product registration and drug approval process in us
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Product Registration and Drug Approval Process in United States
keerthi priya
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overviewBack ground for product registration in the
united statesThe New Drug Application (NDA) and review
processGeneric drug product registration and review
process (ANDA)Post-Approval activities for NDA and ANDAOther considerations for NDA and ANDAPre-Approval inspection
Background for product registration in the United States
All new drug products must be registered and approved by the regulatory agency governing the intended market before the products can be introduced into the market.
The registration process is to ensure the quality, safety, and efficacy of drug products.
The requirements for the development and registration of new drug products in the United states are defined in the Federal Food Drug and Cosmetic Act (FD&C Act) and the regulations promulgated by the FDA.
Introduction
The new drug application (N D A) is a critical component in the drug approval process. The NDA contains Clinical and nonclinical test data and analyses, Drug chemistry information, and Descriptions of manufacturing procedures.
An NDA consists of thousands of pages of information to be reviewed by FDA teams composed of highly qualified individuals with expertise in their respective technical fields.
IntroductionNDAs and ANDAs are submitted to FDAFDA has complex organisation for review and
approval of NDAs and ANDAs.Review and approval are conducted by CDERWhich reports directly to the office of
commissioner of FDAWithin CDER there are number of offices
organized under the office of center director.
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New Drug Application (NDA) Classifications
1. New molecular entity 2. New salt of previously approved drug 3. New formulation of previously approved drug
(not a new salt OR a new molecular entity) 4. New combination of two or more drugs5. Already Marketed Drug Product – Duplication
(i.e., new manufacturer)6. New Indication (claim) for Already Marketed
Drug ( includes switch in marketing status from prescription to OTC)
7. Already Marketed Drug Product – No previously Approved NDA
six different teams are responsible for reviewing an NDA. The teams are organized by technical reviewing responsibilities: Clinical Pharmacology/toxicology, Chemistry ,Statistics, Biopharmaceutical and Microbiology.
The FDA has established guidelines for formatting, assembling, and submitting the NDA. Failure to follow these guidelines can result in deficiencies that could Delay review, Require an amended application, or Result in a refusal to File.
In 1997 the FDA’s Center for Drug Evaluation and Research (CDER) published guidelines that allow sponsors to submit NDAs electronically instead of on paper
NDA starts with FDA form 356h which provides listing of 20 sections.
The Form 356h is completed and signed by the sponsor or the sponsors authorized US agent, who resides or maintains a business site in the United states.
Format and content of NDA
1. Index2. Summary3. Chemistry, Manufacturing and Control4. Samples, Methods Validation Package and Labeling5. Nonclinical Pharmacology and Toxicology6. Human Pharmacokinetics and Bioavailability7. Microbiology ( for anti-microbial drugs only)8. Clinical Data9. Safety Update report ( typically submitted 120
days after the NDA’s submission )10. Statistical11. Case Report Tabulations
11.Case Report Tabulations12.Case Report Forms13. Patent Information14. Patent Certification15. Establishment description16. Debarment certification17. Field copy certification18. User fee cover sheet19. Financial information20. Other
NDA CONTENTSSection 1: Overall NDA index:- It Provides a guide through the entire application
for the FDA reviewers. The index must clearly describe the contents and location of each section by volume and page number.
Section 2: Labeling
It must include all draft labeling that is intended for use on the product container, cartons or packages, including the proposed package insert.
Section 3: Application summary The application summary is an abbreviated version of the entire
application. This overview is one of the few elements of the application that all reviewers receive, and it should give them a clear idea of the drug and its application. The summary usually comprises 50 to 200 pagesApplication Summary The draft product labeling include the following sections 1. Description 2. Clinical Pharmacology 3. Indications and Usage 4. Contraindications 5. Warnings 6. Precautions 7. Adverse Reactions 8. Drug Abuse and Dependence 9. Overdosage 10. Dosage and Administration 11. How Supplied (primary and secondary packages)
Section 4: Chemistry, manufacturing and controls Chemistry, Manufacturing, and Controls (CMC) The first
technical section of the NDA It includes information on The composition, Manufacturing, and Specifications of the drug substance and the drug product. The three main elements are Chemistry, manufacturing and controls information, Samples, Method validation, package.
Section 5: Nonclinical pharmacology and toxicologyProvide individual study reports, including pharmacology, toxicology, ADME studies.Effects related to the therapeutic indication, such as the pharmacodynamic ED50 in dose- ranging studies and the mechanism of action Interactions with other drugs (or cross-reference the location of the information in any of the above subsection)
Section 6: Human Pharmacokinetics and bioavailabilityIncludes data from Phase I safety and tolerance studies in healthy volunteers. Element in the section tabulated summary of studies showing all in vivo biopharmaceutics studies performed
•Summary of analytical method used in in vivo biopharmaceutic study•Pilot or background studies •Bioavailability or bioequivalence studies•Pharmacokinetic studies•In vitro studies
Section 7: Microbiology Includes data for anti infective drug products. requires the following technical information and data:-
•A complete description of the biochemical basis of the drug action on microbial physiology•The drugs antimicrobial spectrum•Describe any known mechanism of resistance to the drug and provide information/data of any known epidemiologic studies demonstrating prevalence to resistance factor•Clinical microbiology laboratory methods
Section 8: Clinical dataIncludes. Background or overview of clinical investigations Clinical pharmacology Controlled clinical trials Uncontrolled clinical trials Other studies and information Integrated summary of effectiveness data Integrated summary of safety information Drug abuse and overdose information Integrated summary of benefits and risks of drug
Section 9: Safety dataStatements in draft labelingContraindicationsWarningsPrecautionsAdverse events
Section 10: Statistical dataAll controlled clinical trial reportsIntegrated efficacy and safety summariesIntegrated summary of risks and benefits
Section 11: Case report tabulation
include complete tabulation for each patient from every adequately are well controlled phase II and Phase III efficacy, clinical pharmacology study. It also tabulation of
safety data from all clinical studies.Section 12: Case report formsinclude the complete CRF for each patient who died during a clinical study or adverse event, regardless of whether the AE is considered to be related to the study drug, even if the patient was receiving a placebo or comparative drug.
13: Patent information (Form 3542a) 14: Patent certification 15: Establishment description (for biologics only) 16: Debarment certification 17: Field copy certification 18: User fee cover sheet (Form FDA-3397) FDA charges a fee for the review of an original NDA, and certain
other NDA submissions. These fees vary according to their type and the need to review clinical data.
19: Financial disclosure (Form FDA 3454, form FDA-3455) 20: Other/pediatric use
The FDA requires drug sponsors to submit multiple copies of the NDA
The archival copy The review copy The field copy
The Archival Copy The Archival Copy Contains all sections of the NDA,
including The cover letter, Form FDA-356h (Application to Market a New Drug, Biologic, or an Antibiotic for Human Use), The administrative sections, Comprehensive NDA index, and All technical sections.
It must contain four copies of the Labeling section. It must contain three additional copies of the CMC and Methods Validation Package in a separate binder. The archival copy is the only copy that contains the Case Report Tabulation and Case Report Forms. The Archival Copy
The Review Copy The Review Copy Intended for reviewers in the corresponding
technical disciplines. In addition to the appropriate technical section, each review copy also includes The cover letter, Form FDA-356h, The administrative sections, Comprehensive NDA index Individual table of contents, The Labeling section, and The Application Summary.
The Field Copy : The Field Copy Required since 1993 for use by FDA inspectors
during pre approval facilities inspections. It includes the Cover letter and Form FDA-356h, The administrative sections, The comprehensive NDA index Individual table of contents, The Labeling section, The Application Summary, and CMC and Methods Validation Package.
The NDA in CTD Format
ICH has developed a Common Technical Document to streamline regulatory submissions in Europe, U.S. and Japan.
CTD is an information format that contains clinical, nonclinical, and manufacturing technical data.
The CTD format features well-defined modules, with a highly specific structure and numbering of sections within the modules. It makes a clear distinction between subjective information sections and objective information sections.
1.0 Regional Administrative Information
1.1 ToC of Module 1 or overall ToC,including Module 1
2.1 ToC of the CTD (Mod 2,3,4,5)
2.2 Introduction
2.3 Quality Overall Summary
2.4 Nonclinical Overview
2.5 Clinical Overview
2.7 Clinical Summary
2.6 Nonclinical Written and Tabulated Summaries
Module 1
Module 3 Module 4 Module 5
2.1
2.2
2.32.4 2.5
2.6 2.7
1.0
QualityNonclinical
Study ReportsClinical
Study Reports
Module 2
Module 2
2.1 OVERALL CTD TABLE OF CONTENTS OF MODULES 2, 3, 4, AND 5
2.2 INTRODUCTION
2.3 QUALITY OVERALL SUMMARY
2.3.S DRUG SUBSTANCE
2.3.S.1 General Information
2.3.S.2 Manufacture
2.3.S.3 Characterization
2.3.S.4 Control of Drug Substance
2.3.S.5 Reference Standards or Materials
2.3.S.6 Container Closure System
2.3.S.7 Stability
2.3.P DRUG PRODUCT
2.3.P.1 Description and Composition of the Drug Product
2.3.P.2 Pharmaceutical Development
2.3.P.3 Manufacture
2.3.P.4 Control of Excipients
2.3.P.5 Control of Drug Product
2.3.P.6 Reference Standards or Materials
2.3.P.7 Container Closure System
2.3.P.8 Stability
Module 2 (Cont.)
2.3.A APPENDICES
2.3.A.1 Facilities and Equipment
2.3.A.2 Adventitious Agents Safety Evaluation
2.3.A.3 Novel Excipients
2.3.R REGIONAL INFORMATION
2.4 NONCLINICAL OVERVIEW
2.4.1 Overview of the Nonclinical Testing Strategy
2.4.2 Pharmacology
2.4.3 Pharmacokinetics
2.4.4 Toxicology
2.4.5 Integrated Overview and Conclusions
2.4.6 List of Literature Citations
2.5 CLINICAL OVERVIEW
2.5.1 Product Development Rationale
2.5.2 Overview of Biopharmaceutics
2.5.3 Overview of Clinical Pharmacology
2.5.4 Overview of Efficacy
2.5.5 Overview of Safety
2.5.6 Benefits and Risks Conclusions
2.5.7 References
Module 2 (Cont.)
2.6 CONTENT OF NONCLINICAL WRITTEN AND TABULATED SUMMARIES
2.6.1 Introduction
2.6.2 Pharmacology Written Summary
2.6.3 Pharmacology Tabulated Summary (Appendix B)
2.6.4 Pharmacokinetics Written Summary
2.6.5 Pharmacokinetics Tabulated Summary (Appendix B)
2.6.6 Toxicology Written Summary
2.6.7 Toxicology Tabulated Summary (Appendix B)
2.7 CLINICAL SUMMARY
2.7.1 Summary of Biopharmaceutics and Associated Analytical Methods
2.7.2 Summary of Clinical Pharmacology Studies
2.7.3 Summary of Clinical Efficacy
2.7.4 Summary of Clinical Safety
2.7.5 References
2.7.6 Synopses of Individual Studies
Module 3
3.1 MODULE 3 TABLE OF CONTENTS
3.2 BODY OF DATA
3.2.S DRUG SUBSTANCE
3.2.S.1 General Information
3.2.S.2 Manufacture
3.2.S.3 Characterisation
3.2.S.4 Control of Drug Substance
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability
3.2.P DRUG PRODUCT
3.2.P.1 Description and Composition of the Drug Product
3.2.P.2 Pharmaceutical Development
3.2.P.3 Manufacture
3.2.P.4 Control of Excipients 3.2.P.5 Control of Drug Product 3.2.P.6 Reference Standards or Materials 3.2.P.7 Container Closure System 3.2.P.8 Stability
Module 3 (Cont.)
3.2.A APPENDICES
3.2.A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation
3.2.A.3 Novel Excipients
3.2.R REGIONAL INFORMATION
3.3 LITERATURE REFERENCES
Module 4
4.1 MODULE 4 TABLE OF CONTENTS
4.2 STUDY REPORTS
4.2.1 Pharmacology
4.2.2 Pharmacokinetics
4.2.3 Toxicology
4.3 LITERATURE REFERENCES
Module 5
5.1 MODULE 5 TABLE OF CONTENTS
5.2 TABULAR LISTINGS OF ALL CLINICAL STUDIES
5.3 CLINICAL STUDY REPORTS
5.3.1 Reports of Biopharmaceutic Studies
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.4 Reports of Human Pharmacodynamic (PD) Studies
5.3.5 Reports of Efficacy and Safety Studies
5.3.6 Reports of Post-Marketing Experience
5.3.7 Case Report Forms and Individual Patient Listings
5.4 LITERATURE REFERENCES
NDA Review Process
TIMINGWithin 45 days after receipt of the NDA, the
reviewing division will meet, and determine if the application is fileable.
If the application is to be filed, then a review plan is established for that NDA, its review priority depending on the importance of the drug
If not fileable, a refuse to file (RTF) letter is sent to the sponsor.
NDA Review Process
Advisory committeeDuring the course of few NDA reviews, issues or controversies
may arise, and the FDA may call for a consultation with one of its advisory commitees
These are comprised of subject matter experts in various
medical and scientific fields.FDA Action letterThe action letter can be in three forms:Approval, approvable and not approvableApproval letter- allows product to be marketed in US after
approval dateApprovable letter- Is sent to an applicant if the FDA believes
the application can be approved, if the sponsor submits additional information or agrees to certain conditions.
Not approvable- the application did not meet FDA requirements and the letter will describe the deficiencies in the NDA
ANDA“ANDA” is the abbreviation for Abbreviated New Drug
ApplicationGeneric drug applications are termed “abbreviated” in
that they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness
ANDA is provided for the marketing of generic drug products after all forms of exclusivity have expired for the RLD( innovator drug)
ANDAs are files under the FD&C Act section 505(j)Generic drug products must be bioequivalent to the innovator
product.The API, dosage form, dose strength, labeling, route of
administration and conditions must be the same.
Goal of ANDATo reduce the price of the drug.
To reduce the time for development.
Increase the bioavailability of the drug in comparison to references list drug.
Basis for an ANDA submission
Patent certification and exclusivity
Sponsors of an ANDA must file a patent certification under one of the following paragraphs:
I. That no patent information on the drug product that is the subject of the ANDA has been submitted to the FDA
II. That such patents has expiredIII. The date on which such patent expiresIV. That such patent is invalid or will not be infringed by the
manufacture, use or sale of the drug product from which the ANDA is submitted
If the ANDA applicant files the paragraph IV certification, the applicant must also notify the innovator within 20dys of filing of an ANDA, and the innovator has 45 days to take action upon receiving the notification. The FDA may hold the approval upto 30 months, depending on the outcome of the litigation, if any.
LabelingDifferences between the applicants proposed labeling, and
labeling approved for the reference listed drug, may include differences in expiration date, formulation, bioavailability or pharmacokinetics, labeling revisions made to comply with current FDA labeling guidelines
All labeling for a generic drug product must be provided in SPL formatting, and in compliance with the Physicians Labeling Rule
NDA ANDA
Applicable for new drug Applicable for generic drug
Take longer time ( 12-15 years)
Compare to NDA less time taken(1-2 years)
More expenditure of money
Comparatively less
Cost of drugs are more Cost of drugs are lessNonclinical studies and clinical investigations are essential
Nonclinical studies and clinical investigations are nonessential except bioavailability and bioequivalence
Bioavailability/ Bioequivalence
Bioequivalence is the absence of a significant difference in the rate and extent of drug available at the site of action after dosing of a test product, compared to a reference product.
Recommendations of study designs and data evaluation for bioequivalence study are listed in regulatory guidance.
Bioequivalence is achieved when the 90% confidence interval (CI) for the ratio of Cmax and AUC of the test product over the reference product on log transformed data is within 80-125%
ANDA/AADA Review Process
Post-Approval Activities For NDA and ANDAAnnual reports: Sponsors of NDA or ANDA must submit an annual report each year,
within 60 days of the anniversary date of US Approval of the application, to the FDA division responsible for reviewing the application.
The report is required to contain in the order listed: Form FDA 2252( Tramittal of periodic reports for drugs for human
use) Summary Distribution data Labelling CMC changes Non clinical laboratory studies Clinical data Status reports of post-marketing study commitments Status of other post-marketing studies Log of outstanding regulatory business (optional)
Other considerations for NDA and ANDASupplemental ApplicationsEstablishment registration and drug listing requirements
for foreign establishments.
Pre-Approval InspectionThe purpose of PAI is to verify the authenticity of data
submitted in the applications, and to evaluate the cGMP compliance of the applicant.
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