BLA/NDA Templates
BIOPHARMAWIRE | RESOURCE LIBRARY
BLA / NDA Templates & Submission Formats
Editable formats, structure templates, and content guidance for FDA regulatory submissions — New Drug Applications and Biologics License Applications
Updated Q4 2025 | BioPharmaWire Editors | Based on ICH CTD guidelines, 21 CFR Parts 314 and 601, and FDA guidance documents
A New Drug Application (NDA) is the vehicle through which a drug sponsor formally requests FDA approval to market a new pharmaceutical product in the United States. A Biologics License Application (BLA) serves the same purpose for biological products — proteins, antibodies, vaccines, cell and gene therapies. Both follow the ICH Common Technical Document (CTD) format, a globally harmonised five-module structure accepted by FDA, EMA, Health Canada, PMDA (Japan), and other major regulators. This guide provides structure templates, content guidance, and annotated formats for the key documents within each module.
NDA vs BLA: Choosing the Right Application Type
New Drug Application (NDA) — 21 CFR Part 314
Filed for small molecule drugs (chemical entities synthesised or extracted from non-biological sources). The NDA pathway covers the majority of traditional pharmaceutical products: oral tablets, capsules, injectable solutions, topical formulations, and similar dosage forms. The evidentiary standard is substantial evidence of safety and effectiveness, typically from two adequate and well-controlled clinical investigations.
Biologics License Application (BLA) — 21 CFR Part 601
Filed for biological products: proteins (including monoclonal antibodies), vaccines, blood products, allergenics, tissues, and cell and gene therapies. BLAs face a higher CMC bar than NDAs — the complexity of biological manufacturing processes means that Module 3 for a BLA is substantially more detailed than for a standard NDA. Cell line development, characterisation of host cell proteins, viral clearance validation, and comparability studies for any manufacturing changes are standard BLA Module 3 components with no NDA equivalent.
The 505(b)(2) Pathway
A third option for new formulations, new routes of administration, new combinations, or new indications of previously approved drugs. The 505(b)(2) NDA relies in part on published literature or FDA’s prior findings of safety and efficacy for a previously approved drug. It requires less original data than a full NDA but must still include a full Module 1 cover package, any new clinical studies conducted by the sponsor, and bridging studies linking the new product to the approved reference. Patent certification (Paragraph IV if applicable) is required.
CTD Module Structure: What Goes Where
Note: The ICH CTD structure is the same for NDA and BLA submissions. The content differs — particularly in Modules 3 and 4 — based on the nature of the product. The table below maps each module and sub-module to its required status and key contents for both application types.
Module | Title | NDA (Small Molecule) | BLA (Biologic) | Key Contents |
ICH COMMON TECHNICAL DOCUMENT (CTD) STRUCTURE — MODULES 1-5 | ||||
1 | Regional Administrative Information | Required | Required | Cover letter, Form FDA 356h, prescribing information (PI), patent info (Form 3542), debarment certification, financial disclosure |
2.1 | Table of Contents (CTD) | Required | Required | Hierarchical TOC covering all CTD sections with hyperlinks in eCTD |
2.2 | Introduction to the Summary Documents | Required | Required | Brief narrative orienting reviewers to the development program and submission strategy |
2.3 | Quality Overall Summary (QOS) | Required | Required | Narrative summary of Module 3 CMC data. Tells the manufacturing story. Reviewed before Module 3. |
2.4 | Nonclinical Overview | Required | Required | Integrated nonclinical narrative: pharmacology, PK, toxicology. Must interpret data, not just summarise. |
2.5 | Clinical Overview | Required | Required | Critical analysis of clinical program. Benefit-risk assessment. Reviewers read this first — it sets the tone for the entire application. |
2.6 | Nonclinical Written & Tabulated Summaries | Required | Required | Pharmacology, PK, and toxicology summaries in written and tabular format. GLP compliance statements required. |
2.7 | Clinical Summary | Required | Required | Biopharmaceutics, clinical pharmacology, clinical efficacy, and clinical safety summaries. ISS and ISE integrated here. |
3 | Quality / CMC | Required | Required | Drug substance and drug product: development, manufacturing, controls, reference standards, stability. For BLAs: extensive cell line and process characterisation. |
4 | Nonclinical Study Reports | Required | Required | Full study reports: pharmacology, PK/ADME, toxicology. Study reports in ICH S-series format. Literature references appended. |
5 | Clinical Study Reports | Required | Required | All clinical study reports in ICH E3 format. Integrated summaries of safety (ISS) and efficacy (ISE). Literature references. |
Module 1: Administrative — Template Formats
Module 1 is the only module that is not harmonised across regions — its content is jurisdiction-specific. For US NDA/BLA submissions, Module 1 must include the following in the order shown.
1.1 — Cover Letter Template
Cover Letter Template — NDA/BLA Submission |
[DATE]
Division of [DIVISION NAME] Office of [OFFICE NAME] Center for Drug Evaluation and Research [or CBER] Food and Drug Administration Silver Spring, MD 20993
RE: [NDA/BLA] Number: [NUMBER IF RESUBMISSION] | [DRUG NAME] ([INN]) | [DOSAGE FORM/ROUTE] | [PROPOSED INDICATION] | [SUBMISSION TYPE: Original / Resubmission / Amendment]
Dear [Division Director Name]:
[SPONSOR LEGAL NAME] (‘the Sponsor’) is submitting this [NDA/BLA] for [drug name], a [brief drug description, e.g. ‘selective KRAS G12C inhibitor’], for the proposed indication of [indication text as it will appear on the label].
This submission includes Modules 1 through 5 of the Common Technical Document (CTD), submitted electronically in eCTD format (Sequence [XXXX]).
[If applicable: This application is submitted under [505(b)(1) / 505(b)(2) / 351(a) / 351(k)] of the Federal Food, Drug, and Cosmetic Act.]
[If applicable: This application is accompanied by a request for [Priority Review / Accelerated Approval / use of surrogate endpoint / other designation].]
The proposed label (Prescribing Information) is included as a separate document in Section 1.14 of this submission.
Questions regarding this submission may be directed to:
[REGULATORY AFFAIRS CONTACT NAME] [TITLE] [COMPANY NAME] [ADDRESS] [PHONE] | [EMAIL]
Respectfully submitted,
[AUTHORISED SIGNATORY NAME] [TITLE], [COMPANY NAME] |
1.2 — Form FDA 356h (Application to Market a New Drug)
Form FDA 356h is the official cover form for NDA submissions. For BLAs, the equivalent is Form FDA 356h (same form, different pathway designation). The form must be completed fully — partial completion is a leading cause of refuse-to-file (RTF) actions. Key fields that are frequently completed incorrectly:
Tip: Field 6 (Proposed Indication): copy the exact indication language from the draft Prescribing Information. Discrepancies between the 356h and the PI are flagged at the RTF review stage.
Tip: Field 11 (Application Type): for 505(b)(2) submissions, clearly indicate the basis of reliance (published literature, FDA’s findings for a listed drug, or both). Incorrect application type selection creates problems at RTF.
Tip: Field 14 (Enclosed Items): check every box that applies and only the boxes that apply. FDA reviewers check this field against the actual submission contents.
Watch out: The 356h must be signed by the applicant (or authorised representative) in ink or via a compliant electronic signature. Unsigned forms are an automatic RTF.
1.14 — Proposed Prescribing Information (PI) Template Structure
The Physician Labelling Rule (PLR) format applies to all NDA/BLA submissions. The PI must follow the exact section order specified in 21 CFR 201.56 and 201.57. Use the annotated format below as a structural template.
Prescribing Information (PI) — PLR Format Template |
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use [DRUG NAME] safely and effectively. See full prescribing information for [DRUG NAME].
[DRUG NAME] ([INN]) [DOSAGE FORM] for [ROUTE OF ADMINISTRATION] Initial U.S. Approval: [YEAR — leave blank for new approvals]
———- INDICATIONS AND USAGE ———- [DRUG NAME] is a [mechanism class] indicated for [indication]. [Limitation of use statement if applicable]
———- DOSAGE AND ADMINISTRATION ———- [Recommended dose, schedule, and duration] [Dose modification table for toxicity/renal/hepatic impairment]
———- DOSAGE FORMS AND STRENGTHS ———- [Description: e.g. Tablets: 100 mg, 200 mg]
———- CONTRAINDICATIONS ———- [List or ‘None’]
———- WARNINGS AND PRECAUTIONS ———- [Boxed Warning if applicable (most serious risks)] [Other W&P in order of clinical significance]
———- ADVERSE REACTIONS ———- Most common adverse reactions (>=X%): [list] To report SUSPECTED ADVERSE REACTIONS, contact [COMPANY] at [PHONE] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
———- DRUG INTERACTIONS ———- [Strong CYP inhibitors/inducers; clinically significant interactions]
———- USE IN SPECIFIC POPULATIONS ———- Pregnancy: [Category / updated labelling language post-PLLR] Lactation, Females/Males of Reproductive Potential, Paediatric Use, Geriatric Use, Renal/Hepatic Impairment as applicable
FULL PRESCRIBING INFORMATION: CONTENTS* [Complete section list mirroring Highlights]
FULL PRESCRIBING INFORMATION [Complete text for each section listed above]
PATIENT COUNSELLING INFORMATION [Key points for patient discussion]
Revised: [MM/YYYY] |
Module 2.5: Clinical Overview — Template Structure
The Clinical Overview is one of the most strategically important documents in the submission. FDA reviewers read it before the clinical study reports in Module 5. It must provide a critical analysis of the clinical data — not a narrative summary — and must explicitly address the benefit-risk assessment. Use the structure below as a template.
Clinical Overview (Module 2.5) — Annotated Template Structure |
2.5.1 Product Development Rationale – Disease background and unmet medical need – Mechanism of action and pharmacological rationale – Summary of nonclinical findings relevant to clinical development – Overview of the clinical development program
2.5.2 Overview of Biopharmaceutics – Formulation development history – Key biopharmaceutics studies (BA, BE, food effect, DDI) – Justification for proposed commercial formulation
2.5.3 Overview of Clinical Pharmacology – PK characteristics: absorption, distribution, metabolism, excretion – PD characteristics and dose-exposure-response relationships – Special populations: renal/hepatic impairment, age, weight, ethnicity – Drug-drug interaction profile
2.5.4 Overview of Efficacy – Study designs and patient populations across efficacy trials – Primary endpoint results (tabulated and interpreted) – Secondary and supportive endpoint results – Subgroup analyses (pre-specified and exploratory) – Comparison to available therapies / contextualisation NOTE: Do not merely report results — provide a critical assessment of the totality of evidence and its limitations.
2.5.5 Overview of Safety – Exposure: cumulative patient-years, duration distribution, doses – Deaths, serious adverse events, adverse events leading to discontinuation – Common adverse events (tabulated by system organ class and PT) – Adverse events of special interest (AESIs) – Laboratory findings, vital signs, ECG findings – Immunogenicity (BLAs and large molecule NDAs) – Special populations safety – Safety in relation to available therapies
2.5.6 Benefits and Risks Conclusions – Summary of demonstrated benefits (magnitude, durability, breadth) – Summary of identified risks (severity, frequency, manageability) – Proposed risk management strategy – Overall benefit-risk conclusion NOTE: This section must provide a clear benefit-risk determination. Reviewers use this section to understand whether the sponsor believes the benefit-risk is positive and why.
2.5.7 Literature References – Full citations for all external references used in Section 2.5 |
Module 2.7.4: Clinical Safety Summary — Template Structure
The Integrated Summary of Safety (ISS) is one of the two most scrutinised documents in Module 2.7. It must integrate safety data across all clinical studies in a way that allows FDA to assess the overall safety profile of the drug. The ISS is the primary source for the safety sections of the Prescribing Information.
ISS / Module 2.7.4 — Annotated Template Structure |
2.7.4.1 Exposure to the Drug – Safety population definition – Total exposure: patient numbers, patient-years, dose distribution – Duration of exposure distribution (frequency table) – Demographic characteristics of safety population
2.7.4.2 Adverse Events – Definition of TEAE (treatment-emergent adverse event) – Overall AE summary table (any AE, SAE, AE leading to DC, deaths) – Common AEs: table by PT and SOC, all grades and Grade >=3 – AEs of special interest (mechanistically expected or labelled risks) – Serious adverse events: narratives for fatal and selected non-fatal SAEs – AEs leading to dose modification (reduction, delay, discontinuation)
2.7.4.3 Deaths – All deaths on-study and within protocol-specified follow-up – Individual narratives for all on-treatment deaths – Assessment of relationship to study drug
2.7.4.4 Other Significant Adverse Events – Significant AEs not meeting SAE criteria but clinically important – Events requiring medical intervention or hospitalisation
2.7.4.5 Clinical Laboratory Evaluations – Haematology, chemistry, urinalysis: shift tables and markedly abnormal values – Liver function: DILI assessment using Hy’s Law criteria – Renal function trends
2.7.4.6 Vital Signs, Physical Findings, ECG – QTc analysis (if applicable; E14 study or thorough QT data) – Blood pressure, heart rate, weight changes
2.7.4.7 Safety in Special Populations – Elderly, renal/hepatic impairment, paediatric (if applicable) – Intrinsic and extrinsic factor analyses
2.7.4.8 Safety in Relation to Exposures (PK/PD Relationships) – Exposure-safety analyses for key adverse events – Dose-response for safety endpoints
2.7.4.9 Immunogenicity (BLAs and relevant NDAs) – Anti-drug antibody (ADA) incidence, titre, persistence – Impact of immunogenicity on PK, efficacy, and safety
2.7.4.10 Safety Update (if post-original submission data available) – New safety data accrued since original data cut-off
2.7.4.11 Conclusions – Overall safety assessment – Proposed labelled risks and risk management approach |
eCTD Submission: Technical Requirements
File Naming and Folder Structure
FDA requires eCTD submissions to follow the ICH M8 eCTD specification and FDA’s eCTD Technical Conformance Guide. Key requirements:
Tip: All filenames must be lowercase, use hyphens not underscores, and contain no special characters. Maximum filename length is 64 characters including extension.
Tip: PDF files must be PDF/A compliant (archival format), bookmarked at the section level, and searchable (no scanned images without OCR). Font embedding must be complete.
Tip: The eCTD sequence for an original NDA/BLA is 0000. Amendments are numbered sequentially (0001, 0002, etc.). Each sequence must include an updated XML backbone.
Watch out: Test the eCTD package with FDA’s eSubmitter validation tool before submission. Common technical errors that cause rejection: broken hyperlinks, non-bookmarked PDFs, incorrect module folder naming, and missing or malformed XML lifecycle files.
Watch out: Large submissions (>10 GB) must be submitted on physical media (encrypted USB or DVD) to FDA’s Central Document Room, not via the ESG portal. Confirm size limits with FDA before submission day.
Section 508 Accessibility
FDA requires that all documents in NDA and BLA submissions comply with Section 508 accessibility standards. This means PDFs must be tagged, have meaningful document titles, include alt-text for all images and tables, and have correct reading order. Non-compliant documents will be returned. Build 508 compliance into the document production workflow from the start — retrofitting at the end of the process is significantly more time-consuming.
Common Refuse-to-File (RTF) Reasons
Watch out: Missing or incomplete clinical study reports. FDA will RTF an NDA or BLA that does not include full clinical study reports for all pivotal trials. Summary tables are not a substitute for full CSRs.
Watch out: Prescribing Information not in PLR format. Non-PLR formatted PI is a leading RTF trigger. Ensure the PI follows 21 CFR 201.56-57 section order exactly, including the Highlights section.
Watch out: Patent certification missing or incorrect. For NDA submissions under 505(b)(1) or 505(b)(2), patent certifications (Form 3542 and the relevant paragraph certification letter) must be complete at submission.
Watch out: CMC data package insufficient for proposed manufacturing sites. Each manufacturing site in the submission must be identified, and facilities used for commercial manufacture must be GMP-compliant. Unregistered sites are a common RTF trigger for BLAs.
Tip: Submit a pre-NDA/BLA meeting request 6-12 months before planned submission to align with FDA on dossier completeness. FDA will indicate any anticipated RTF issues at the Type B pre-NDA/BLA meeting, giving the sponsor time to address them before filing.
Tip: Use FDA’s ‘Rolling Review Readiness Assessment’ for Fast Track and BTD products. FDA will review submitted modules and flag any potential RTF issues before the complete submission, reducing the risk of an RTF at the final filing stage.
This guide and the templates contained herein are editorial products of BioPharmaWire intended as general reference formats based on ICH CTD guidelines, 21 CFR Parts 314 and 601, and publicly available FDA guidance as of Q4 2025. They are not legal or regulatory advice and do not substitute for sponsor-specific regulatory strategy developed with qualified professionals. Requirements are subject to change — always verify against current FDA guidance before submission.