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A Seminar on IND and NDA Process for New Drug Products:

A Seminar on IND and NDA Process for New Drug Products Presented by: AAFTAB ANWAR M.PHARM PHARMACOLOGY

Drug development process::

Drug development process: Challenging and expensive activity of the pharmaceutical industry. With the advent of technologies in biological screening procedures of new chemical entities the time involved in drug discovery has gone down in recent years but the cost of drug discovery has touched a new high.

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Aim: 1. Develop clinically efficacious and safer drug 2. Economically viable , 3. Discover entirely new class of drug 4.Explore the mechanism / pharmacodynamic properties .

New Drug Development Process.:

New Drug Development Process. Initial Synthesis Animal Testing I N D A P P L I C A T I O N Phase I Phase II Phase III Phase IV Adverse Reaction Reporting Surveys/ Sampling Testing Inspections Range 1-3 Yrs. Avg:18 Mos. FDA Time 30 Day Safety Review Range 2-10 Yrs. Avg : 5 Yrs. NDA Submitted NDA Approved Range 2 Mon – 7 Yrs. Avg:24 Mos. Average of Approximately 100 Months From Initial Synthesis to Approval of NDA Treatment Use Preclinical Clinical Development NDA Review Post-Marketing

Introduction to the IND…!!!:

Introduction to the IND…!!! What is an IND…??? An IND is an Investigational New Drug application i.e. the documentation required for submission by the sponsor and clearance by the U.S. Food and Drug Administration (FDA) in order to use a drug product not previously authorized for marketing in the United States. The IND provisions apply to new drugs, new antibiotics and new biologics.

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When is an IND required…??? In general: An IND is required when an unapproved drug (or biologic) is used in a clinical investigation An IND is always required prior to initiation of a clinical study of an investigational new drug in the U.S. in addition an IND is require before initiation of a clinical study of the drug approved for some uses.

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What is the legal basis for an IND…??? The requirement for an investigational new drug application is define in the law governing development of new drugs in the U.S. i.e. the Federal Food ,Drug and Cosmetic Act (FD & C Act) The fundamental requirements of the FD & C Act for new drugs are as follows: Proof of safety Substantial evidence of efficacy Informative labeling for the product

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Demonstration of manufacturing of the product to the desired strength, quality, purity and identity. Signed agreement from investigators

Essential Principle of an IND…!!!:

Essential Principle of an IND…!!! IND must present adequate information to permit the FDA to evaluate the drug’s suitability for use in the proposed clinical study. The central focus of the initial IND should be the general investigational plan and the protocol for the first proposed human study. To assure that human subjects who participate in the proposed study will not be exposed to unreasonable and significant risk.

Content of an initial IND…!!!:

Content of an initial IND…!!! Form FDA 1572 Table of contents Introductory statement General investigational plan Investigators brochure Clinical protocols Chemistry, manufacturing and control data Pharmacology and toxicology data Previous human experience

The FDA Form “1572”:

The FDA Form “1572” IND sponsors are required to obtain a signed FDA Form “1572” from each clinical investigator, containing: Name and address of CI Name and code number of any protocol(s) Name and address of research facility and any clinical labs Names and addresses of responsible institutional review board (IRB) Names of sub-investigators Signed commitment by the investigator

Introductory Statement:

Introductory Statement Description of the investigational drug All active ingredients Drug’s pharmacological classification Structural formula Route of administration Summary of previous human experience. Formulation of the dosage forms. Objectives and planned duration of proposed clinical investigation

Investigational Plan:

Investigational Plan Description of clinical studies planned for the experimental drug Purpose for the drug or research study Indications to be studied Types of trials to be initiated Number of study subjects Risks

Investigator’s Brochure 21 CFR 312.23(5)(i)-(v):

Investigator’s Brochure 21 CFR 312.23(5)(i)-(v) Structural formula of drug Summary of pharmacological, toxicological, pharmacokinetic effects in animals Safety and effectiveness Reprints of related articles Purpose of study Dose/dose frequency Method of administration Monitoring procedures

Clinical Protocols :

Clinical Protocols FDA reviews protocols to Ensure subjects not exposed to any unnecessary risks Phase 2 and 3 studies designs are adequate to provide the type and amount of information Demonstrate effectiveness and safety Considered the most important part of the IND IND review of protocols is intended to evaluate safety of the drug Estimate number of subjects Describe safety Exclusion and Inclusion Describe dosing regimen

Chemistry, Manufacturing and Control Data (CMC):

Determine the adequacy of methods used to manufacture and assay investigational compound Safety concerns Describe drug substance Method of preparation Reagent and solvents Acceptable limits and analytical methods to ensure quality and purity of drug Chemistry, Manufacturing and Control Data (CMC)

Pharmacology and Toxicology Data:

Pharmacology and Toxicology Data Pharmacology and Drug Disposition Integrated Toxicology Summary

Previous Human Experience:

Previous Human Experience Marketed (foreign) or previously tested in humans Drug Active ingredients Must provide specific information relevant to FDA’s evaluation

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Catagories of IND : Commercial INDs - Goal is to obtained marketing approval for a new product. Non-commercial INDs – It include a) Investigator IND- In this case, the physician is both the sponsor and investigator. b) Emergency use IND- FDA authorize immediate dispensing of a non-approved drug in a life threatening situation when no standard acceptable therapy is available. c) Treatment IND- FDA will permit investigational drug to be used to treat a serious or life threatening disease, or if there is no comparable alternative drug available. ex-advanced cases of AIDS, herpes simplex encephalitis and subarachnoid hemorrhage.

Submission of the IND:

Submission of the IND Sponsor must submit Original Two copies Translation required Accurate and completed English translation for any information written in a foreign language Must submit original foreign language document on which translation was based


THIRTY DAYS FOR INTIAL INDs : The FDA must have time to review an initial IND before the investigation and the first clinical investigation is initiated. This review time is essential to protect the public health because the FDA must assure that. Based on the evidence of presented in the initial IND, it is reasonable for proceed with the first proposed clinical investigation.


FDA REVIEW OF INITIAL INDs: Initial INDs for investigational drugs are sent by the sponsor to the appropriate reviewer division of the FDA’s Center for Drug Evaluation and Research (CDER). INDs are assigned by therapeutic category to the relevant FDA reviewing division. A review team is assembled to work in multidisciplinary collaborative effort to review the IND . The review team consists of regulatory reviewer from each of technical disciplines plus review coordinator.

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Member of the FDA’s review team for a drug regulatory application Medical officer chemist pharmacologist biostatistian Clinical pharmacologist microbiologist Consumer safety officer

Nature of FDA review of the initial IND ::

Nature of FDA review of the initial IND : The IND contain sufficient information to allow reviewer to assess risk to human who will enter the proposed study. Humans will not be exposed to unreasonable or significant risk or illness or injury from the drug. The proposed clinical investigator is qualified training and experience to conduct the proposed study. The clinical investigators brochure in not misleading, erroneous or materially incomplete.

Clinical Holds To Delay/Suspend A Study:

Clinical Holds To Delay/Suspend A Study Phase I clinical holds Subject safety concerns Phase II & III clinical holds Concerns about safety or efficacy

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IND review flow chart

New Drug Application (NDA):

New Drug Application (NDA) NDA is an application submitted to the FDA for permission to market a new drug . To obtained this permission a sponsor submits preclinical and clinical test data to NDA for analyzing the drug information, description of manufacturing procedures.

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After NDA received by the agency, it undergoes a technical screening .This evaluation ensure that sufficient data and information have been submitted in each area to justify “filing” the application that is FDA formal review. At the conclusion of FDA review of an NDA, there are 3 possible action that can sent to sponsor : Not approvable- in this letter lists of deficiencies and explain the reason. Approvable- it means that the drug can be approved but minor deficiencies that can be corrected like-labeling changes and possible request commitment to do post-approval studies. Approval- it state that the drug is approved.

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If the action taken is either an approvable or a not approvable, if not FDA provides applicant with an opportunity to meet with Agency and discuss the deficiencies .

Abbreviated New Drug Application (ANDA) & Abbreviated Antibiotic Drug Application (AADA):

Abbreviated New Drug Application (ANDA) & Abbreviated Antibiotic Drug Application (AADA) An ANDA & AADA is submitted to FDA office of Generic Drug to obtained the approval to market a generic drug product. A generic drug is one of that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use. Review of data. ANDA/AADA Approved- After review of data of an AND application , an approval letter may be issued to the applicant detailing the condition of approval and providing them with the ability to market the generic drug product.

Clinical Research Regulation in Australia-Therapeutic Good Administration (TGA):

Clinical Research Regulation in Australia-Therapeutic Good Administration (TGA) TGA regulate the registration and marketing of all drugs and medical devices in Australia, as well as conduct of clinical trails and compassionate use of unregistered drugs. Institutional Ethics Committee (IEC) is responsible for giving the approval to do the clinical trail study. The trail must be approved by both the TGA and IEC.

Clinical Research Regulation in Europe- The European Agency for the Evaluation of Medicinal Products (EMEA):

Clinical Research Regulation in Europe- The European Agency for the Evaluation of Medicinal Products (EMEA) The EMEA is a decentralized body of the European Union. It has its headquarters in London since January 1995. Its main responsibility is the protection and promotion of public and animal health. It has about 360 staff member in 2004. The Executive director is head of the EMEA. The Agency’s budget and work programme are approved by the Management Board.

Clinical Research Regulation in UK-Medicine & Healthcare Products Regulatory Agency (MHRA):

Clinical Research Regulation in UK-Medicine & Healthcare Products Regulatory Agency (MHRA) The UK drug agency is the MHAR which replaced the Medical Devices Agency (MDA) and the Medicines Control Agency (MCA) in April 2003. The MHRA is the component authority for medical devices and the Licensing Authority for pharmaceutical advised by Committee on Safety of Medicines (CSM). Key activities of MHRA:- 1.Regulating medical devices. 2.Licensing of medicines before marketing & subsequent variation. 3.Regulation of clinical trails. 4.Issuing safety warning.

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5.Monitoring of medicines and acting on safety concern after marketing, 6.Evaluating medical devices to inform purchasing and encourage safe use. 7.Maneging the General Practice Research Database (GPRD). 8.Setting quality standard for drug substance through the “British Pharmacopoeia”. 9.Providing advice and guidance on medicines and medical devices.

Clinical Research Regulating in India- Drug Controller General of India (DCGI) :

Clinical Research Regulating in India- Drug Controller General of India (DCGI) The office of DCGI runs under Central Drug Standard Control Organization. It has main responsibility of regulating clinical trials in India. Matters related to product approval and standards , clinical trials , introduction of new drug , and import licenses of new drugs are handled by DCGI .

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Drugs Technical Advisory Board(DTAB) It has technical experts and these advices the central and state governments on all technical matters arising out of the enforcement of drug control. No rules can be made by the central government without consulting DTAB board.

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Drugs Consultative Committee: It has central and state drug control official as members. Its main function is to ensure the drug control measures and enforce them uniformly over all the states. Genetic Engineering approval Committee (GEAC): It is authority to approve rDNA pharmaceuticals products. GEAC’s role is to assess the bio-safety /environmental safety aspect of the biotechnological product.


REFERENCES: CDER Guidance: IND Application Process (interactive session) A Review for OCRA US RAC Study Group September 2005, Ginger Clasby, MS, Promedica International European journal of pharmacology. Crystal clinical services (regulatory affairs) modules 3

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