Product registration and drug approval process in us

Download Product registration and drug approval process in us

Post on 15-Nov-2014




1 download




Product Registration and Drug Approval Process in United States keerthi priya*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 inspectionBackground for product registration in the United StatesAll 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.IntroductionThe 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.*New Drug Application (NDA) ClassificationsNew molecular entity New salt of previously approved drug New formulation of previously approved drug (not a new salt OR a new molecular entity) New combination of two or more drugsAlready Marketed Drug Product Duplication (i.e., new manufacturer)New Indication (claim) for Already Marketed Drug ( includes switch in marketing status from prescription to OTC)Already Marketed Drug Product No previously Approved NDAsix 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 FDAs Center for Drug Evaluation and Research (CDER) published guidelines that allow sponsors to submit NDAs electronically instead of on paperNDA 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 NDAIndexSummaryChemistry, Manufacturing and ControlSamples, Methods Validation Package and LabelingNonclinical 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 NDAs submission )10. Statistical11. Case Report Tabulations11.Case Report Tabulations12.Case Report Forms13. Patent Information14. Patent Certification15. Establishment description16. Debarment certification17. Field copy certification18. User fee cover sheet19. Financial information20. OtherNDA 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 performedSummary of analytical method used in in vivo biopharmaceutic studyPilot or background studies Bioavailability or bioequivalence studiesPharmacokinetic studiesIn 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 physiologyThe drugs antimicrobial spectrumDescribe any known mechanism of resistance to the drug and provide information/data of any known epidemiologic studies demonstrating prevalence to resistance factorClinical microbiology laboratory methodsSection 8: Clinical dataIncludes.Background or overview of clinical investigationsClinical pharmacologyControlled clinical trialsUncontrolled clinical trialsOther studies and informationIntegrated summary of effectiveness dataIntegrated summary of safety informationDrug abuse and overdose informationIntegrated summary of benefits and risks of drugSection 9: Safety dataStatements in draft labelingContraindicationsWarningsPrecautionsAdverse eventsSection 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 certification15: Establishment description (for biologics only)16: Debarment certification17: Field copy certification18: 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 useThe FDA requires drug sponsors to submit multiple copies of the NDA The archival copy The review copy The field copyThe 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 FormatICH 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. Module 22.1Overall CTD Table of Contents of Modules 2, 3, 4, and 52.2Introduction2.3Quality overall summary2.3.Sdrug substance2.3.S.1General Information2.3.S.2Manufacture2.3.S.3Characterization2.3.S.4Control of Drug Substance2.3.S.5Reference Standards or Materials2.3.S.6Container Closure System2.3.S.7Stability2.3.Pdrug product2.3.P.1Description and Composition of the Drug Product2.3.P.2Pharmaceutical Development2.3.P.3Manufacture2.3.P.4Control of Excipients2.3.P.5Control of Drug Product2.3.P.6Reference Standards or Materials2.3.P.7Container Closure System2.3.P.8StabilityModule 44.1Module 4 table of contents4.2study reports4.2.1Pharmacology4.2.2Pharmacokinetics4.2.3Toxicology4.3LITERATURE REFERENCESModule 55.1MODULE 5 TABLE OF CONTENTs5.2TABULAR LISTINGS OF ALL CLINICAL STUDIES5.3Clinical study reports5.3.1Reports of Biopharmaceutic Studies5.3.2Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials5.3.3Reports of Human Pharmacokinetic (PK) Studies5.3.4Reports of Human Pharmacodynamic (PD) Studies5.3.5Reports of Efficacy and Safety Studies5.3.6Reports of Post-Marketing Experience5.3.7Case Report Forms and Individual Patient Listings5.4LITERATURE REFERENCESNDA Review ProcessTIMINGWithin 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 drugIf not fileable, a refuse to file (RTF) letter is sent to the sponsor.NDA Review ProcessAdvisory 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 commiteesThese 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 NDAANDAANDA 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 effectivenessANDA 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 submissionPatent certification and exclusivity Sponsors of an ANDA must file a patent certification under one of the following paragraphs:That no patent information on the drug product that is the subject of the ANDA has been submitted to the FDAThat such patents has expiredThe date on which such patent expiresThat such patent is invalid or will not be infringed by the manufacture, use or sale of the drug product from which the ANDA is submittedIf 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 guidelinesAll labeling for a generic drug product must be provided in SPL formatting, and in compliance with the Physicians Labeling Rule Bioavailability/ BioequivalenceBioequivalence 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 ProcessPost-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)SummaryDistribution dataLabellingCMC changesNon clinical laboratory studiesClinical dataStatus reports of post-marketing study commitmentsStatus of other post-marketing studiesLog 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.*THANK YOU