INDA (INVESTIGATIONAL NEW DRUG APPLICATIONS)

INVESTGATIONAL NEW DRUG APPLICATIONS

1. Investigational New Drug Applications Prepared by ASHISH M.S. Pharmaceutics Dept. Of pharmaceutics NIPER-Raebareli

2. CONTENTS INDA-definition Why INDA required ? Types of INDA Contents of IND Resources of INDA INDA procedures overview FDA receipt of INDA INDA REVIEW Phases after INDA

3. Investigational new drug application-Definition Investigational New Drug (IND ) program is the means by which a  pharmaceutical company obtains permission to start human clinical trials and to ship an experimental drug  across state lines  (usually to clinical investigators) before a marketing application for the drug has been approved. The IND is the means through which the sponsor technically obtains this exemption from the FDA. Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines.

4. USFDA DRUG APPROVAL PROCESS

5. When INDA Required ? INDA is required if any pharmaceutical company wants to conduct clinical trails of an unapproved drug. INDA would be required to conduct clinical trails if the drug is New chemical entity , not approved for indication under investigation in new dosage form. Being administered at new dosage level. In combination with another drug which is not approved. All clinical studies where new drugs are administered to human subjects , regardless of the whether the drug is commercially developed , require an IND.

6. TYPES OF IND Investigator IND This is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.  A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population. 2) Emergency Use IND     It allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with  21CFR ,  Sec. 312.23  or Sec.  312.20 .  It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.

7. 3) Treatment IND This is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place .

8. CONTENTS OF INDA Animal Pharmacology and Toxicology Studies Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.  Also included are any previous experience with the drug in humans. Manufacturing Information Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.  This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.

9. Clinical Protocols and Investigator Information C ommitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations . Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials.  During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

10. Resources for IND Applications Pre-INDA Consultation Program   Done by CDER (center for drug evaluation and research)  to provide early communications between sponsors and new drug review divisions to provide guidance on the data necessary to warrant IND submission. Guidance Documents for INDs Guidance documents represent the Agency's current thinking on a particular subject. These documents provide FDA review staff and applicants/sponsors with guidelines to the processing, content, and evaluation/approval of applications and also to the design, production, manufacturing, and testing of regulated products.

11. Laws and Regulations Code of Federal Regulations (CFR) The CFR is divided into 50 titles that represent broad areas subject to Federal regulations. Section 21 of the CFR contains most regulations pertaining to food and drugs.  The regulations document all actions of all drug sponsors that are required under Federal law. The following regulations apply to the IND applications:

12. NUMBER REGULATIONS 21CFR Part 201 Drug Labelling 21CFR Part 312 Investigational New Drug Application 21CFR Part 314 INDA and NDA Applications for FDA Approval to Market a New Drug (New Drug Approval) 21CFR Part 316 Orphan drugs 21CFR Part 50 Protection of Human Subjects 21CFR Part 54 Financial Disclosure by Clinical Investigators 21CFR Part 56 Institutional Review Boards 21CFR Part 58 Good Lab Practice for Nonclinical Laboratory [Animal studies]

13. IND rewrite was published by FDA in 1987, which resulted in a logical flow of information. IND has 8 to 11 sections falling under four general areas- Animal pharmacology Manufacturing information on drug safety and drug product Clinical protocols Information on investigator qualifications

14. Overview of IND Application Procedures When submitting original IND applications, sponsors are expected to send their applications in triplicate (one original and two copies). Electronic submissions should be considered whenever possible. Each application should be accompanied by: Form 1571 (IND application cover) Form 1572  (Investigator’s statement) Form 3674 (certification requirement & mandatory registration and reporting of results for applicable clinical trials)

15. Pre-IND Meetings(21 CFR 312.82) Request must be submitted in writing (fax is fine) and should include: Description of product Description of clinical indication and approach Identification of purpose, objectives, and draft of specific questions Suggested dates and times for meeting Pre-IND meetings are scheduled within 60 days from receipt of request. FDA will respond to request within 14 days of receipt of request.

16. Meeting package must be submitted 4 weeks prior to meeting, includes: Pre-clinical data Product manufacturing scheme Data regarding product characterization/proposed specifications Proposed clinical protocol Specific questions grouped by discipline (product, pre-clinical, clinical). One hour formal meeting held by telephone unless unique situation. FDA issues official minutes to applicant within 30 days of formal meeting

17. Master File Submission(21 CFR 314.420) Alternative mechanism for submission of product & manufacturing information Does not include clinical protocol Permits holder to incorporate the information by reference when submitting an IND To authorize other persons to reference information, without direct disclosure.

18. How and where to Send the Application The initial IND submission and each subsequent submission to the IND should be accompanied by a Form FDA 1571 and must be submitted in triplicate (the original and two photocopies are acceptable). Initial IND submissions are done at For a Drug: Food and Drug Administration Center for Drug Evaluation and Research Central Document Room For a Therapeutic Biological Product: Food and Drug Administration Center for Drug Evaluation and Research Therapeutic Biological products control room  

19. FDA Receipt of the IND Upon receipt of the IND by FDA, an IND number will be assigned, and the application will be forwarded to the appropriate reviewing division. The reviewing division will send a letter to the Sponsor-Investigator providing notification of the IND number assigned, date of receipt of the original application, address where future submissions to the IND should be sent , and the name and telephone number of the FDA person to whom questions about the application should be directed.  Studies shall not be initiated until 30 days after the date of receipt of the IND by FDA unless you receive earlier notification by FDA that studies may begin.

20. IND Review Team Review team includes: Regulatory Project Manager Product Reviewer Pharmacology/Toxicology Reviewer Clinical Reviewer Statistical Reviewer If product includes a device or drug, consult reviewers from CDER are assigned if needed, during initial processing.

21. Clinical Holds (21 CFR 312.42) Hold : An order issued by FDA to delay a proposed clinical investigation or to suspend an ongoing investigation Once active, an IND may be placed on hold if the grounds listed under 21 CFR 312.42(b) are met. Partial Hold : A delay or suspension of part of the clinical work under an IND e.g. IND has 2 protocols, one may proceed & one may not.

22. Phases of Investigation after successful INDA Phase I Investigational Studies- Designed to evaluate safety and side effects Phase II Investigational Studies- Designed to evaluate efficacy and dose ranging Phase III Investigational Studies- Expanded study, additional information on efficacy and safety New Drug Application

23. REFERENCES https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application S.K. Gupta , Basic Principles of Clinical Research and Methodology , 1 st Edition , Jaypee Brothers Medical Publishers (P) Ltd.