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 What is INDA ?  Types of INDAs  Objectives of INDAs  Format & Contents of an INDA  IND Safety reports  IND Annual Reports  IND Review Process  Withdrawal of an IND  Inactive Status  References 2/33

What is INDA ? 3/33 (Fig. Flow chart illustrating the various steps in preclinical and clinical development of pharmaceutical Products)

 INDA is a vehicle through which a sponsor advances to the next stage of drug product development known as clinical trials (human trials).  It includes data and information in three broad areas: 1. Animal Pharmacology and Toxicology Studies 2. Manufacturing Information 3. Clinical Protocols and Investigator Information  The regulations in 21 CFR 312 cover procedures and requirements for Investigational New Drug Applications (INDAs).  These regulations define the roles and responsibilities of FDA reviewers, IND sponsors, and clinical investigators. 4/33

Sponsor  A sponsor is an individual, company, institution, or organization that takes responsibility for and initiates a clinical study (21 CFR 312.3(b), )  A sponsor is responsible for: Selecting qualified investigators Selecting qualified investigators Ensuring study monitoring Ensuring study monitoring Maintaining an effective IND, and Maintaining an effective IND, and Ensuring AE risk information is provided to the FDA and investigators Ensuring AE risk information is provided to the FDA and investigators 5/33

Investigator  An investigator is an individual under whose immediate direction the study drug is administered or dispensed. If a team is involved, the leader is the investigator; other team members are sub-investigators (21 CFR 312(b), ).  An investigator is responsible for : Ensuring the study is conducted according to the plan Ensuring the study is conducted according to the plan Protecting the rights, safety and welfare of subjects, and Protecting the rights, safety and welfare of subjects, and Control of drug under investigation Control of drug under investigation 6/33

Sponsor-Investigator  A sponsor-investigator is an individual who both initiates and conducts a study and under whose immediate direction the study drug is administered or dispensed. This person must follow the requirements pertaining to a sponsor and those pertaining to an investigator (21 CFR 312(b)). 7/33

1. Commercial INDs 2. Emergency use INDs 3. Treatment INDs 8/33

 To focus FDA’s attention during early phase of clinical research on assuring the safety of human test subjects.  To provide sponsors with a greater measure of flexibility in conducting Phase 1 trials.  To facilitate consultation between FDA & sponsors, especially after there is an indication that the new drug is safe and efficacious in humans. 9/33

 Cover Sheet (Form FDA 1571)  Table of Contents  Introductory Statement & General investigational plan  Investigator’s Brochure  Protocols  Chemistry, Manufacturing & Control Information  Previous Human Experience with the Investigational Drug  Additional Information 10/33

 Name of drug  Submission date  Sponsor identification  Phase of proposed clinical investigation  Sponsor commitments  Identification of clinical monitor and safety evaluator  Information regarding transfer of responsibilities to a contract research organization 11/33

Drug Name ® IND table of contents Item Title volume/page 3 Introductory statement & general investigational plan… 3 Introductory statement & general investigational plan… (i) Introductory statement…. (i) Introductory statement…. (ii) summary of previous human experience with drug……. (ii) summary of previous human experience with drug……. (iii) If the drug has been withdrawn from Investigation/ Marketing… (iii) If the drug has been withdrawn from Investigation/ Marketing… iv) General Investigational Plan….. 12/33

5 Investigator’s Brochure……. 6 Protocol…….. 7 Chemistry, Manufacturing & Control Information… (a) Drug substance………… (a) Drug substance………… (b) Drug Product……………. (b) Drug Product……………. (c) Placebo (if applicable)… (c) Placebo (if applicable)… (d) Labeling……………………. (d) Labeling……………………. (e) Environmental Analysis …. (e) Environmental Analysis …. 8 Pharmacology & Toxicology Information……. 13/33

9 Previous Human Experience with the Investigational Drug……. (i) Summary of Previous Human Experience…. (i) Summary of Previous Human Experience…. (ii) If the drug is a combination of drug previously investigated/ marketed……. (ii) If the drug is a combination of drug previously investigated/ marketed……. (iii) If the drug has been marketed outside the United States…… (iii) If the drug has been marketed outside the United States…… 10 Additional Information (as applicable for radioactive drugs or drugs with dependence or abuse potential)…. 14/33

It consists of four subsections: 1 st subsection: (Introductory statement)  Name of drug  P’cological Class  Structural formula  Route of administration  Broad objectives  Planned duration of the proposed clinical investigation 15/33

2 nd subsection:  Brief summary of any previous human experience with the drug, including investigational or marketing experience in other countries. 3 rd subsection:  It is a statement as to whether or not the drug has been withdrawn from investigation or marketing in any country for any reason of safety or efficacy. 16/33

4 th subsection:  Brief description of overall investigational plan for drug during the following year like: Indications to be studied, kinds of clinical trials to be conducted in first year. 17/33

 Sponsor must provide to all clinical investigators, not required for sponsor investigators (21 CFR ).  It must include:  Brief product description  Pharmacology/toxicology summaries  Previous human experience  Description of anticipated risk and any special monitoring needs  Updates as appropriate 18/33

Drug Name® Investigator's Brochure Table of contents Page Introduction…………………….. Chemistry………………………. Physical Properties…… How Supplied……………. Pharmacology…………………. Specific Effect Studies… General Studies…………. 19/33

Toxicology……………………….. Acute Toxicity……………. Multidose Toxicity………. Special Toxicity Studies……… Reproductive Studies…… Mutagenicity Studies……. Pharmacokinetics……………… Preclinical……………………. Clinical…………………………. Clinical Trial………………………. Phase 1………………………… Phase 2/3… …………………. 20/33

Safety/Efficacy Overview Safety………………………….. Efficacy……………………….. Possible Risks and Side Effects… References…………………………. 21/33

 Phase 1 protocol provides an outline of investigation by specifying information such as estimated number of test subjects, inclusion/exclusion criteria and dosing plan.  Phase 2 and Phase 3 protocols are detailed, describing all aspects of the studies, such that any deviation in a design if required, it can be established in the protocol from the beginning. 22/33

 Statement of the objectives and purpose of the study  Patient inclusion/exclusion criteria  Estimate of number of patients to be studied  Description of study design  Dosing information including planned maximum dosage and duration of individual patient exposure to the Drug  Description of the observations and measurements planned to fulfill the study objectives All the protocols are required to contain the following elements: 23/33

 Drug Substance Physical, chemical or biological characteristics of the drug substance, along with the name and address of the manufacturer Description of the general method of preparation, identification of the analytical methods and acceptable limits used to assure the identity, purity and strength of the drug substance Stability data must be sufficient to support the stability of drug substance throughout the preclinical and proposed clinical studies 24/33

 Drug Product Qualitative & Quantitative compositions Manufacturing facility, manufacturing and packaging procedure, identification of analytical methods, acceptable limits used to assure identity, purity, and strength of components and finished products Stability data to support duration of proposed clinical studies.  Labeling A copy of all labels and labeling to be provided to each clinical investigations must be submitted.  Environmental Analysis Identification and quantities of any chemical substances emitted during the manufacture of the product, use of resources and energy, etc. 25/33

26/33 Previous Human Experiences with the Investigational Drug Such findings if available must be submitted whether drug is marketed in U.S. or other foreign country. Additional Information  Any information that sponsor believes will aid in the evaluation of the application.  IND Amendments: Protocol Amendments Information Amendments

 If a sponsor notify any unexpected fatal / life threatening experience associated with the use of the drug requires to notify the FDA by telephone no later than 3 working days after receipt of the information, followed by a written report within 10 days. 27/33

(21 CFR )  To be submitted within 60 days of the anniversary of “in effect” date  Include enrollment, demographic and conduct status information for each study  Adverse event summaries (safety reports, deaths, dropouts)  Drug action information  Preclinical study status information 28/33

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 It is option of a sponsor to withdraw an IND at any time without prejudice.  On withdrawn, sponsor must notify the FDA. 30/33

 On sponsor’s request FDA may place an IND on inactive status if no subjects have entered clinical studies for at least two years or if the IND has been on clinical hold for at least one year.  After remaining on inactive status for five years, the FDA may terminate an IND. 31/33

1. 2.Remington the science and practice of pharmacy, 20th edition, Lippincott,Williams & Wilkins, page no: New Drug Approval Process: second Edition, Revised and Expanded, edited by Richard A. Guarino page no: 39-64, /33

Thanks to All