A Seminar on IND and NDA Process for New Drug Products

Presented by: AAFTAB ANWAR M.PHARM PHARMACOLOGY

Drug development process:

Challenging

and expensive activity of the pharmaceutical industry. 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.

With

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.

Preclinical

I N D

Clinical Development

NDA Review

Post-Marketing Adverse Reaction Reporting

Initial Synthesis

Phase I

Animal Testing

A P P L I C A T I O N

Phase II

Phase IV
Surveys/ Sampling Testing

Phase III Treatment Use

Range 1-3 Yrs. Avg:18 Mos.

FDA Time 30 Day Safety Review

Range 2-10 Yrs. Avg : 5 Yrs.

Inspections Range 2 Mon 7 Yrs. Avg:24 Mos.

NDA Submitted NDA Approved

Average of Approximately 100 Months From Initial Synthesis to Approval of NDA

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.

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.

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 2. Substantial evidence of efficacy 3. Informative labeling for the product
1.

Demonstration of manufacturing of the product to the desired strength, quality, purity and identity. 5. Signed agreement from investigators
4.

Essential Principle of an IND!!!

IND

must present adequate information to permit the FDA to evaluate the drugs 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!!!

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

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
Description of the investigational drug All active ingredients Drugs 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

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

Investigators 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

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

Pharmacology and Toxicology Data

Pharmacology and Drug Disposition

Integrated Toxicology Summary

Previous Human Experience

Marketed (foreign) or previously tested in humans

Drug Active ingredients

Must provide specific information relevant to FDAs evaluation

Catagories of IND :
1. 2.

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

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 FDAs 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.

Medical officer

chemist

pharmacologist

Consumer safety officer biostatistian microbiologist

Clinical pharmacologis t

Member of the FDAs review team for a drug regulatory application

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

Phase I clinical holds

Subject safety concerns

Phase II & III clinical holds

Concerns about safety or efficacy

IND review flow chart

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.

1)
2)

3)

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.

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)

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 AustraliaTherapeutic 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 EuropeThe 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 Agencys budget and work programme are approved by the Management Board.

Clinical Research Regulation in UKMedicine & 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.

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 IndiaDrug 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 .

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.

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. GEACs role is to assess the bio-safety /environmental safety aspect of the biotechnological product.

REFERENCES:

CDER Guidance: IND Application Process (interactive session) http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm

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