1. Michigan Research Ethics Conference M. Ammar Hatahet, MD, MPH, FACP Clinical Professor of Medicine, Michigan State University Chair, Centralized IRB, McLaren HealthCare Director, Center for Diabetes Management and Weight Control April 29 th, 2016, East Lansing, Michigan

2. Objectives To discuss IRB review and best submission practices of Investigator Initiated Biomedical Research. (IIBR) Discuss IND and IDE submissions to the FDA. Review the role the IRB plays in investigator- initiated studies. – scientific validity – subject safety – safety monitoring SR v. NSR Devices

3. IIBR and the Players The subjects The investigators The sponsors The regulators The IRB

4. Human Subjects Research “ DHHS: Common Rule ” Is it Research – Systematic investigation – Generalizable conclusions Examples: Does it involve Human Subjects – Obtaining information about living individuals through either direct interaction/intervention or through identifiable private information Examples:

5. Human Subject Research “ FDA ” Does it involve a “Test Article” – DRUG/BIOLOGIC (a chemical or biological substance – other than food – that achieves it's primary intended purposes through chemical action within or on the body or which is dependent upon being metabolized for the achievement of any of its primary intended purposes) – or MEDICAL DEVICE (an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory) that is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals OR to affect the structure or any function of the body

6. Human Subject Research “ FDA ” The activity is an experiment that involves a test article and one or more human subjects *The activity is subject to requirements for prior submission to the Food and Drug Administration; or *The activity is intended to be submitted later to, or held for inspection by, the FDA as part of an application for a research or marketing permit. An experiment includes any use of a drug other than the use of a marketed (approved) drug in the course of medical practice. For medical devices, it is limited to activities being conducted to determine the safety or effectiveness of a device

7. Human Subject Research “ FDA ” It involves Human Subjects if – The research involves one or more individuals who become a subject in research, either as a recipient of the test article or as a control or For medical devices, – an individual on whose specimen an investigational device is used

8. Role and Power of the FDA The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established by the Agency to protect the consumer's health, safety, and pocketbook. Section 21 of the Code of Federal Regulations (CFR 21) contains most regulations pertaining to food and drugs.

9. Investigational New Drug (IND) Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA.

10. IND FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer), having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.

11. Types of IND An Investigator IND 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. Emergency Use IND allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND. 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. Treatment IND 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.

12. Investigational Device Exemption (IDE) An investigational device exemption (IDE) allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data. Clinical studies are most often conducted to support a PMA (Pre-market approval). Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated

13. Investigators Interest Obtain grants Enroll as many subjects as possible Get as much data as possible Write up and publish Recognition and promotion “Just to graduate from residency”

14. Residents Studies Required but not necessarily needed competency – Chore > last minute Limited time available – On-call, post call, duty hours limits > short cuts First timers – Never done clinical research > incomplete Inconsistent guidance – Faculties lack of knowledge or time > repeated mistakes Lack of knowledge with regard to the regulations – No prior exposure to FDA or HHSA > missing criteria Lack of access to support – Grant writers, time protection > rudimentary projects

15. Investigator ’ s Responsibilities Towards the advancement of science Towards the hosting institution Towards the granting agency Towards the subjects It is ultimately the responsibility of the Investigator to protect the rights and welfare of the subjects. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM187 772.pdf**

16. Balancing Act The IRB role is to assure the protection and welfare of the subjects without impeding the advancement of science

17. Historical Perspective 45 CFR 46 - Basic DHHS Policy for Protection of Human Research Subjects Originally adopted May, 1974, Revised January 13, 1981, Revised June 18, 1991 Federal Policy for the Protection of Human Subjects - “The Common Rule” June 18, 1991 Departments of Agriculture, Energy, Commerce, HUD, Justice, Defense, Education, Veterans Affairs, Transportation, and HHS. NSF, NASA, EPA, AID, Social Security Administration, CIA, and the Consumer Product Safety Commission.

18. Vulnerable Subjects Additional Protections Included in 45 CFR 46: Subpart B - Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research (revised December 13, 2001) Subpart C - Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Subpart D - Additional DHHS Protections for Children Involved as Subjects in Research

19. 45 CFR 46/21 CFR 56 §111(a) “In order to approve research covered by these regulations the IRB shall determine that all of the following requirements are satisfied” – Risks to subjects are minimized – Risks are reasonable in relation to anticipated benefits – Selection of subjects is equitable – Informed consent is appropriately sought from each subject – Informed consent is appropriately documented

20. And when appropriate: Data collection is monitored to ensure subject safety Privacy and confidentiality of subjects is protected Additional safeguards are included for vulnerable populations

21. Why the External Observer IRBs cannot rely solely on investigators to identify risks No one can be objective about their own work – We tend to underestimate the risks involved in things with which we are familiar or comfortable – We tend to overestimate the benefits of things to which we are attached The IRB has to do an independent evaluation of the risks

22. Risks Determination IRB Responsibilities: Identify Risks Determine that risks are minimized Determine that “risks to subjects are reasonable in relation to anticipated benefits” Determine that subjects are adequately informed about “any reasonably foreseeable risks or discomforts” – Identifying risk requires scientific expertise on the part of the IRB and when the IRB does not have the necessary expertise it must use outside consultants otherwise the IRB may not be in compliance

23. Investigator ’ s Responsibilities Supervision of the Conduct of a Clinical Investigation Protecting the Rights, Safety, and Welfare of Study Subjects

24. Subjects Safety Appropriate delegation of study-related tasks – The investigator should maintain a list of the appropriately qualified persons to whom significant trial-related duties have been delegated. Adequate training of personnel Adequate Supervision of the Conduct of an Ongoing Clinical Trial

25. FDA ’ s examples of tasks inappropriately delegated Screening evaluations, including obtaining medical histories and assessment of inclusion/exclusion criteria Physical examinations Evaluation of adverse events Assessments of primary study endpoints Obtaining informed consent

26. Factors affecting Adequate Supervision of the Trial Inexperienced study staff Demanding workload for study staff Complex clinical trials (e.g., many observations, large amounts of data collected) Large number of subjects enrolled at a site A subject population that is seriously ill Conducting multiple studies concurrently Conducting a study from a remote (e.g., off-site) location

27. Protecting the Rights, Safety, and Welfare of Study Subjects (21 CFR 312.60 and 812.100). Providing reasonable medical care for study subjects for medical problems arising during participation in the trial that are, or could be, related to the study intervention Providing reasonable access to needed medical care, either by the investigator or by another identified, qualified individual (e.g., when the investigator is unavailable, when specialized care is needed) Adhering to the protocol so that study subjects are not exposed to unreasonable risks

28. Protocol Violations that Present Unreasonable Risks Failure to adhere to inclusion/exclusion criteria that are specifically intended to exclude subjects for whom the study drug or device poses unreasonable risks – (e.g., enrolling a subject with decreased renal function in a trial using nephrotoxic drug) may be considered failure to protect the rights, safety, and welfare of the enrolled subject. Failure to perform safety assessments intended to detect drug toxicity within protocol-specified time frames – (e.g., CBC for an oncology therapy that causes neutropenia) may be considered failure to protect the rights, safety, and welfare of the enrolled subject.

29. What is a Significant Risk Device? What is a Significant Risk Device? 21 CFR 812.3(m) Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; Is purported or represented to be for use supporting or sustaining human life and presents 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 the health, safety, or welfare of a subject.

30. Who Decides Whether A Device Study is SR or NSR? Sponsors are responsible for making the initial risk determination and presenting it to the IRB. Unless FDA has already made a risk determination for the study, the IRB must review the sponsor's SR or NSR determination for every investigational medical device study reviewed and modify the determination if the IRB disagrees with the sponsor. – FDA is also available to help the sponsor, clinical investigator, and IRB in making the risk determination. – IRB must document how that determination is made

31. Significant Risk Device SR device studies must follow all the IDE regulations at 21 CFR 812. SR device studies must have an IDE application approved by FDA before they may proceed.

32. NSR Device Studies NSR device studies must follow the abbreviated requirements at 21 CFR 812.2(b). These abbreviated requirements address labeling, IRB approval, informed consent, monitoring, records, reports, and prohibition against promotion. However, there is no need to make progress reports or final reports to FDA. NSR device studies do not have to have an IDE application approved by FDA. Sponsors and IRBs do not have to report the IRB approval of an NSR device study to FDA. This means that an IRB may approve an NSR device study and an investigator may conduct the study without FDA knowing about it.

33. NSR Device Studies The IRB serves as the FDA’s surrogate for review, approval, and continuing review of the NSR device studies. An NSR device study may start at the at the institution as soon as the IRB reviews and approves the study and without prior approval by FDA

34. IRB Responsibilities IRBs should have standard operating procedures that explain how the IRB makes SR and NSR determinations and that the decision should be documented. FDA considers this determination to be part of the IRB’s responsibilities for conducting its initial review of a study. (See 21 CFR 56.108) IRBs should make the SR or NSR determination about a study by reviewing relevant information at a convened meeting. This information includes the description of the device, reports of prior investigations conducted with the device, the proposed investigational plan, and subject selection criteria. The sponsor should provide the IRB with a risk assessment and the rationale used in making its SR or NSR determination.

35. An IRB may agree or disagree with the sponsor’s initial NSR assessment. If the IRB determines the study is NSR, the IRB may approve the study using the criteria at 21 CFR 56.111. The study may begin without submission of an IDE application to FDA. If the IRB disagrees with the sponsor’s NSR assessment and decides the study is SR, the IRB must tell the clinical investigator, and where appropriate, the sponsor. (See 21 CFR 812.66) IRB Responsibilities

36. An IRB may approve the study as an SR device study, but the study may not begin until FDA approves the sponsor’s IDE application. To facilitate the IRB’s review of the study, an IRB may ask the sponsor for proof (i.e., a copy of FDA’s approval or conditional approval letter) that an SR study has an FDA-approved IDE application. The IRB should document its SR/NSR determination, the rationale and the evidence used if any, in the IRB meeting minutes. IRB Responsibilities

37. IRB Determination SR v. NSR What is the basis for the risk determination? The risk determination is based on the proposed use of a device in an investigation, and not on the device alone. What is the nature of harm that may result from use of the device? SR studies are those that present a potential for serious risk to the health, safety, or welfare of a subject. Will the subject need to undergo an additional procedure as part of the investigational study, for example, a surgical procedure? IRBs should consider the potential harm the procedure could cause as well as the potential harm caused by the device.

38. Examples The study of a change to a commercially available pacemaker (e.g., new leads, battery pack, or software) poses an SR because the device is used to support or sustain human life and it presents a potential for serious harm to the subjects. This is true even though the changed pacemaker may potentially pose less risk, or only slightly greater risk, in comparison to the commercially available model. The study of an extended wear contact lens is SR because wearing the lens continuously overnight while sleeping presents a potential for injuries not normally seen with daily wear lenses, which are NSR.

39. More SR Devices Collagen Implant Material for use in ear, nose and throat, orthopedics, plastic surgery, urological and dental applications Tissue Adhesives for use in neurosurgery, gastroenterology, ophthalmology, general and plastic surgery, and cardiology. Epidural and Spinal Catheters Epidural and Spinal Needles Esophageal Obturators Balloon Dilation Catheters for benign prostatic hyperplasia (BPH) Biliary Stents

40. Examples of NSR Conventional Gastroenterology and Urology Endoscopes and/or Accessories Conventional General Hospital Catheters (long- term percutaneous, implanted, subcutaneous and intravascular) Conventional Implantable Vascular Access Devices (Ports) Conventional Laparoscopes, Culdoscopes, and Hysteroscopes Digital Mammography

41. Other Issues with Devices IRBs should not confuse their responsibility to make an SR/NSR determination for a device study with the concept of “minimal risk.” – “Minimal Risk” is a term used in the IRB regulations in part to identify certain studies that IRBs may approve through an expedited review procedure. – For a device study to be eligible for expedited review, it must be an NSR study AND present no more than minimal risk to the subject. (See 21 CFR 56.110)

42. More about Devices IRBs should not confuse their responsibility to review and approve research for conduct at a clinical site with the SR/NSR determination. IRBs make the SR/NSR determination before the IRB conducts its review of the study under Part 56. The judgment about whether a study poses a significant risk or nonsignificant risk is based on the significance of the potential harm that may result from participation in the study, including the use of the device; whereas the IRB’s decision to approve a study for implementation is based on the study’s risk-benefit assessment.