educate • fund • connect • support

1. educate • fund • connect • support MIAP – Introduction to INDs and IDEs E Mitchell Seymour, PhD RAC Research Faculty Regulatory Project Manager

2. educate • fund • connect • support MICHR is here to enable & enhance clinical & translational research. We do this by being a catalytic partner who educates,funds,connects,and supports research teams at U-M.

3. educate • fund • connect • support Why Created in 2006, awarded a $55M CTSA grant from the NIH in 2007, and renewed in May 2012, MICHR is part of a consortium of CTSA institutions working together to accelerate discoveries toward better health. MICHR serves the entire U-M campus.

4. educate • fund • connect • support MICHR Research Support Services • Michigan Clinical Research Unit • IND/IDE Regulatory Assistance • Biostatistical Design & Analysis • Study Monitoring • Database Development • Study & Data Management Mentoring • Clinical Trials Office • Clinical Research InformaticsTools

5. “MICHR IND/IDE INVESTIGATOR ASSISTANCE PROGRAM” MIAP Regulatory assistance with IND/IDE application submission & support

6. What is the definition of a drug? • “Articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease…” and • “Articles (other than food) intended to affect the structure or any function of the body of man or other animals”

7. What constitutes a drug? • Exogenous compounds (small and large molecule, organic and inorganic) • Endogenous compounds • Live organisms • Cosmetics • Food (when used/applied in a certain way…) • Dietary supplements • Conventional foods

8. Applicable Regulations The Federal Food, Drug, and Cosmetic Act (FD&C Act) gives the FDA authority to regulate drugs and devices Drugs/Biologics • Code of Federal Regulations (CFR) 21 CFR Part 312: Investigational New Drugs (IND) Devices • Code of Federal Regulations (CFR) 21 CFR Part 812: Investigational Device Exemptions (IDE)

9. Academic Research – “Investigator” vs. “Sponsor-Investigator” • 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/device 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. Sponsor-Investigators must also conclude or close investigations.

10. When is an IND Needed?? • Sponsor-Investigator intends to conduct a clinical study with an investigational drug • Sponsor-Investigator intends to conduct a study with an approved drug, but… • In a new indication/population • Dosage form OR • Dosage range that is not covered in the current package insert (off label)

11. Changed Risk of Product and/or to Population • Route of Administration • Drug approved for oral administration is going to be given intravenously • Dose • Increases in dose, frequency, or duration of administration can increase risk • Decrease in dose can also increase risk • Patient Population • Adult to children • Moving from very ill population to a less ill population

12. IND Exemption Criteria • The drug product is lawfully marketed in the United States. • The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to support any other significant change in the labeling of the drug. • In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug. • The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product. • The investigation is conducted in compliance with the requirements for review by an IRBand with the requirements for informed consent. • The investigation is not intended to promote or commercialize the drug product.

13. January 2004http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071717.pdf

14. October 2010 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM229175.pdf

16. What Information is Submitted in an IND Application? • Clinical Protocol • Draft Informed Consent Document • Draft Case Report Forms • PI CV (signed and current, dated) • Investigator Brochure (for investigational study drug, also for multi-site studies with an approved drug) • Labeling information (for approved drug) • Letter of Authorization (LOA) to Cross-reference the approved drug • Relevant reference articles

17. IND Application Content Requirements per 21 CFR 312.2 * Not required for Sponsor-Investigator INDs for single-site studies • Cover Sheet (FDA Form 1571) • Table of Contents • Introductory statement and General Investigational Plan • Investigator Brochure* (provided by the company or by investigator) • Study Protocol and Informed Consent • Chemistry, Manufacture, and Control Information (can be via LOA, IB) • Pharmacology and Toxicology Information (can be via LOA, IB) • Previous Human Experience (can be via LOA, IB) • Additional Information (draft Case Report Forms, pertinent professional guidances, manuscripts) Written by or provided by the investigative team!

18. IND Maintenance IND Amendments Protocol Amendments • New protocol • Changes in protocol • New investigator Information Amendments • New toxicology, chemistry, or other technical information • New Investigator’s Brochure IND Safety Reports • Unexpected fatal or life threatening suspected adverse reactions – 7 calendar days • Unexpected serious suspected adverse reactions – 15 calendar days IND Annual Reports • Submitted to FDA within 60 calendar days of the IND Anniversary Date

19. Expanded Access to Investigational Drugs • Types of Expanded Access • Single-patient - Emergency Use • Single-patient - Non-emergency Use • Intermediate-size patient populations • Treatment IND or treatment protocol

20. Devices The first regulatory hurdle… “Significant Risk”, or “Non-significant Risk”?

21. January 2006http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf

22. Who Decides Whether a Device is SR or NSR? Sponsor-Investigator - makes the initial risk determination - presents the IRB with this informationIRBs Required to determine whether the device study involves a SR or NSR device. For an investigational device that is considered to be non-significant risk, the IRB can approve the “IDE”.FDA Is available to help, and is the final arbiter!

23. What is the sponsor’s responsibility to the IRB for NSR device studies? Provide reviewing IRB(s) with an explanation of why the device is not a SR - Description of device - Reports of prior investigations - Proposed investigational plan - Subject selection criteria Inform IRB if FDA determined the study to be NSR

25. A Significant Risk device is an investigational device that: • is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; • is for use in supporting or sustaining human life and represents a potential for serious risk to the health, safety, or welfare of a subject; • is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or • otherwise presents a potential for serious risk to a subject.

26. Non-significant Risk (NSR) Devices • NSR devices are devices that do not pose a potential for serious risk to the human subjects. • A NSR device study requires only IRB approval prior to initiation of a clinical study. Sponsors of studies involving NSR devices are not required to submit an IDE application to FDA for approval. Submissions for NSR device investigations are made directly to the IRB of each participating institution. • If the IRB disagrees and determines that the device poses a SR, the sponsor must report this finding to FDA within five working days [§812.150(b)(9)]. • FDA considers an investigation of a NSR device to have an approved IDE when IRB concurs with the NSR determination and approves the study.

27. What are the Requirements for NSR Device Studies? Abbreviated requirements per 21CFR 812.2(b) • Labeling • IRB approval • informed consent • monitoring • record keeping • reports • prohibition against promotion. • NSR studies are considered to have an approved IDE therefore no IDE to FDA • Sponsors and IRBs do not have to advise FDA of NSR device studies • IRBs must make a SR or NSR determination for every NSR study (21 CFR 812.66)

28. IDE Exempt if: • Used in accordance with indications/labeling • Non-invasive diagnostic • Consumer preference testing • Solely for veterinary use • Research on or with lab animals

29. IDE Application Content Requirements per 21 CFR 312.2 Written by or provided by the investigative team! (1) The name and address of the sponsor. (2) A complete report of prior investigations of the deviceand a complete investigational plan (Protocol) (3) A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, where appropriate, installation of the device (4) An example of the agreements to be entered into by all investigators to comply with investigator obligations under this part, and a list of the names and addresses of all investigators who have signed the agreement. (5) A certification that all investigators who will participate in the investigation have signed the agreement, that the list of investigators includes all the investigators participating in the investigation, and that no investigators will be added to the investigation until they have signed the agreement. (6) A list of the name, address, and chairperson of each IRB that has been or will be asked to review the investigation and a certification of the action concerning the investigation taken by each such IRB. (7) The name and address of any institution at which a part of the investigation may be conducted (8) If the device is to be sold, the amount to be charged and an explanation of why sale does not constitute commercialization of the device. (9) An environmental assessment (if applicable) or claim of exemption therefrom (10) Copies of all labeling for the device. (11) Copies of all forms and informational materials to be provided to subjects to obtain informed consent. (12) Any other relevant information FDA requests for review of the application.

30. Providing valuable support services for research studies MICHR IND/IDE Investigator Assistance Program (MIAP)Provides Comprehensive: • Regulatory Expertise… • Regulatory Support… • Regulatory Education… …to Investigators and their Team involved in FDA-regulated research.

31. MIAP Team MICHRMIAP@med.umich.edu Jeanne Wright MIAP Lead jeanburn@umich.edu Kevin Weatherwax Manager, MIAP kweath@umich.edu Bill Reisdorph MIAP Team Member reisdorp@umich.edu Mona Moore MIAP Team Member monamoor@umich.edu E. Mitchell Seymour, PhD MIAP Team Member seymoure@umich.edu

32. MIAP Team • Various certifications from the Regulatory Affairs Professional Society, the Association of Clinical Research Professionals, the Society of Clinical Research Associates, the National Association of IRB Managers, and the American Society for Quality. • Varied backgrounds in academia and industry with expertise in life sciences, chemistry (drug discovery R&D), nursing, Human Subjects Research Protection, Good Clinical Practice, Good Laboratory Practice, Good Manufacturing practice, quality assurance, and clinical trial • operations. • Mean year professional experience = 26.3 • Research (clinical + preclinical) = 15.2 • Regulatory Affairs = 10.5

33. MIAP SERVICES OVERVIEW • Agent/Device development/regulatory strategy consultation • IND/IDE consultation including determination of need for IND or IDE • Pre-IND/IDE FDA meeting requests and support • Protocol/Informed Consent review • IND/IDE application preparation and submission to FDA • Clinical hold/conditional approval response preparation/submission • Communication with the FDA, IRB and other regulatory bodies • IND/IDE “maintenance” support • Safety report submissions • Protocol amendments • Annual reports • Investigator Amendments • Informational Amendments

34. Contact us! MICHRMIAP@med.umich.edu https://www.michr.umich.edu/services/regulatorysupport/miap Want this slide deck? seymoure@med.umich.edu