regulatory sk.pptx
- 1. NON CLINICAL DEVELOPMENT: GLOBAL SUBMISSION OF IND,NDA & ANDA 1 SUBMITTED BY SATHISH KUMA.P Mpharm-1st semester Nandha college of pharmacy 7/2/2023
- 2. CONTENT 2 • Introduction • Global Submission of IND • Global Submission of NDA • Global Submission ofANDA 7/2/2023
- 3. Introduction 3 Non- Clinical development Phase primarily aims to identify which candidate therapy has the greatest probability of success, assess it’s safety & Build solid scientific foundations before transition to the Clinical development Phase. Also, during this phase candidate compound should meet non medical objectives, including defining the intellectual property rights & making enough medicinal product available for clinical studies. 7/2/2023
- 4. GLOBAL SUBMISSION OF IND 4 INTRODUCTION The investigational new drug application is the result of a successful preclinical development programme IND is also a vehicle through which a sponsor advances to next stage of drug development known as clinical trials. 7/2/2023
- 5. 5 There are 2 main categories 1. Commercial:- • Permits sponsor to collect data on ‘clinical safety& effectiveness’ needed for application for marketing in the form of NDA. 2. Non-commercial (Research) :- • Permits sponsor to use drug in research to obtain ‘advanced scientific knowledge’of new drug . • No plan to market the product . 7/2/2023
- 6. 6 Types of IND 1. Investigator INDs: It is submitted by Physician who both initiates & conduct an investigation and under whose immediate direction the investigational drug is administered or dispensed. 2. Emergency Use INDs: It allows FDA to authorize use of experimental drug in an emergency situation that does not allow time for submission of an IND in a normal way. 3. Treatment IND (Expanded access IND): Submitted for experimental drugs showing promise in clinical testing of serious conditions while final work is conducted & FDA review takes place. 7/2/2023
- 7. Criteria for IND application A clinical study is required for an IND if it is intended to support a : • New indication. • Change in approved route of administration or dosage level. • Change in approved patient population (e.g. pediatric) or a population at greater or increase in risk (elderly ,HIV positive , immuno compromised ) • Significant change in the promotion of an approved drug 7 7/2/2023
- 8. Format And Content Of IND 1) Cover sheet (Form FDA1571). 2) Atable of contents. 3) Introductory statement & General Investigational plan. 4) Investigator’s Brochure. 5) Protocols. 6) Chemistry , Manufacturing &Control information. 7) Pharmacology and toxicology information. 8) Previous human experience with investigational product. 9) Additional Information 7/2/2023
- 9. IND Application must contain information in three broad areas: a) Animal Pharmacology & Toxicology Studies: Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. If any previous experience with the drug in humans. b) Manufacturing Information: Information regarding to the composition, manufacturer, stability &controls used for manufacturing drug substance and product. c) Clinical Protocols and Investigator Information: Detailed protocols proposed clinical studies to assess whether initial phase trials will expose subjects to unnecessary risks. Information and qualification of Clinical Investigators – professionals . 7/2/2023
- 11. • After pre-clinical investigations when the new molecule has been screened for pharmacological activity and acute toxicity potential in animals the sponsor requires permission from FDA for its clinical trials in humans. • The sponsor submits the application for conduct of human clinical trials called Investigational New Drug (IND) application to FDA. • Once IND application is submitted , the sponsor must wait for 30 days before initiating any clinical trial. 7/2/2023
- 12. • Clinical trials in humans can begin only after IND is reviewed by the FDA and a local institutional review board (IRB). • IRBs approve clinical trial protocol, informed consent of all participants and appropriate steps to prevent subjects from harm. • If the FDA accepts the IND request within 30 days of submission, clinical testing of the new molecule on human may begin by the investigator. 7/2/2023
- 13. • At this point, the molecule under the legal status of FDA becomes a new drug subject to specific requirements of drug regulatory system. • If at any time during clinical testing, the data furnished to FDA indicate the IP to be toxic under the criterion of FDA’s Benefit/Risk ratio, FDA can terminate clinical trial and its actions are not subject to any judicial review. 7/2/2023
- 14. Application submission:- • Most of INDs are paper submission. While only 12%INDs submitted electronically,28% of IND Amendments are submitted electronically a result of maintaining a growing number of INDs submitted electronically to date. TIMELINE: • 30 days after FDA receives the application , unless FDA notifies the sponsor that the investigations described in the application are subject to a clinical hold. • Any earlier notification issued with approval clinical investigations in IND may begins. 7/2/2023
- 15. GLOBAL SUBMISSION OF NDA • Vehicle through which drug sponsors formally propose that the regulatory body (FDA) approve a new pharmaceutical for sale & marketing. • The data gathered during the ‘animal studies’ & ‘Human clinical trials’ of an Investigational new product become part of NDA. The goal of NDA are to provide enough information to permit FDA reviewers to establish the following : • Safety & Effectiveness of drug ? - Proper labelling ? • Are the methods used for manufacturing (GMP) the Drug & Controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality &purity ? 7/2/2023
- 16. The goal of NDA are to provide enough information to permit FDAreviewers to establish the following : • Safety & Effectiveness of drug ? • Proper labelling ? • Are the methods used for manufacturing (GMP) the Drug & Controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality &purity ? 7/2/2023
- 17. Classification of NDA • Centre for drug evaluation and Research(CDER) classifies new drug applications according to the type of drug being submitted and its intended use: a . New molecular entity b. New salt of previously approved drug c. New formulation of previously approved drug d. New combination of two or more drugs e.Already marketed drug product- Duplication (i.e., new manufacturer) f.New indication (claim) for already marketed drug (includes switching marketing status from prescription to OTC) g.Already marketed drug product ( no previously approved NDA) 7/2/2023
- 18. Format and Contents of NDA As outlined in Form no.-FDA-356th , Application to Market a New drug for Human use .NDA consists of many different sections: • Index • Labelling • Application Summary • CMC (chemistry, manufacturing & controls • Non clinical- (Animal) Pharmacology & Toxicology • Human pharmacokinetics & Bioavailability. • Microbiology (for antimicrobial drugs only) • Clinical data 7/2/2023
- 19. • Safety Update Report • Statistics • Case report Tabulations • Case report forms • Patent information • Patent certification • Other information. Format: It involves 3 copies; 1. Archival Copy 2. Review Copy 3. Field Copy 7/2/2023
- 20. 1.ARCHIVAL COPY • It is a complete copy of an application for submission. • It should include a cover letter to: i. Confirm any agreements or understanding between FDA& applicant. ii. Identify a contact person regarding the application. iii. Identify the reviewing division of FDA iv. Convey any other important information about application . 7/2/2023
- 21. 2.REVIEW COPY • Divided into 6 technical sections shown with specific colour: • Chemistry, manufacturing & controls(CMC) • Non clinical pharmacology & toxicology • Human pharmacokinetics & Bioavailability- • Microbiology (if required ) • Clinical data – • Statistical • Separately bound copy of the Quality Section • It is directly send to appropriate field office . 3.FIELD COPY 7/2/2023
- 22. NDA CONTENTS Index : - Comprehensive table of contents Show the location of every section in archival NDA by volume & page number Labelling : -Draft labelling used on Product container, Cartons or packages, proposed package insert. Application Summary : An abbreviated version of entire application. Involves few elements of application that all reviewers review. Gives a clear idea of Drug &its application. - 7/2/2023
- 23. CMC: First technical section of NDA Includes information on Composition, manufacturing and specifications of drug substance & drug product. Non clinical pharmacology & toxicology: Provides a description of all animal & in vitro studies with drug. Provide individual study reports, including pharmacology, toxicology &ADME studies. Human pharmacokinetics& Bioavailability : Includes data from phase I safety & tolerance studies in healthy volunteers &ADME studies. PK parameter , giving value of Cmax , AUC, tmax , Ke , Vd 7/2/2023
- 24. Microbiology: Required for anti-infective drug product. Used in case of involvement of antimicrobial drugs. Clinical Data: Largest document & complex section • List of investigators& list of INDs and NDAs • Background/overview of clinical investigations • Clinical pharmacology • Controlled & Uncontrolled clinical trials • Other studies & information. Safety update reports: Safety updates should be submitted 4 months after initial application, following the receipt of an approval letter & any other time that FDArequests. 7/2/2023
- 25. Statistics: Description & documentation of Statistical analyses performed to evaluation of controlled clinical trials &other safety information. Case Report Form Tabulations:Complete tabulations for each patient from every well controlled phase II &phase III and from every phase I clinical pharmacology studies & also Safety data . Case Report Forms(CRFs): Complete CRFs of each patient who died during a clinical study & patients who were dropped from study. Others:Patent information &certification, Establishment description, Debarment & Field copy certification, User fee cover sheet , Financial disclosure. 7/2/2023
- 27. TIMELINE Review time frames: • Within 180 days of receipt of an application, FDA will review approval , approvable or not approval letter ,this period is called the ‘review clock’ • Applicant may withdraw at this period & later resubmit it . • The time period may be extended by mutual agreement between FDA& applicant . 7/2/2023
- 28. Filling timeline frames: • Within 60 days after FDA receives , a determination is made whether application may be filed. • This determines whether sufficient information is provided to proceed with in depth review. • If FDA files the application ,applicant will be notified in written .the date of filling will be the date 60 days after FDA received application. • The date of filling begins the 180 days period of review ,if FDA refuses it then applicant can meet with FDA& discuss. 7/2/2023
- 29. ABBREVIATED NEW DRUG APPLICATION (ANDA) • An ANDA contains data submitted to U.S food & drug administration (FDA’s CDER) ,office of generic drugs request for review and ultimate approval of a generic drug. • Once ANDA is approved ,an applicant may manufacture &market the generic drug product to provide a Safe, Effective, Low cost alternative to public. • A generic drug product is one compared with innovator drug product in Dosage form, Strength, Route of administration Quality, Performance characteristics & intended use. 7/2/2023
- 30. • All approved products, both innovator & generic are listed in Orange Book. • Use of bioequivalence as the base for approving generic drug products was established by the "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the HATCH-WAXMANACT. • It is because of this Act that there is the availability of less costly generic drugs into the market without conducting costly and duplicative clinical trials. 7/2/2023
- 31. FORMAT & CONTENT OFANDA a .Application summary b. Chemistry, Manufacturing and controls section c. Non clinical pharmacology and toxicology section d. Human pharmacokinetics & bioavailability section e. Clinical and statically section f. MicrobThe patent certification involved in ANDA that includes: g. iology section 7/2/2023
- 32. Paragraph I - That the patent information has not been submitted to FDA. Paragraph II - That the patent has expired Paragraph III - That the patent will expire (on date of marketing) Paragraph IV - Patent is invalid, unenforceable or will not be infringed by manufacture, use or sale of generic drug. 7/2/2023
- 33. Bioequivalence: Ageneric drug is considered to be Bioequivalent to Branded Drug if, The rate & extent of absorption do not show a significant difference from listed drug or Extent of absorption does not show a significant difference in rate is intentional or not medically significant. NON EQUIVALENT 7/2/2023
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- 35. INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER (IMPD) AND ITS INVESTIGATION 7/2/2023
- 36. ➢Introduction to Dossier and Registration Dossier ➢Contents of the Dossiers ➢Goals of Dossiers ➢List of Dossier used in p’ceutical industries ➢Format of Dossier ➢Importance of effective Dossier management ➢What is IMPD? ➢Objective and General structure of IMPD ➢Types of IMPD ➢What IMPD shouldAccompany ➢References 7/2/2023
- 37. • Dossier: The word 'Dossier' has the english meaning as a collection or file of documents on the particular subject, especially a file containing detailed information about a person or a topic. • Example: Patient Medication Record(PMR) • Any formulation is prepared for human use or the benefit of the recipient is called as “Pharmaceutical product for human use”. • Process of critiquing and assessing the dossier of pharmaceutical product containing its detailed about administrative, chemistry, preclinical & clinical information and the permission granted by the regulatory agencies of a country with a view to support its marketing or approval in a country is called as “Marketing approval” or Registration Dossier. 7/2/2023
- 38. • “Registration Dossier” of the pharmaceutical product is a document that contains all technical data (administrative, quality, nonclinical, and clinical) of a pharmaceutical product to be approved / registered / marketed in a country. • It is more commonly called as New Drug Application (NDA) in the USA or Marketing Authorization Application (MAA) in European Union (EU) and other countries as simply Registration Dossier. • It is used for licensing approval/ market authorization of a drug. 7/2/2023
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- 40. • Is the drug safe and effective in its proposed use(s) when used as directed, and do the benefits of the drug outweigh the risks? •Is the drug’s proposed labelling appropriate, and what it contain? •Are the methods used in manufacturing (Good Manufacturing Practice, GMP) drug and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity? 7/2/2023
- 41. List of Common Dossiers which are used in Pharmaceutical Industries ● Following are the some common forms of Dossiers which are widely and commonly used in the pharmaceutical industries. 1. CTD Dossier. 2. e-CTD Dossier 3. ACTD Dossier 4. Country Specific Registration Dossier. 7/2/2023
- 42. The Dossier is submitted in the form of Common Technical Document i.e CTD The CTD is divided into five modules, in which the Module 1 (Administrative Information) is region specific and remaining all the four modules are common for all the regions. Following are the modules of CTD: Module 1: Administrative Module Module 2: CTD summary Module 3: Quality reports Module 4: Pre-Clinical study reports Module 5: Clinical study reports 7/2/2023
- 43. ● Below is the figure of the CTD dossier which shows the Modules 1-5 it is consider as one of the format of Dossier. 7/2/2023
- 44. The registration dossier for medicines is an important document which is submitted for review to regulatory agencies by pharma companies for approval to market their medicines. Utmost care should be taken during its compilation and filing as it plays a direct role in earliest possible availability of medicines in the market which in turn translates into business for the company. Regulatory affairs professionals need to ensure the safety, quality and efficacy of the medicines for which they are filing registration dossier. • Note : The dossiers could be anything among DMF , ASMF , ANDA, NDAor MAA. 7/2/2023
- 45. IMPD is an abbreviated term for investigational medicinal product dossier. IMPD resembles to the Module 3 of CTD in structure. IMPD is serve as a basis for approval of clinical trials by the competent authorities in the EU. The Clinical Trials Directive (2001/20/EC) came into force in April 2001, harmonizing the laws, regulation and administrative provision of member states relating to implementation of GCP in the conduct on medicinal products for human use. The directive introduced a harmonized procedure for the authorization to perform a clinical study in any one of the EU Member States. 7/2/2023
- 46. ● IMPD is file containing detailed information/records about particular drug product. ● IMPD is one of several pieces of investigational medicinal product (IMP) related data require whenever the performance of a clinical trail is intended in one or more EU member states. ● The IMPD includes summaries of information related to the Quality, Manufacture and Control of the any Investigational Medicinal Product (IMP) (including reference product and placebo) data from non-clinical studies and its clinical use. 7/2/2023
- 47. Objectives: Since Clinical trials are often be designed as multi- center studies, potentially involving different members states, it is the aim of this guideline to define harmonized requirements of the documentation to be submitted throughout the European Community. General Structure of IMPD: The IMPD has a single general structure which is common for both the types of IMPD : Quality Data (CMC) Non clinical pharmacological data and toxicological data Previous clinical trial data and human experience data Overall risk and benefit assessment. 7/2/2023
- 48. Following are the two types of IMPD: 1. Full IMPD 2. Simplified IMPD Full IMPD: When applying for clinical trial authorization, full IMPD is required when little or NO information about an IMP has been previously submitted to competent authorities. Simplified IMPD: A simplified IMPD may be submitted if information has been assessed previously as part of marketing authorization to competent authority. 7/2/2023
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- 51. • Covering letter • Application form • List of all CAs where application has been submitted • Copy of IEC approval or comments • Any letter of concern received from any MS • Copy of any scientific advice • Aletter of authorization for use when applicant is not the sponsor • Confirmation that CA will accept application in English • Informed consent form • Subject information ( if any) • Arrangement for recruitment of subjects • Protocol with any amendments • Summary of protocol in the national language • Peer review of trial if available • Ethical assessment by principal investigator • IB • Report of any trial with same IMP • Example of label in the national language 7/2/2023
- 52. ➢Swapna G, Bindu M, Anusha P, Rupa T, Mohini D,Venkkana ,B “comparitive study of dossier submission process for drug product in USA, EU, & “Indian regulatory”W.J. of Pharma RES. Volume 3, issue 6, 406-411. ➢RichardA,Guarino M.D. ,New DrugApproval Process fifth edition. 7/2/2023
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