b)(2) | New formulation, new dose form, new combination |
| BLA (Biologics License Application) | Biologics | Public Health Service Act section 351 | Monoclonal antibodies, vaccines, cell and gene therapies |
| ANDA (Abbreviated NDA) | Generic copies of approved drugs | Section 505(j) | Generic small-molecule drugs |
| 351(k) BLA | Biosimilars | PHS Act section 351(k) | Biosimilar antibodies |
Most small-molecule NDAs are reviewed by FDA's Center for Drug Evaluation and Research (CDER), while vaccines, blood products and cell and gene therapies are reviewed by the Center for Biologics Evaluation and Research (CBER). Many therapeutic biologics, including most antibodies, are reviewed by CDER.
A "new molecular entity" (NME) is a drug containing an active ingredient never before approved by the FDA. NMEs and original BLAs are reviewed under the PDUFA "Program," which adds a 60-day filing period before the review clock starts.
How long does FDA review take?
Under the Prescription Drug User Fee Act (PDUFA) performance goals, the FDA commits to act on 90% of applications within these windows:
| Application type | Standard review | Priority review |
|---|---|---|
| NME NDA or original BLA | 10 months after the 60-day filing date (about 12 months from submission) | 6 months after the 60-day filing date (about 8 months from submission) |
| Non-NME original NDA | 10 months from receipt | 6 months from receipt |
| Class 1 resubmission after a CRL | 2 months from receipt | 2 months from receipt |
| Class 2 resubmission after a CRL | 6 months from receipt | 6 months from receipt |
A major amendment submitted during review (for example substantial new data) can extend the goal date by three months, and only one such extension is allowed per review cycle. The FDA's published goals are in the PDUFA performance goals letter.
Within 60 days of receipt, the FDA either files the application or issues a refuse-to-file (RTF) letter if it is too incomplete to review. Around day 74 the FDA usually communicates review issues it has identified so far. Late in the cycle the sponsor and FDA hold a late-cycle meeting and negotiate the label.
Priority review vs standard review
Priority review is a designation for drugs that, if approved, would offer a significant improvement in the safety or effectiveness of treating, diagnosing or preventing a serious condition. It shortens the review goal from 10 months to 6 months. It does not lower the evidence standard.
A sponsor can also use a priority review voucher, earned for example by getting approval of a drug for a rare pediatric disease or a tropical disease, to obtain priority review for a different application. Vouchers can be sold, and voucher sales are disclosed as material events by small biotechs.
Expedited programs
| Program | Who qualifies | Main benefit | Stage it applies to |
|---|---|---|---|
| Fast track | Drugs for serious conditions addressing an unmet medical need | More frequent FDA meetings; rolling submission of the application | Development and review |
| Breakthrough therapy | Drugs for serious conditions with preliminary clinical evidence of substantial improvement over available therapy | All fast track features plus intensive FDA guidance and senior management involvement | Development and review |
| Priority review | Drugs offering significant improvement for a serious condition | 6-month review goal instead of 10 | Review |
| Accelerated approval | Drugs for serious conditions with unmet need | Approval based on a surrogate or intermediate endpoint | Approval |
The FDA's overview is at fda.gov: fast track, breakthrough therapy, accelerated approval, priority review. A drug can carry several designations at once. Orphan drug designation is separate: it covers drugs for diseases affecting fewer than 200,000 people in the US and brings incentives such as seven years of market exclusivity after approval.
What is accelerated approval?
Accelerated approval lets the FDA approve a drug for a serious condition based on a surrogate endpoint, such as tumor shrinkage or a lab biomarker, that is reasonably likely to predict a real clinical benefit, rather than waiting for outcomes such as survival. The sponsor must conduct confirmatory trials. Since the Food and Drug Omnibus Reform Act of 2022, the FDA can require confirmatory trials to be underway before approval and has a faster procedure for withdrawing the approval if confirmatory trials fail or are not done with due diligence. Withdrawals of accelerated approvals are notable negative events for the companies involved.
What is a complete response letter (CRL)?
A complete response letter is the FDA's notice that it cannot approve the application in its current form. It lists the deficiencies, which may involve clinical data (efficacy not demonstrated, safety concerns), manufacturing (facility inspection findings, chemistry, manufacturing and controls issues), or both, and often recommends what is needed to resolve them.
What happens next:
- The sponsor can resubmit, withdraw, or request a hearing.
- A Class 1 resubmission addresses minor items such as labeling and gets a 2-month review goal.
- A Class 2 resubmission addresses anything more substantial, such as new clinical data or a reinspection, and gets a 6-month review goal.
The company's press release is its own summary of the CRL. The FDA has begun publishing complete response letters, which lets investors compare the company's description with the agency's text.
Advisory committees
The FDA may convene an advisory committee (AdComm) of outside experts to discuss an application and vote on questions such as whether benefits outweigh risks. The vote is not binding, but it is a widely watched signal. AdComm meetings are announced in the Federal Register and briefing documents are typically posted about two business days before the meeting, which can itself move the stock.
Worked example: Acme Bio (ticker ACMB)
Hypothetical Acme Bio develops a new antibody for a rare autoimmune disease.
| Date | Event | Disclosure |
|---|---|---|
| Month 0 | IND submitted | Press release when clearance arrives after the 30-day window |
| Months 1 to 30 | Phase 1 and Phase 2 trials; breakthrough therapy designation granted | Data releases, designation press release |
| Months 30 to 54 | Phase 3 trial meets primary endpoint | Topline data press release, 8-K |
| Month 60 | BLA submitted | Press release |
| Month 62 | FDA accepts the BLA with priority review; PDUFA date set 8 months after submission | Press release with PDUFA date |
| Month 66 | FDA requests more manufacturing data; Acme submits a major amendment; goal date extends 3 months | 8-K or press release |
| Month 71 | FDA issues a CRL citing manufacturing inspection findings | Press release, often premarket |
| Month 74 | Acme files a Class 2 resubmission | Press release with new goal date about 6 months out |
| Month 80 | FDA approves the BLA | Approval press release |
At each step the market updates the probability of approval and the expected launch timing.
How to track FDA news on Quantisnow
- The FDA news feed streams approvals, CRLs, designations and clinical holds as companies announce them.
- Top FDA approvals lists the most recent approval news.
- Follow biotech tickers through following tickers and set alerts so PDUFA outcomes reach you as they cross the wire.
- 8-K filings capture the formal SEC disclosure that usually accompanies material FDA events.
FAQ
How long does FDA approval take?
From the start of human trials, development commonly takes many years. The final review of a new molecular entity is targeted at about 12 months from submission under standard review or about 8 months under priority review.
What is the difference between an NDA and a BLA?
An NDA is used for most chemically synthesized drugs and is governed by the Food, Drug, and Cosmetic Act. A BLA is used for biologics such as antibodies, vaccines and gene therapies and is governed by the Public Health Service Act.
What does a complete response letter mean?
A CRL means the FDA has finished its review but cannot approve the application as submitted. It lists deficiencies the sponsor must resolve; the sponsor can then resubmit, which starts a new 2-month or 6-month review cycle.
Does priority review mean a drug is more likely to be approved?
No. Priority review shortens the review goal from 10 months to 6 months for drugs that could offer a significant improvement for a serious condition. The evidence standard for approval is the same.
What is a clinical hold?
A clinical hold is an FDA order that delays a proposed trial or suspends an ongoing one, usually over safety concerns or deficiencies in the protocol. The sponsor must address the issues before the FDA lifts the hold.