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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

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What is INDA ?

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(Fig. Flow chart illustrating the various steps in preclinical and clinical development of pharmaceutical Products)

INDA is a vehicle through which a sponsor advances INDA is a vehicle through which a sponsor advances to the next stage of drug product development to the next stage of drug product development known as clinical trials (human trials) .known as clinical trials (human trials) .

It includes data and information in three broad areas:It includes data and information in three broad areas:1.1. Animal Pharmacology and Toxicology StudiesAnimal Pharmacology and Toxicology Studies2.2. Manufacturing InformationManufacturing Information3.3. Clinical Protocols and Investigator InformationClinical Protocols and Investigator Information

The regulations in 21 CFR 312 cover procedures and The regulations in 21 CFR 312 cover procedures and requirements for Investigational New Drug requirements for Investigational New Drug Applications (INDAs) .Applications (INDAs) .

These regulations define the roles and These regulations define the roles and responsibilities of FDA reviewers, IND sponsors, and responsibilities of FDA reviewers, IND sponsors, and clinical investigators .clinical investigators .

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Sponsor

A sponsor is an individual, company, institution, or A sponsor is an individual, company, institution, or organization that takes responsibility for and initiates a organization that takes responsibility for and initiates a clinical study (21 CFR 312.3(b), 312.50)clinical study (21 CFR 312.3(b), 312.50)

A sponsor is responsible for:A sponsor is responsible for: Selecting qualified investigatorsSelecting qualified investigators Ensuring study monitoringEnsuring study monitoring Maintaining an effective IND, andMaintaining an effective IND, and Ensuring AE risk information is provided to the FDA and Ensuring AE risk information is provided to the FDA and

investigatorsinvestigators

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Investigator

An investigator is an individual under whose immediate An investigator is an individual under whose immediate direction the study drug is administered or dispensed. direction the study drug is administered or dispensed. If a team is involved, the leader is the investigator; If a team is involved, the leader is the investigator; other team members are sub-investigators other team members are sub-investigators (21 CFR 312(b), 312.60) .(21 CFR 312(b), 312.60) .

An investigator is responsible for :An investigator is responsible for : Ensuring the study is conducted according to the planEnsuring the study is conducted according to the plan Protecting the rights, safety and welfare of subjects, Protecting the rights, safety and welfare of subjects,

andand Control of drug under investigationControl of drug under investigation

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Sponsor-Investigator

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

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1.1. Commercial INDsCommercial INDs

2.2. Emergency use INDsEmergency use INDs

3.3. Treatment INDsTreatment INDs

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To focus FDA’s attention during early phase of To focus FDA’s attention during early phase of clinical research on assuring the safety of clinical research on assuring the safety of human test subjects.human test subjects.

To provide sponsors with a greater measure of To provide sponsors with a greater measure of flexibility in conducting Phase 1 trials.flexibility in conducting Phase 1 trials.

To facilitate consultation between FDA & To facilitate consultation between FDA & sponsors, especially after there is an sponsors, especially after there is an indication that the new drug is safe and indication that the new drug is safe and efficacious in humans.efficacious in humans.

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Cover Sheet (Form FDA 1571)Cover Sheet (Form FDA 1571) Table of ContentsTable of Contents Introductory Statement & General investigational Introductory Statement & General investigational

planplan Investigator’s BrochureInvestigator’s Brochure ProtocolsProtocols Chemistry, Manufacturing & Control InformationChemistry, Manufacturing & Control Information Previous Human Experience with the Previous Human Experience with the

Investigational Drug Investigational Drug Additional InformationAdditional Information

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Name of drugName of drug Submission dateSubmission date Sponsor identificationSponsor identification Phase of proposed clinical investigationPhase of proposed clinical investigation Sponsor commitmentsSponsor commitments Identification of clinical monitor and safety Identification of clinical monitor and safety

evaluator evaluator Information regarding transfer of responsibilities Information regarding transfer of responsibilities

to a contract research organizationto a contract research organization

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Drug NameDrug Name®®

IND table of contentsIND table of contentsItem Title Item Title

volume/pagevolume/page 33 Introductory statement & general investigational plan… Introductory statement & general investigational plan… (i) Introductory statement….(i) Introductory statement…. (ii) summary of previous human experience with (ii) summary of previous human experience with

drug…….drug……. (iii) If the drug has been withdrawn from Investigation/ (iii) If the drug has been withdrawn from Investigation/

Marketing…Marketing…iv) iv) General Investigational Plan…..General Investigational Plan…..

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5 Investigator’s Brochure…….5 Investigator’s Brochure…….6 Protocol……..6 Protocol……..7 Chemistry, Manufacturing & Control 7 Chemistry, Manufacturing & Control Information…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 8 Pharmacology & Toxicology Information…….Information…….

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99 Previous Human Experience with the Investigational Previous Human Experience with the Investigational Drug…….Drug…….

(i) Summary of Previous Human Experience….(i) Summary of Previous Human Experience…. (ii) If the drug is a combination of drug previously (ii) If the drug is a combination of drug previously

investigated/investigated/ marketed…….marketed……. (iii) If the drug has been marketed outside the (iii) If the drug has been marketed outside the

United States……United States……

10 Additional Information (as applicable for 10 Additional Information (as applicable for radioactive drugs or drugs with dependence or radioactive drugs or drugs with dependence or abuse potential)….abuse potential)….

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It consists of four subsections:It consists of four subsections:

11stst subsection subsection: (Introductory statement): (Introductory statement) Name of drugName of drug P’cological ClassP’cological Class Structural formulaStructural formula Route of administrationRoute of administration Broad objectivesBroad objectives Planned duration of the proposed clinical Planned duration of the proposed clinical

investigationinvestigation

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2nd subsection:

Brief summary of any previous human experience with the drug, including investigational or marketing experience in other countries .

3rd 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 .

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44thth subsection: 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.

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Sponsor must provide to all clinical investigators, not required for sponsor investigators (21 CFR 312.55).

It must include: Brief product description Pharmacology/toxicology summaries Previous human experience Description of anticipated risk and any special

monitoring needs Updates as appropriate

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Drug Name®Investigator's Brochure

Table of contentsPage Introduction……………………..Chemistry………………………. Physical Properties…… How Supplied……………. Pharmacology…………………. Specific Effect Studies… General Studies………….

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Toxicology……………………….. Acute Toxicity……………. Multidose Toxicity………. Special Toxicity Studies………

Reproductive Studies…… Mutagenicity Studies…….Pharmacokinetics……………… Preclinical……………………. Clinical………………………….Clinical Trial………………………. Phase 1………………………… Phase 2/3… ………………….

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

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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. 22/3

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Statement of the objectives and purpose of the Statement of the objectives and purpose of the study study

Patient inclusion/exclusion criteriaPatient inclusion/exclusion criteria Estimate of number of patients to be studied Estimate of number of patients to be studied Description of study designDescription of study design Dosing information including planned maximum Dosing information including planned maximum

dosage and duration of individual patient dosage and duration of individual patient exposure to the Drugexposure to the Drug

Description of the observations and Description of the observations and measurements planned to fulfill the study measurements planned to fulfill the study objectivesobjectives

All the protocols are required to contain the following elements:

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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

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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.

LabelingA 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. 25/3

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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.

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(21 CFR 312.33) 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

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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.

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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.

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1.www.fda.gov/cder/about/history/time1.htm2.Remington the science and practice of

pharmacy, 20th edition, Lippincott,Williams & Wilkins, page no: 930-943

3. New Drug Approval Process: second Edition, Revised and Expanded, edited by Richard A. Guarino page no: 39-64, 243-263

4.www.fda.gov/cder/handbook/indbox.htm5.www.fda.gov/cder/handbook/

ndabox.htm6.www.fda.gov

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Thanks to All