ANDA and NDA submission

Abbreviated New Drug Application (ANDA) –

An ANDA is submitted to the FDA’s Center for Drug Evaluation and Research (CDER), Office of Generic Drugs, for approval of a generic drug. Once approved, it allows marketing of a safe, effective, and low-cost alternative to a brand-name drug.

Key Characteristics

·                  Generic must match the reference listed drug (RLD) in:

o        Dosage form

o        Strength

o        Route of administration

o        Quality and performance

o        Intended use

·                  ANDA is “abbreviated” because animal and human clinical trials are not required.

·                  Applicant must demonstrate bioequivalence (BE).

·                  FDA reviews bioequivalence, chemistry/microbiology (CMC), labeling, and facility inspections.

2. ANDA Certification Clauses (Paragraph Certifications I–IV)Every ANDA must include one of the following patent certifications:

📌 Para I – No Patent Filed

·                  Required patent information for the RLD has not been submitted.

·                  FDA may approve generics immediately.

·                  Multiple applicants may enter at the same time.

📌 Para II – Patent Expired

·                  The listed patent has already expired.

·                  FDA may approve generics immediately.

📌 Para III – Patent Not Expired (Future Expiry Date)

·                  Patent valid and will expire on a specific date.

·                  FDA may approve the ANDA, but approval becomes effective only on patent expiry.

📌 Para IV – Patent Invalid or Not Infringed

·                  Generic applicant claims:

o        The patent is invalid, or

o        The generic product will not infringe the patent.

·                  Applicant must notify the patent holder (“Notice Letter”).

·                  Filing a Para IV can trigger a 30-month stay.

3. Para IV Certification & 30-Month Stay

When Para IV is filed:

1.                The generic applicant notifies the patent holder.

2.                The patent holder has 45 days to sue.

Case 1: Patent Holder Does NOT Sue Within 45 Days

·                  No 30-month stay.

·                  FDA may approve the ANDA immediately (if all other requirements are met).

Case 2: Patent Holder Sues Within 45 Days → 30-Month Stay Begins

During the 30-month stay:

If Court Decision Favors Patent Holder

·                  FDA cannot approve the ANDA until patent expiry.

·                  No generic entry before patent expiration.

If Court Decision Favors ANDA Applicant

·                  180-day exclusivity begins for the first applicant.

·                  FDA cannot approve later applicants until:

o        First applicant markets the drug ANDA

o        Its 180 days exclusivity expires.

If 30-month stay expires with no court decision

·                  FDA may approve the ANDA.

Summary of Entry Conditions

·                  First applicant enters first with 180-day exclusivity.

·                  Subsequent applicants may enter only after exclusivity expires.

4. ANDA Submission Requirements

1. FDA Form 356H

Includes:

·                  Applicant’s name and address

·                  Drug name, strength, dosage form, indication

·                  OTC/Rx status

2. Index

·                  Volume and page list for all sections of the submission.

5. Basis for Submission

·                  Reference Listed Drug (brand name)

·                  Dosage form (tablet, capsule, injection, etc.)

·                  Strength

·                  Special or unique formulation details

6. Conditions of Use

·                  ANDA must match the RLD in:

o        Indications

o        Dosage regimen

o        Contraindications

o        Warnings and precautions

·                  Labelling must be the same except for permissible differences (e.g., manufacturer-specific changes).

7. Active Ingredient Statement

·                  Must declare the same active ingredient as the reference drug.

·                  For combination products, provide statements for each active ingredient.

8. Dosage Form, Strength & Route of Administration

·                  Must match the reference drug exactly.

9. Bioequivalence (BE) Requirements

Must demonstrate:

·                  Same rate and extent of absorption

·                  Pharmacokinetic parameters:

o        Cmax

o        AUC (AUC₀₋ₜ and AUC₀₋∞)

BE Study Components:

·                  Study design (typically a 2-way crossover)

·                  Dose and administration details

·                  Sample collection times

·                  Analytical methodology for plasma/serum measurements

10. Labeling Requirements

Submit:

·                  RLD’s currently approved labeling

·                  Proposed generic product labeling

·                  Label-to-label comparison

11. CMC (Chemistry, Manufacturing & Controls)

Includes:

Composition

·                  List of active and inactive ingredients

Manufacturing

·                  Process description

·                  Site and equipment

·                  In-process controls

Specifications

·                  Tests for identity, potency, purity, impurities, dissolution, microbial quality

Analytical Procedures

·                  Detailed test methods

·                  Validation reports for accuracy, precision, reproducibility

12. Human PK & BA

·                  PK study protocols

·                  Dosing procedures

·                  Sampling schedule

·                  Bioanalytical method validation

13. Samples Submitted

·                  Four samples each of:

o        Drug substance

o        Drug product

·                  Sufficient for FDA to test at least three times

14. Case Report Forms & Tabulations

·                  Subject data from BE studies

·                  Must be reviewed with FDA OGD bioequivalence staff prior to submission

15. ANDA Review Flowchart (Integrated Summary)

Step 1: Filing Review

FDA checks if the ANDA is:

·                  Acceptable and complete

·                  If not → Refuse-to-File Letter issued

Step 2: Review by OGD/CDER

Parallel reviews occur:

a. Bioequivalence Review

·                  If unacceptable → Bioequivalence Deficiency Letter

b. Chemistry / Microbiology Review

c. Labeling Review

d. Plant Inspection Request

·                  Conducted by FDA inspectors

·                  If unacceptable → Not Approvable Letter

Step 3: Pre-Approval Inspection

·                  If satisfactory → Proceed

·                  If unsatisfactory → Approval pending satisfactory results

Step 4: Final Decision

ANDA Approved once all reviews and inspections are acceptable.

16. Purpose of ANDA Submission

To confirm the generic drug is:

·                  Pharmaceutically equivalent

·                  Bioequivalent

·                  Therapeutically interchangeable

·                  Safe, effective, and high-quality

📌 NDA Submission – 

An NDA (New Drug Application) is the official request submitted to a regulatory authority (like US FDA) to approve a new drug for marketing.
In India, the equivalent process is New Drug Approval under CDSCO, but the term NDA is globally used.

The purpose of an NDA is to provide complete evidence that a drug is:
✔ Safe
✔ Effective
✔ Manufactured with high quality
✔ Has benefits outweighing risks

📌 Objectives of NDA Submission

1. To demonstrate safety & efficacy from preclinical and clinical studies.
2. To provide complete data on CMC (Chemistry, Manufacturing & Controls).
3. To propose labeling, including indications, dose, warnings.
4. To provide risk–benefit assessment.
5. To ensure quality, stability, purity, and batch-to-batch consistency.

📌 Regulatory Basis

US-FDA

NDA is submitted under:

• 21 CFR Part 314
• SOPs defined in FDA guidance documents

India

Similar process under:

• New Drugs and Clinical Trials Rules (NDCTR) 2019
• Schedule Y (older reference)

📌 When is an NDA Required?

NDA is required for approval of:

1. New chemical entity (NCE/NME)

New active ingredient not approved before.

2. New dosage form

tablet → injection, etc.

3. New route of administration

oral → transdermal, etc.

4. New combination

FDCs.

5. New strength or formulation

extended-release, nanoformulation.

6. New indication

drug for new disease/age group.

**📌 Format of NDA – CTD (ICH Common Technical Document)

NDA follows CTD format, divided into 5 Modules:

✨ Module 1: Administrative Information (region-specific)

Includes:
✔ FDA forms (Form 356h)
✔ Patent certification
✔ Cover letter
✔ Labeling & Package insert
✔ Orphan drug designation
✔ REMS (Risk Evaluation and Mitigation Strategy)
✔ Ethics committee approvals

✨ Module 2: Summaries

Executive summaries of all data:

2.1 CTD Introduction

2.2 Quality Overall Summary (QOS)

CMC summaries

2.3 Non-clinical Overview & Summary

• Pharmacology
• Toxicology

2.5 Clinical Overview

• Benefit–risk summary

2.7 Clinical Summary

• Study summaries (Phase I–III)

✨ Module 3: Quality (CMC Data)

Very important! Contains:

Drug Substance Information

• Structure
• Synthesis
• Impurities
• Characterization

Drug Product Information

• Formulation
• Manufacturing process
• Excipients
• Specifications
• Stability data
• Batch analysis

Goal: Ensure quality, purity, potency, stability.

✨ Module 4: Nonclinical Study Reports

Includes complete animal study data:

Pharmacology

• Primary pharmacodynamics
• Secondary pharmacodynamics
• Safety pharmacology

Toxicology

• Acute toxicity
• Repeat-dose toxicity
• Genotoxicity
• Carcinogenicity
• Reproductive toxicity
• Local tolerance

✨ Module 5: Clinical Studies (Human Data)

Contains reports of Phase I, II, III clinical trials:

Human Pharmacokinetics (ADME)

• Absorption
• Distribution
• Metabolism
• Excretion

Human Pharmacodynamics

Efficacy Studies

Safety Studies

Post-marketing experience (if applicable)

📌 NDA Submission Process Steps

1. Pre-NDA Meeting

Sponsor discusses data with FDA/CDSCO
→ Clarifies deficiencies
→ Ensures smooth submission

2. NDA Submission

Electronically through eCTD format.

3. Filing Review (60 days)

Regulator checks:
✔ Application completeness
✔ Acceptable format
✔ All modules available
If acceptable → Filed for full review.

4. Scientific Review

Performed by multidisciplinary team:

• Clinicians
• Pharmacologists
• Statisticians
• CMC experts

They evaluate:
✔ Safety
✔ Efficacy
✔ Quality
✔ Labeling
✔ Risk–benefit profile

5. Advisory Committee Review (if needed)

Independent experts review controversial/complex NDAs.

6. Inspection

FDA conducts inspections:

• Clinical trial sites
• Manufacturing facilities (GMP)
• Bioequivalence centers

7. Regulatory Decision

Possible outcomes:

🟢 Approval

Drug can be marketed.

🟡 Approvable Letter

Approval only after minor issues addressed (labeling/SOPs).

🔴 Complete Response Letter (CRL)

Major deficiencies → NDA rejected; sponsor must correct issues.

📌 Types of NDA

1.     Traditional NDA
Full reports of safety, efficacy, CMC.

2.     505(b)(1) NDA
Full NDA with own studies.

3.     505(b)(2) NDA
At least some data from published literature or other studies (easier than full NDA).

4.     ANDA (Abbreviated NDA)
For generics (no clinical trials, only bioequivalence).

📌 NDA Review Timelines (US-FDA)

Standard Review: 10 months

Priority Review: 6 months

Priority review is for:

• Serious diseases
• Unmet medical needs
• Orphan drugs

📌 Mnemonic to Remember NDA Modules

“A – S – Q – N – C”
👉 Administrative (Module 1)
👉 Summaries (Module 2)
👉 Quality (Module 3)
👉 Non-clinical (Module 4)
👉 Clinical (Module 5)

📌 Mnemonic for NDA Objectives

“S.E.Q.L.”
✔ Safety
✔ Efficacy
✔ Quality
✔ Labeling

📌 Short Notes Version (for exams)

NDA is a regulatory submission to obtain marketing approval for a new drug. It includes administrative, CMC, nonclinical, and clinical data organized in 5 CTD modules. It demonstrates safety, efficacy, quality, and proposes labeling. Steps include pre-NDA meeting, filing review, scientific review, advisory committee, facility inspections, and final approval.