1. 7/2/20161 Investigational New Drug Application (INDA) PRESENTED BY:- Dillip Kumar Jena Dept of pharmaceutics & pharmaceutical Technology LMCP

2. 7/2/20162 WHAT I WILL TELL INTRODUCTION REGULATORY ASPECT TYPE OF IND REQUIERMENT IND CONTENT OF IND IND AMENDMENT ANNUAL REPORT OF IND CONCLUSION

3. 7/2/20163 What is INDA General introduction this data and information is generated and gathered from three broad areas: Animal P’cology & Toxicology studies Manufacturing information Clinical Protocols & Investigator Information

4. 7/2/20164 Regulation The regulations in 21 CFR 312 cover procedures and requirements for Investigational New Drug Applications (INDs) These regulations define the roles and responsibilities of FDA reviewers, IND sponsors, and clinical investigators

5. 7/2/20165 Definitions Sponsor A sponsor is an individual, company, institution, or organization that takes responsibility for and initiates a clinical study (21 CFR 312.3(b), 312.50)

6. 7/2/20166 Sponsor A sponsor is responsible for: Selecting qualified investigators Ensuring study monitoring Maintaining an effective IND, and Ensuring AE risk information is provided to the FDA and investigators

7. 7/2/20167 Definitions 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), 312.60)

8. 7/2/20168 Investigator An investigator is responsible for: Ensuring the study is conducted according to the plan Protecting the rights, safety and welfare of subjects, and Control of drug under investigation

9. 7/2/20169 Definitions 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))

10. 7/2/201610 IND Requirements

11. 7/2/201611 IND Requirements (cont’d) For a lawfully marketed product, no IND submission is required if three specific conditions apply (21 CFR 312.2) –The study is not intended to support a new indication or labeling change –The study does not intend to support a change in advertising –The study does not involve a route, dosage or patient population, etc. that increases risk

12. 7/2/201612 NOTE! The FDA may be aware of other studies that may affect evaluation of potential risk, and the FDA is subject to confidentiality requirements and by law can not share this specific information with others

13. 7/2/201613 TYPE OF IND 1.Commercial IND 2.Emergency use IND 3.Treatment IND

14. 7/2/201614 Objective 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.

15. 7/2/201615 IND Content Requirements 21 CFR 312.23 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

16. 7/2/201616 Cover Sheet (form FDA 1571) The form is provided for basic information like 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.

17. 7/2/201617 Table of Contents Table of Contents Drug Name ® IND table of contents Item title volume/page Introductory statement & general investigational plan… (i) Introductory statement…. (ii) summary of previous human experience with drug……. (iii) If the drug has been withdrawn from Investigation/Marketing……

18. 7/2/201618 iv) General Investigational Plan….. 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…….

19. 7/2/201619 9)Previous Human Experience with the Investigational Drug……. (i) Summary of Previous Human Experience…. (ii) If the drug is a combination of drug previously investigated/marketed……. (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)….

20. 7/2/201620 Introductory Statement & General Investigational Plan : 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

21. 7/2/201621 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

22. 7/2/201622 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

23. 7/2/201623 Investigator’s Brochure (IB) Sponsor must provide to all clinical investigators, not required for sponsor investigators (21 CFR 312.55). It must include: –Brief product description –Pharm/tox summaries –Previous human experience –Description of anticipated risk and any special monitoring needs –Updates as appropriate

24. 7/2/201624 Drug Name® Investigator's Brochure Table of contents Page Introduction…………………….. Chemistry………………………. Physical Properties…… How Supplied……………. Pharmacology…………………. Specific Effect Studies… General Studies………….

25. 7/2/201625 Toxicology……………………….. Acute Toxicity……………. Multidose Toxicity………. Special Toxicity Studies……… Reproductive Studies…… Mutagenicity Studies……. Pharmacokinetics……………… Preclinical……………………. Clinical…………………………. Clinical Trial………………………. Phase 1………………………… Phase 2/3… ………………….

26. 7/2/201626 Safety/Efficacy Overview Safety………………………….. Efficacy……………………….. Possible Risks and Side Effects… References………………………….

27. 7/2/201627 Introductory Content Elements Cover Sheet (Form FDA 1571) Table of Contents Introductory Statement (description of product, formulation, route, broad study objectives, relevant previous use, foreign experience) General Investigational Plan (rationale, indication, general approach, anticipated studies including number of subjects and possible risks)

28. 7/2/201628 5 Protocols 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.

29. 7/2/201629 All the protocols are required to contain the following elements: 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

30. 7/2/201630 CMC Information Emphasis in Phase I is on identification and control of raw materials and new drug substance, including information on any placebo as well Even for Phase I, need enough information to assess safety Extent of expected information increases as drug development proceeds Throughout product development, good documentation of all manufacturing and testing steps is essential Deficiencies in CMC information can result in clinical hold

31. 7/2/201631 Pharm/Tox Information Animal studies may be conducted to obtain proof of concept or tox information Studies should support proposed clinical dose and regimen Best to get CBER concurrence on pivotal tox protocols prior to initiation Need to submit complete study reports for tox studies, including summary and individual animal data

32. 7/2/201632 Other IND Items Previous human experience needs to be included (if applicable) Additional information such as pre- IND meeting minutes or critical references should be included as well Serial numbering of pages of an IND is required (21 CFR 312.23(11)(e)) as this facilitates reference if the FDA has questions

33. 7/2/201633 IND Protocol Amendments 21 CFR 312.30 A new protocol Safety or design related changes to an existing protocol New investigator (notification is required within 30 days of being added) These should be submitted to the FDA prior to implementation IRB approval is needed prior to implementation

34. 7/2/201634 IND Information Amendments 21 CFR 312.31 Information amendments advise the FDA of: New tox, CMC or other technical information Notice of discontinuance of a clinical study

35. 7/2/201635 IND Safety Reports: 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.

36. 7/2/201636 Annual Reports 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

37. 7/2/201637 Annual Reports (cont’d) CMC change information Revised/updated investigator brochure with revisions described Foreign marketing experience Outstanding business with the FDA

38. 7/2/201638 Annual Reporting of Adverse Events RECOMMENDATIONS For solicited events – tabulate by study, study group and severity For unsolicited events use a line listing by study SAEs should be highlighted and discussed Include numerators and denominators Include cumulative cross-study, multi-year summaries Include all events regardless of attribution of relatedness to study drug

39. 7/2/201639 Specific Responsibilities of Sponsors Selecting qualified investigators and monitors (21 CFR 312.53) Obtaining investigator information (signed Form FDA 1572 and CV) Controlling shipment of drug – only to participating investigators Obtaining clinical protocol information Obtaining financial disclosure information Providing each investigator an investigator brochure (21 CFR 312.55) Informing investigators of new safety observations (see 21 CFR 312.32 on IND safety reports)

40. 7/2/201640 Specific Responsibilities of Sponsors Review ongoing investigations (21 CFR 312.56) Monitor study progress for compliance with protocol Dealing with noncompliant investigators Review and report to FDA safety and effectiveness data (annual reports and IND safety reports)

41. 7/2/201641 Specific Responsibilities of Sponsors Maintenance of adequate records (21 CFR 312.57) including: –Tracking of drug shipment and information –Recording financial interest of investigators –Keeping records for 2 years post approval or post last IND drug shipment –Retention of reserve samples and standards for certain tests Providing FDA with records upon request (21 CFR 312.58) Proper disposition of unused investigational drug (21 CFR 312.59)

42. 7/2/201642 Specific Responsibilities of Investigators Control administration of investigational drug (21 CFR 312.61) Provide qualification and study conduct information to sponsor Following the protocol (commitment to this required per Form FDA 1572) Maintenance of records (21 CFR 312.62) including: –Drug disposition –Case histories (CRFs, ICFs, medical records) –Keeping records for 2 years post approval or post study discontinuation

43. 7/2/201643 Withdrawal of an IND It is option of a sponsor to withdraw an IND at any time without prejudice. On withdrawn, sponsor must notify the FDA.

44. 7/2/201644 Conclusions Two major outcomes from the IND discussion are: 30 days after an IND is submitted to the FDA, if the sponsor has not heard anything from the FDA it can be assumed that the drug is not on a clinical hold and clinical trials may be started The Investigator’s Brochure, which will be used during that important first clinical study and in every clinical study thereafter, acts as the approved labeling for the drug while it is under an IND

45. 7/2/201645 List of references 1.www.fda.gov/cder/about/history/time1.ht mwww.fda.gov/cder/about/history/time1.ht m 2.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.htmwww.fda.gov/cder/handbook/indbox.htm 5.www.fda.gov/cder/handbook/ndabox.htm 6.www.fda.govwww.fda.gov

46. 7/2/201646

47. 7/2/201647 Specific Responsibilities of Investigators Reports to sponsor (21 CFR 312.64) –Providing progress reports for IND annual report –Promptly reporting safety concerns –Provision of final report after study completion –Providing financial disclosure information Assuring IRB review (21 CFR 312.66) Providing FDA with records upon request (21 CFR 312.68)