The Basics on What is Research, Human Subjects Protection, IRB, and Getting Your Study Approved

1. The Basics on What is Research, Human Subjects Protection, IRB, and Getting Your Study Approved Mary-Tara Roth, RN, MSN, MPH Karla Damus, PhD, MSPH, MN, RN, FAAN BUMC Clinical Research Resources Office (CRRO) 2016

2. Clinical Research Resources Office Supported by the BU CTSI and Human Research Protection Program (HRPP), Serving all BUMC Clinical Researchers CRRO website: www.bumc.bu.edu/crro CTSI website: https://www.bu.edu/ctsi/

3. Objectives • Part 1 • Ethics in research • What is research • Review of the Regulations guiding human subjects research • Provide a few definitions to get started. • Part 2 • Identify the role of the IRB and criteria for approval of a research project. • List practical tips to aid in your IRB submissions.

5. Time Magazine article on medical research (4/22/02)- #1 question to ask your doctor about participating in a trial: “What is the primary purpose of the clinical trial, to help cure patients or to advance medical knowledge?” Should be asking instead: To what extent will being in this study possibly help cure me or make me feel better? More important: How does that compare to my other options?” Menikoff, 2006, What the Doctor Didn’t Say

6. “At the very least, by joining a clinical trial, you will receive the best established therapy. At most, you will be among the first to receive a treatment that proves to be better, either more effective or less hazardous.” (Brody, NYT, Oct 15, 2002) • “Despite widespread belief that enrollment in clinical trials leads to improved outcomes in patients with cancer, there are insufficient data to conclude that such a trial effect exists.” (Peppercorn et al, Lancet, 2004; 363: 263-70) From Menikoff, 2006, What the Doctor Didn’t Say

7. What is Human Subjects Research?

8. Research vs. Practice “Drawing the line between research and accepted practice….[is] the most difficult and complex problem facing the Commission.” - Jay Katz, MD, physician and ethicist From Kay, 1975, as quoted in Levine, 1988: Ethics and Regulation of Clinical Research

9. Gray Area Innovations Novel treatments/procedures Off-label treatments Departures from SOC Non-validated practices QI/QA projects Case report vs. “n of 1” Clinical Practice Clinical Research “When a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research.” Belmont Report, 1979

10. Gray Area • Significant innovations should be incorporated into a research project to establish safety & efficacy. RESEARCH • Individual therapy Intent • Designed to contribute to generalizable knowledge. • Unit/program/dept. specific (i.e. QI/QA) Extent • More evidence to support goals • Little/less known PRACTICE

11. An example… • “…for each of these patients, in the absence of any research or clinical evidence of efficacy [for treating Lyme disease in this way], and in the face of increased risk of infection from indwelling venous access, Dr. J prescribed a course of intravenous antibiotics to be administered to patients for several months.” North Carolina Medical Board 4/21/06

12. An example… • “Any treatment of lyme disease …. For greater than 2 months total time must be included in a formal research protocol with IRB supervision…” • “…breached his patients' informed consent, and therefore engaged in unprofessional conduct, including, but not limited to, departure from, or the failure to conform to, the standards of acceptable and prevailing medical practice, or the ethics of the medical profession…” North Carolina Medical Board 8/21/06

13. Is it right to conduct research on humans? If so, what makes it right?

14. An Ethical Challenge in Clinical Research Subjects are at risk of “exploitation” at many levels because we need them in order to accomplish our goals. Christine Grady, PRIMR, 2007 • Research is supposed to be designed to generate knowledge to help people in the future. • Benefit of the individual research subject is not the primary goal of research (though some may benefit). • The research subjects are the “means” to generating the knowledge that will be used to help others. SO…..

15. A Case: The Facelift study • Two accepted procedures; 20 yr debate on which is better: • Cutting the skin at hairline and pulling it up/back, or • More aggressive cutting muscle beneath the skin at the side and pulling the muscle back and up and reattaching it. • More aggressive procedure thought to be better long term, but may have increased risk of nerve damage. • 21 patients rx’d to either limited/conventional SMAS (superficial muscular aponeurotic system) on one side and extended SMAS or composite rhytidectomy on the other. • Followed clinically x 1 yr; photos reviewed by 3 independent face lift surgeons. - Ivy et al, J. Plastic and Reconstructive Surgery, vol 98 (7), pp 1135-1143 - PJ Hilts, NYT, 6/21/98

16. Facelift study Before After - Ivy et al, J. Plastic and Reconstructive Surgery, vol 98 (7), pp 1135-1143 - PJ Hilts, NYT, 6/21/98

17. Facelift study Qs • Is it research? • Why/Why not? • Is it human subjects research? • Why/Why not? • Is it regulated by FDA? By OHRP? • Does it need IRB review? • If so, what do you think the IRB would say?

18. Research protections born out of scandal • WWII Nazi Experiments • Nuremberg Code • Declaration of Helsinki • Post WWII - US • Tuskegee • Belmont Report • Beecher

19. Henry K. Beecher • “Ethics and Clinical Research” NEJM, 6/16/1966 • 22 examples of mainstream research judged to be ‘unethical’ or ‘questionably ethical.’ • Resulted in heightened awareness of public and of government officials.

20. Beecher example • “During bronchoscopy a special needle was inserted through a bronchus into the left atrium of the heart. This was done in an unspecific number of subjects, both with cardiac disease and with normal hearts. The technique was a new approach whose hazards were at the beginning quite unknown. The subjects with normal hearts were used, not for their possible benefit but for that of patients in general.”

21. US Response to Unethical Research(translation of ethical principles into regulations) • National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) • Established in 1974 by the US Congress (National Research Act). • Charged to identify ethical principles and develop guidelines to govern the conduct of human subjects research (established the IRB but did not cover the military or privately funded research) • Commission met from Dec 1974 through Sept 1978 • Report first published in 1978 and then published in the Federal Register on 4/18/79 • Also published 16 other reports focused on ethical issues in research involving vulnerable populations; many recommendations were codified as federal regulations • Belmont Report: Published in federal register April 18, 1979

22. www.hhs.gov/ohrp

23. Modern Ethical Research Principles • Violations of ethical principles contributed to the development of our current regulatory framework. • Belmont Principles: Respect, Beneficence, Justice • Ethical underpinnings of our regs • Emphasis on: • Informed consent prior to research participation • Voluntary participation • Independent ethics review

24. What happens if we don’t get it right? • Possible harm to the patient/subject. • Breach of ethical obligations to the patient/subject. • Formal evaluation by OHRP and/or FDA. • Determination letters /Warning letters and resulting corrective actions, enforcement actions (including debarment). • OHRP holds institution responsible for conduct of its agents; FDA holds sponsor, investigator and IRB responsible. • State licensing board findings/actions. Erosion of public trust in the research enterprise.

25. If we don’t get it right… Time, 4/22/02 Bloomberg Report 11/3/05 Risk of public mistrust…

26. When the Rules Aren’t Followed • Ellen Roche • 24 years old • Healthy volunteer in NIH-funded study to find out more about lung function • Volunteers were to breathe in hexamethonium; researchers would monitor their lung response • Ellen (3rd subject) inhaled the hexamethonium on May 4th, 2001, developed a cough, admitted to the ICU on May 9th. She died on June 2nd, 2001. • Jesse Gelsinger • 18 years old • Suffered from onithinetranscarbamylase deficiency (OTCD) • Had mild version  fairly normal life • UPenn trial testing safety of a new method to deliver healthy OTC genes to pts’ livers; to be used in infants with severe form of the disease. • Gene infusion on Sept. 13th, 1999 • Jesse died Sept. 17th, 1999

27. Human Subjects Protection Lapses "What we have witnessed-esoteric or complex standards have not been the issue, but rather the most basic elements of what it takes to properly conduct clinical studies. Enrollment of patients who did not meet the eligibility criteria for the study; Failure to report adverse events as required; Failure to ensure that a protocol was followed; Inadequate training for study staff; Investigators changing protocols without proper notice to the IRB and to FDA; Failure to incorporate agreed-upon protocol changes…” Dr. Jane Henney, Commissioner, FDA, May 11, 2000

28. Human Subjects Protection Lapses “…I would underscore, these are not isolated incidents occurring on the fringes of science or by physicians with no academic credentials. We have found these problems in some of the most renowned research centers in the country and these unacceptable practices by leaders in their fields of study.“ Dr. Jane Henney, Commissioner, FDA, May 11, 2000

29. Ethical Questions • Can we enroll subjects who may not have sufficient decision-making capacity to give informed consent? • What kind of consent is appropriate for a study with no indiv. benefits? • How much can we pay participants to participate? • Can I use data from this study to answer a new research question? • What should we tell participants about research test results? • How much of the consent form should we expect subjects to understand and how do we determine comprehension? • Should we continue a greater than minimal risk study that is enrolling slowly and unlikely to reach its target accrual goal?

31. Protection of Human Subjects - Regs Regulations Guidance Funding research Policies Guidance Regulations Guidance IRB Investigator Sponsor Protection of Human Subjects

32. Regulations Guiding Clinical Research Subpart A: Protection of Human Subjects 45 CFR 46 21 CFR 312, 812, 50, 54, 56 OHRP FDA Informed Consent • Assurance • Oversight • Engagement • Sponsor/investigator roles and conduct • Drug/device dev’t & testing process IRB Review/ Functions/ Operations 45 CFR 160, 162, 164 • Subpart B: Pregnant women, Fetuses, neonates • Subpart C: Prisoners • Subpart D: Children • Subpart E: IRB Registration HIPAA ( Health Insurance Portability and Accountability Act of 1996) • Privacy and Security of protected health information

33. What is ICH GCP? ICH Harmonised Tripartite Guideline, Guideline for Good Clinical Practice, E6 FDA Guidance: published in the Federal Register on May 9, 1997; “represents the [FDA’s] current thinking on good clinical practices”. … an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well being of trial subjects are well-protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

34. Definitions • Research (OHRP regs: 45 CFR 46.102 (d)) • “… a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” • Clinical Investigation (FDA regs: 21 CFR 312.3 (b)) • “… any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.”

35. Definitions • Human Subject (OHRP regs: 45 CFR 46.102 (f)) • “… a living individual about whoman investigator (whether professional or student) conducting research obtains: • Data through interventions or interactions with the individual, or • Identifiable private information.”

36. Definitions • Interaction/Intervention(45 CFR 46.102 (f)) • Both physical procedures by which data are gathered… and manipulations of the subject or the subject’s environment that are performed for research purposes. Interaction includes communication or interpersonal contact between investigator and subject.

37. Definitions (**See OHRP guidance on coded data/specimens, 2008: http://www.hhs.gov/ohrp/policy/cdebiol.html) • Private information (45 CFR 46.102 (f)) • … info about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). • Private information must be individually identifiable i.e. the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.”

38. Exempt determination… 45 CFR 46.101 (b)* 1. Normal educational practices in established educational settings 2. Educational tests, surveys, interviews, or observation of public behavior ‐unless identified & sensitive** 3. Research on elected or appointed public officials or candidates for public office 4. Research using existing data, if publicly available or recorded without identifiers (existing = at time of submission to IRB) 5. Evaluation of public benefit service programs 6. Taste and food quality eval./consumer acceptance studies *None of the categories apply to Prisoner research (Subpart C). ** does not apply to research with children except for research involving observation of public behavior when investigator(s) do not participate in the activities being observed.

39. Determining when OHRP Regs Apply… • Does the activity involve Research? (46.102(c)) If yes, then….. 2) Does the research involve Human Subjects? (46.102(f)) If yes, then…. 3) Does the human subjects research meet criteria for Exempt from 45 CFR 46? (46.101(b)) Decision Trees: http://www.hhs.gov/ohrp/policy/checklists/decisioncharts.html

40. Notice of Proposed Rule-making (NPRM) Changing regs for changing times…. • Announcement of revisions to modernize, strengthen, make more effective the Federal Policy for the Protection of Human Subjects • NPRM published in the Federal Register on 9/8/15 • Tighter rules on informed consent • Informed consent generally required for secondary research with biospecimen (even if it is anonymous) • Broad consent for future unspecified researcher uses • Level of review more proportional to the risks • Some minimal risk studies  exempt • Some exempt studies  “excluded”

41. Equivalent protections • Minimal risk research that does not receive federal funding • Additional flexibility to requirements • Lesser requirements still protects subjects for low risk research

42. Equivalent protections • New expedited requirements and exempt categories • Minimal risk…. 3 year progress report; new minimal risk categories (blood collection; tissue collection; radiation) • New exempt categories (so now there are 10) • Research on adults able to consent for themselves investigating individual or group characteristics or behavior • Research on children using survey/interviews • Research using materials that have been or will be collected for nonresearch purposes • Research using materials that have been for research when the consent for the research does not preclude such additional research

43. Institutional Review Board (IRB) • Formally designated committee; at least 5 members • Function as an ethics committee; primary responsibility: protect rights and welfare of research subjects • Review, approve, conduct periodic review (at least annually) of biomedical and behavioral research • Document that reviews take place in compliance with regs • Empowered to approve, require modifications or disapprove research

44. Types of IRB Submission/Review • Convened Meeting (Full Board) • Greater than minimal risk research • Expedited • 8 expedited categories • Minimal risk research • Exempt or NHSR • Minimal risk • 6 categories of exemption • NHSR = not human subjects research • Not research OR no human subjects

45. The 111 Criteria: Criteria for IRB Approval “In order to approve research covered by these regulations the IRB shall determine that all of the following requirements are satisfied…” 21 CFR 56.111 45 CFR 46.111

46. The 111 Criteria 1. Risks to subjects are minimized. 2. Risks to subjects reasonable in relation to benefits. 3. Selection of subjects is equitable. 4. Informed consent process. 5. Informed consent documentation. 6. Adequate provision for monitoring the data. 7. Provisions to protect privacy /maintain confidentiality. 8. Safeguards for vulnerable populations.

47. Deferral Decision • Usually because insufficient information provided to the IRB for them to make a determination for one or more of the 111 criteria. • If reviewed by the board, protocol will have to be revised and resubmitted and come back to the full board.

48. Back to the Facelift study • Is it research? • Why/Why not? • Is it human subjects research? • Why/Why not? • Is it regulated by FDA? By OHRP? • Does it need IRB review? • If so, what do you think the IRB would say?

49. Facelift study • Authors claimed IRB approval and informed consent not necessary: • “This was not an experiment… It was a clinical project to evaluate surgical procedures. These were not experimental procedures we are using. We didn’t need to go to the IRB … because it wasn’t investigative research.” • (S. Aston, as quoted in NYT, 6/21/98, P.H. Hilts)

50. Myprotocol! The BEST Scientific Study EVER!!!!