Investigational New Drug (IND) Orientation Responsibilities of IND Sponsor-Investigators

1. Investigational New Drug (IND) OrientationResponsibilities of IND Sponsor-Investigators MICHR IND/IDE Assistance Program (MIAP)

2. Definitions • Sponsor is an individual, company, academic institution, or other organization that takes responsibility for and initiates a clinical investigation. The sponsor is not the “funding organization” by FDA definitions. • Investigator is an individual under whose immediate direction a drug is administered or dispensed • Sponsor-Investigator is an individual who both initiates and conducts an investigation. The requirements/responsibilities under this part include both those applicable to an investigator and a sponsor.

3. APPLICABLE REGULATIONS • The Federal Food, Drug, and Cosmetic Act (FD&C Act) gives the FDA authority to regulate drugs and biologics • Code of Federal Regulations (CFR) • 21 CFR Part 312: Investigational New Drugs • Contains procedures and requirements governing the use of investigational new drugs • Applies to all clinical investigations of products that are subject to section 505 of the FD&C Act • Website for INDs: • IND Regulations

4. Regulations 21 CFR §11 Electronic Records; Electronic Signatures 21 CFR §50 FDA (21 CFR) Protection of Human Subjects 21 CFR §54 Financial Disclosure by Clinical Investigators 21 CFR §56 Institutional Review Boards 21 CFR §58 Good Laboratory Practices 21 CFR §211, § 810 Good Manufacturing Practices 21 CFR §1271 Good Tissue Practices

5. Regulations Investigational Application 21 CFR §312 IND Drugs and Biologics 21 CFR §812 IDE Devices 21 CFR §809 IVD In Vitro Diagnostics Marketing Application 21 CFR §601 BLA Biologics 21 CFR §314 NDA Drugs 21 CFR §814 PMA Devices

6. Good Clinical Practice (GCP) www.fda.gov/oc/gcp/ GCP is a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials. Not Law, but FDA has adopted GCP. (follow them…)

7. FDA RESPONSIBILITIES OF IND INVESTIGATORS • Conduct study in compliance with GCP, protocol, & applicable IND/IDE regulations • Ensure informed consent of each subject is obtained (and retained) • Personally conduct or supervise the investigation • Protect the rights, safety, and welfare of participants • Ensure adequate medical care for the study participants • Obtain necessary approvals from IRB • Maintain and retain drug/device disposition and patient case history records • Provide written reports to the IRB, as required • Ensure changes are not implemented without prospective IRB/FDA approval • Promptly report serious adverse events to the sponsor, IRB, and FDA • Furnish Progress reports and Safety reports • Ensure all study team members are informed about their obligations noted above

8. FDA RESPONSIBILITIES OF IND SPONSOR-INVESTIGATORSIN ADDITION TO THE INVESTIGATOR RESPONSIBILITIES,SPONSOR-INVESTIGATORS ARE REQUIRED TO: • Select qualified investigators at other institutions for multi-site trials • Provide information to other investigators and study staff to ensure that the study is performed properly • Ensure proper monitoring of the study • Ensure the study is performed in accordance with the general investigational plan and protocol • Submit necessary amendments/supplements to FDA • Ensure that FDA and all participating investigators are promptly informed of significant new adverse effects or risks • Maintain adequate records • Maintain proper control of the study drug/device

9. FDA Form 1571 (CFR 21 §312.23(a)(1)(i-ix)) • Contractual agreement between sponsor and FDA • Contains name of person responsible for conduct and progress of the study (Item 15) • Contains name of person responsible for the review and evaluation of information relevant to the safety of the drug (Item 16) • Sponsor or sponsor’s authorized representative agrees to conduct investigation in accordance with all applicable regulatory requirements (Item 17)

10. FDA Form 1571

11. FDA Form 1571

12. IND Maintenance(IND Amendments) • IND Amendment (Documents submitted to an active IND) • The 4 major types are… • Protocol Amendments (21 CFR §312.30) • Information Amendments (21 CFR § 312.31) • IND Safety Reports (21 CFR § 312.32) • IND Annual Reports (21 CFR § 312.33)

13. FDA Submissions - Responsibilities To FDA

14. Amendments - New Protocol • New study that is not covered by a protocol already contained in the IND • Must submit the new protocol to the FDA • The new protocol can begin after both conditions have been met: • The protocol has been approved by the IRB • The sponsor has submitted the protocol to the FDA for its review • There is no need to wait for the 30 day review period at the FDA unless we have specifically asked the FDA for advice on the protocol content • Contact MIAP early to discuss regulatory strategy

15. Amendments - Changes in a Protocol • A sponsor shall submit a protocol amendment describing any change in a Phase I protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study • Examples: • Any increase in drug dosage or duration of exposure of any individual subjects • Any significant increase in the number of subjects under study • Any significant change in the design of a protocol (the addition or dropping of a control group) • The addition of a new test, or procedure, that is intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety

16. Amendments – Changes in a protocol (continued) • A protocol change may be implemented provided the following two conditions are met: • The change has been approved by the IRB with responsibility for review and approval of the study • The sponsor has submitted the change to FDA for its review • No need to wait 30 days unless we have specifically asked for feedback • Contact MIAP early in process to discuss regulatory strategy • IRB Minor Amendment: URGENT REQUEST • PLEASE contact MIAP immediately when starting this process

17. Amendments – Changes in Protocol (continued) • Documents required to submit to the FDA • Summary of Changes Document for protocol • Tracked changed version of protocol • Clean version of protocol • Tracked changed version of informed consent document • Clean version of informed consent document

18. Amendments – New Investigator • A sponsor shall submit a protocol amendment when a new investigator is added to carry out a previously submitted protocol • The sponsor shall notify FDA of the new investigator within 30 days of the investigator being added • Try to group new investigators/and or sites together • Also includes new lab, new clinic • Can submit together with a change in protocol or new protocol submission • Required paperwork • Form 1572 • Investigator CV – signed and dated on first page

19. FDA Form 1572

20. FDA Form 1572

21. Amendments – Information • New toxicology, chemistry, or other technical information • New Investigator’s Brochure • Submit at the time of change, but, to the extent feasible, not more than every 30 days • Can submit with protocol amendment or new investigator amendment

22. IND Safety Report • Unexpected fatal or life threatening suspected adverse reactions • Must submit to the FDA within 7 calendar days of receiving the notification • Complete MedWatch 3500 A • Follow-up reports must be submitted as soon as possible • Unexpected serious suspected adverse reactions • Must submit to the FDA within 15 calendar days of receiving the notification • Complete MedWatch 3500A • Follow-up reports should be submitted within 15 days of receiving the first notification (not required if 7 day report is complete) • If FDA requests any additional data or information, the sponsor must submit it to the FDA as soon as possible, but no later than 15 calendar days after receiving the request • Contact MIAP if the IRB (at any site) disagrees with the Sponsor-Investigator assessment of attribution and causality

23. Safety Reporting Via MedWatch How to report Patient/Subject Product info (drug, biologic, device, etc.) Description of Event or Problem Relevant tests/labs Reporter

24. Annual Report • Due to the FDA within 60 calendar days of the IND Anniversary Date (date IND was deemed “safe to proceed”) • MIAP will contact study coordinator and PI approximately 60 days before the report is due to obtain required information • Patient demographics • Study information (number of patients enrolled, number of sites, etc.) • Adverse events • Any other new information • MIAP will complete the annual report template and send to study coordinator and PI to review • MIAP will send final annual report to the FDA • Upload FDA annual report into eResearch application (ORIO)

25. Monitoring theTrial • Clinical Trial Monitoring is required for clinical trials conducted under an IND • Clinical Trial Monitorexamines quality of trial conduct: • Perform on-site (if indicated, also off-site) evaluations of trial-related activities • Identify deviations in protocol conduct • Review documents for Adverse Events • Drug accountability – see also handout of IDS monitoring • Extent and frequency of monitoring as appropriate: • Length, complexity, subject enrollment and other aspects of the trial

26. MonitoringtheTrial: DSMB • Additional measure of human subject protection • Evaluates accumulating data from a clinical trial • Generally, established by the sponsor • Select members, should be independent • Charter generally written by sponsor, may have consultation by members • Recommendations regarding the conduct and design of the trial (safety and efficacy) • Does not visit sites or substitute for clinical trial monitors • Send DSMB reports to the IRB for review

28. The FDA Calls – now what? • Make immediate internal notifications • IRB • Regulatory Affairs • MIAP • Review UMHS Policy 01-01-020 “External/Third Party Reviews • IRBMED ORIO Reporting • “As soon as possible after notification of the audit and prior to a site visit by an external oversight entity (e.g. sponsor, FDA). For FDA audits, you should also call the IRBMED Office

29. Most Common Violations Noted by the FDA • Failure to follow the protocol • example: Required testing is incomplete • Recordkeeping errors • Informed consent problems/issues

30. Most Significant Violations noted by the FDA • Enrollment of ineligible subjects • Violation of protocol affecting safety • Extensive data corrections and questionable changes • Inadequate oversight of study personnel • Inappropriate delegation of authority • Poor oversight of sites • No Informed consent • Failure to communicate with IRB

32. If you are doing something in eResearch then it may need to be reported to the FDA! Contact MIAP. Protocol deviations – dosing errors, safety reasons Lapse in IRB Approval Urgent Amendment request Addition of new site Adverse event

33. Add MIAP lead as a study team member in eResearch • Add as administrative staff • Question 1.6 NO to edit right • Question 1.7 YES to include this person on all correspondence

34. MIAP Established to Provide Comprehensive: • Regulatory Expertise… • Regulatory Support… • Regulatory Education Services… To Faculty Investigators and their Team Involved In FDA Regulated Clinical Research At The University of Michigan

35. MIAP SERVICES OVERVIEW • Agent/Device development strategy consultation • IND/IDE consultation including determination of need for IND or IDE • Pre-IND FDA meeting requests and support • Protocol development • IND/IDE application preparation and submission • Clinical hold response preparation/submission • Communication with the FDA, IRB and other regulatory bodies • IND/IDE “maintenance” support • Safety report submissions • Protocol amendments to the FDA • Annual reports to the FDA • Clinical Trial Monitoring • Investigators meetings • Site initiation visits • Interim site monitoring visits • Study close out activities

36. MIAP Activities FY 2012 • Supported 31 active INDs (representing 34 active clinical study protocols) and 2 IDEs • Submitted 21 new IND applications and 2 new IDE applications to the FDA • Submitted 5 single-patient (expanded access) INDs and 2 emergency use IDEs to the FDA • Submitted over 110 IND/IDE life-cycle maintenance submissions to the FDA • Submitted 10 IND exemption requests to the FDA • Submitted 3 pre IND/IDE meeting packages to the FDA

37. MIAP is here to help with INDs and IDEs MIAP contacts: Kevin Weatherwax, BS, CCRC, CCRA Manager, MICHR IND/IDE Assistance Program (MIAP) Michigan Institute for Clinical and Health Research (MICHR) University of Michigan Health System NCRC Bldg # 400 2800 Plymouth Road Ann Arbor, MI 48109-2800 Phone: 734-998-6275 Pager: 734-936-6266, #9912 Fax: 734-998-7318 Website: www.MICHR.umich.edu kweath@med.umich.edu

38. MIAP contacts (cont’d): MICHR/MIAP CLINICAL RESEARCH PROJECT MANAGERS: Mona Moore, MS, RAC Bill Reisdorph, MS, CQA, RAC Phone: 734-998-7818 Phone: 734-998-8427 monamoor@med.umich.edureisdorp@med.umich.edu Jeanne Wright, RN, BSN, MT, CCRP, RAC E. Mitchell Seymour, PhD, RAC Phone: 734-998-7598 Phone: 734-998-6421 jeanburn@med.umich.eduseymoure@med.umich.edu MIAP TEAM Shared group e-mail for documents: MICHRMIAP@med.umich.edu

39. Office of Human Research Compliance Review (OHRCR) Director Ron Maio, D.O., M.S., Professor, Department of Emergency Medicine ronmaio@umich.edu 734 647-0489 Research Compliance Associates Terry VandenBosch, PhD, RN, CIP, CCRP terryvb@umich.edu 734 647-0457 Ted Hamilton, MS tedah@umich.edu 734 647-1622

40. UMMS Regulatory Affairs • Ray Hutchinson, MD, MS, Associate Dean • 734 615-1702 • rhutchin@umich.edu • Pat Ward, MPA, Director • 734-647-1954 • patward@umich.edu

41. Office of the General Counsel Kara Morgenstern, JD, MPH, Assistant General Counsel Phone: 734-763-6240 kmorgens@umich.edu Institutional Review Board - IRBMED Judith Birk, JD, IRBMED Director Phone: 734-647-7615 Fax: 734-763-1234 jbirk@umich.edu

42. Investigational Drug Service (IDS) Helen Tamer, Pharm.D. Clinical Pharmacist Phone: 734-936-7469 Fax: 734-647-9302 hrtamer@umich.edu Amy Skyles, Pharm. D. Clinical Pharmacist Phone: 734-936-8210 Fax: 734-936-7027 ajskyles@med.umich.edu Drug shipment address: University of Michigan Hospital Department of Pharmacy Services-IDS UH B2D400 1500 E. Medical Center Drive Ann Arbor, MI 48109-0008 Attention: Investigational Drug Service

43. Labeling of Investigational Agents • 21 CFR §312.6 • Immediate packaging of product • “Caution: New Drug – Limited by Federal (or United States) law to investigational use” • The labels and labeling shall not • Bear false and misleading statements • Represent that the drug is safe and effective for purposes being investigated

44. 734.998.7474 www.michr.umich.edu 360° support for your research study Educate Pre-doctoral, post-doctoral, faculty, & staff programs Connect Outreach, Partnerships, Recruitment, Mental Health, Child Health Support Consultation MCRU Project Management Data Management Biostatistics Regulatory Support Biorepository Informatics Tools Ethics Fund Pilot Grants Grant Writing

45. Reaching Us • “Visit” www.michr.umich.edu • “Read” Breakthrough • “Like” Facebook • “Follow” Twitter • “Watch” YouTube • “Call” 734.998.7474 • “Email” um_michr@umich.edu

46. Q & A Thanks for your attention!