1. Drawing the Lines – Determining What Needs IRB Review 2009 VA Chair IRB Meeting October 7-8, 2009 Bethesda, MD Michael A. Carome, M.D. CAPT, U.S. Public Health Service Associate Director for Regulatory Affairs Office for Human Research Protections

2. Presentation Overview Why do lines need to be drawn? What are the lines that need to be drawn? What errors are commonly made when drawing the lines? Relationship between human subjects research and: QI/QA, public health, clinical practice.

3. Why do lines need to be drawn? To determine which activities are covered by the regulations for the protection of human subjects. To help ensure that the rights and welfare of human subjects are protected for research that is covered by the regulations. To avoid applying the regulations unnecessarily to activities not covered by the regulations

4. “Drawing the lines” – It sounds so easy! X Activities Covered by the regulations

5. For most activities, it is easy. For some activities it can be difficult (e.g., certain QI activities, public health, innovative care, program evaluations).

6. What are the lines that need to be drawn?

7. The Federal Policy for the Protection of Human Subjects Codified by HHS at 45 CFR part 46, subpart A, and by VA at 38 CFR part 16 Last revised June 23, 2005

8. Applicability of the Common Rule: The Three Major Lines Research [§___.102(d)]? Human subjects [§___.102(f)]? Exempt [§___.101(b)]?

9. Line 1: The Definition of Research A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. [§___.102(d)]

10. Line 1: The Definition of Research Activities which meet this definition constitute research for the purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities. [§___.102(d)]

11. Line 1: The Definition of Research 1

12. Line 2: The Definition of Human Subject A living individual about whom an investigator conducting research obtains: (1) Data through intervention or interaction with the individual; or (2) Identifiable private information. [§___.102(f)]

13. Line 2: The Definition of Human Subject A living individual about whom an investigator conducting research obtains: (1) Data through intervention or interaction with the individual; or (2) Identifiable private information. [§___.102(f)]

14. Line 2: The Definition of Human Subject A living individual about whom an investigator conducting research obtains: (1) Data through intervention or interaction with the individual; or (2) Identifiable private information. [§___.102(f)]

15. Line 2: The Definition of Human Subject A living individual about whom an investigator conducting research obtains: (1) Data through intervention or interaction with the individual; or (2) Identifiable private information. [§___.102(f)]

16. Identifiable Private Information Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place. [§___.102(f)]

17. Identifiable Private Information Private information includes 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). [§___.102(f)]

18. Identifiable Private Information Private information must be individually identifiable in order for obtaining the information to constitute research involving human subjects. Individually identifiable: The identity of the subject is or may readily be ascertained by the investigator or associated with the information. [§___.102(f)]

19. OHRP Guidance on Research Involving Coded Private Information or Biological Specimens OHRP does not consider research involving only coded private information or specimens to involve human subjects if the following conditions are both met: (1) the private information or specimens were not collected specifically for the currently proposed research project through an interaction or intervention with living individuals; and (2) the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because, for example, there are agreements, procedures, or legal requirements in place that prohibit the release of the key to the code to the investigators under any circumstances until the individuals are deceased.

20. Line 2: The Definition of Human Subject 1 2

21. Line 3: Application of the Exemptions §___.101(b)(1): Certain research conducted in established or commonly accepted educational settings, involving normal educational practices. §___.101(b)(2) and (3): Certain research involving educational tests, survey procedures, interview procedures, or observations of public behavior.

22. Line 3: Application of the Exemptions §___.101(b)(4): Certain research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens. §___.101(b)(5): Certain federal research and demonstration projects. §___.101(b)(6): Certain taste and food quality evaluation and consumer acceptance studies.

23. Line 3: Application of the Exemptions 1 2 3

24. Line 1: The Most Frequent Source of Difficulty 1- Research 2- Human Subject 3- Non-exempt Activities covered by the regulations**

25. What errors are commonly made when drawing the lines?

26. Error 1: The “Either-Or” Conceptual Error X Activities ResearchQI

27. Error 1: The “Either-Or” Conceptual Error X Activities ResearchQI

28. Error 1: The “Either-Or” Conceptual Error X Activities ResearchQI

29. The Belmont Report - Boundary Between Practice and Research “The distinction between research and practice is blurred partly because both often occur together….” The word “practice” could be replaced with “quality improvement activities,” “public health activities,” and others.

30. Error 2: Failing to separate human subjects research and non-human subject research activities when both occur together Research Clinical Care Research

31. Deciding Whether a Research Activity is Separate/Independent of the Activity of Interest Is the activity of interest (e.g., clinical intervention, program, or service) initiated for a research purpose? Is the activity of interest (e.g., clinical intervention, program, or service) altered or controlled in some way for a research purpose?

32. Error 3: Failing to Apply all Components of the Definition of Research a systematic investigation, including research development testing and evaluation, designed to develop or contribute to generalizable knowledge

33. Error 4: Relying on Criteria that are not Derived from the Definition of Research Is the activity located at more than one institution? Is the primary intention of the activity to contribute to generalizable knowledge? Is there significant risk to the individuals involved in the activity? Are the individuals involved in the activity expected to benefit from their participation? Are individuals randomly assigned to different interventions? Are there plans to publish the results?

34. Error 5: Not Applying the Lines in Order Exempt [§___.101(b)]? Human subjects [§___.102(f)]? Research [§___.102(d)]?

35. Error 6: Not Obtaining Sufficient Information to Make a Determination Example: “One of our faculty members is going to conduct a survey of students enrolled in his classes over the next year. Is this exempt research?”

36. Error 7: Misapplication of the Exemptions Failure to recognize the restrictions on the applicability of the exemptions on research involving children or prisoners. Misapplication of exemption 2 with respect to interpretation of “existing.” Misapplication of exemption 2 with respect to temporarily recording data in a manner that subjects can be identified. Misapplication of exemption 5 to the study or evaluation of something other than a federal public benefit or service program.

37. Error 7: Misapplication of the Exemptions Not using one exemption category because the research does not satisfy the criteria for another exemption category.

38. Applicability of the Common Rule: Additional Lines 1- Research 2- Human Subject 3- Non-exempt Activities covered by the regulations**

39. Applicability of the Common Rule: Additional Lines Is the institution engaged in the research? Is the research conducted or supported by HHS or VA? OR Does the institution hold an applicable assurance of compliance (e.g., did the institution elect to extend its FWA to all research regardless of support)?

40. Applicability of the Common Rule: Additional Lines Is the institution engaged in the research? Is the research conducted or supported by HHS or VA? OR Does the institution hold an applicable assurance of compliance (e.g., did the institution elect to extend its FWA to all research regardless of support)?

41. OHRP’s October 16, 2008 Guidance on Engagement in Human Subjects Research

42. Applicability of the Common Rule: Additional Lines Is the institution engaged in the research? Is the research conducted or supported by HHS or VA? OR Does the institution hold an applicable assurance of compliance (i.e., did the institution elect to extend its FWA to all research regardless of support)?

43. Applicability of the Common Rule: Additional Lines Is the institution engaged in the research? Is the research conducted or supported by HHS or VA? OR Does the institution hold an applicable assurance of compliance (i.e., did the institution elect to extend its FWA to all research regardless of support)?

44. Drawing Lines for Specific Categories of Activities Quality assurance (QA)/quality improvement (QI) activities Public health activities Clinical practice

45. Quality Assurance/Quality Improvement (QA/QI) Activities

46. QI/QA Activities Non-research examples: – QI activities solely for the purpose of measuring and reporting provider performance data for clinical, practical, or administrative use – Peer auditing of healthcare provider medical records with patient-specific and healthcare- provider-specific feedback. – A hospital implements a procedure known to reduce pharmacy prescription errors, and collects prescription information from medical charts to assess adherence to the procedure and determine whether medication error rates have decreased as expected.

47. QI/QA Activities Research example: – Fick, DM, et al. A randomized study to decrease the use of potentially inappropriate medications among community dwelling older adults in a southeastern managed care organization. Am J Managed Care. 2004; 10:761-768

48. QI/QA Activities Research example (cont): – Aim: to examine the effectiveness of a strategy to change physician prescribing behavior and decrease use of potentially inappropriate medications (PIM) in members of a managed care organization (MCO). – Hypothesis: an intervention directed at primary care physicians to decrease PIM will decrease overall number of PIMs prescribed in the intervention group. – Design: prospective randomized block design – Study population: all primary care physicians and patients 65 years or older in a MCO. Physicians randomized to usual care or intervention group. Am J Manag Care. 2004; 110:761-768

49. QI/QA Activities Research example (cont): – Intervention group: (1) personally addressed letter to physician describing in detail all physician’s patients who received one or more PIM; (2) detailed education brochure listing PIMs; (3) list of suggested PIM alternative medications (that were independently suggested and reviewed by 5 geriatricians and pharmacists not affiliated with the MCO). Physicians invited to use fax-back form to comment on any PIM prescribing changes in response to (1)-(3). Am J Manag Care. 2004; 110:761-768

50. QI/QA Activities Research example (cont): – Outcome measures for intervention and control groups: physician behavior change for PIM use, cost and use outcomes, and drug-related problems assessed at 6, 12, and 18 months after the intervention was implemented. – Conclusion: The intervention was simple and had a decrease in overall PIM prescribing in a sample of older adults. This study describes a low-cost, replicable method to contact and educate physicians on drug therapy issues in older adults. Am J Manag Care. 2004; 110:761-768

51. Public Health Activities

52. Non-research examples: – State public health department activities to track incidence and prevalence of infectious diseases such as HIV infection, viral hepatitis, etc. – Public health agency seeks to identify source of outbreak of food-borne Salmonella infections.

53. Public Health Activities Research example 1: – A public health agency implements an activity designed to systematically determine the reliability and validity of a newly developed diagnostic test for a particular infectious disease.

54. Public Health Activities Research example 2: – A public health agency receives reports indicating an unusual number of ER visits for severe nausea and diarrhea. – Preliminary investigation suggests possible cause may be a contaminant in the water supply of affected individuals. – A study is designed to test the hypothesis that a specific contaminant in the water supply is causing the GI illness.

55. Public Health Activities Research example 2 (cont): – Random samples of people living in areas with water supply containing the contaminant and of people living in areas without contaminated water supply are selected. – Individuals selected undergo detailed survey on recent symptoms and exposures and blood and urine tests to measure levels of the identified contaminant.

56. Public Health Activities Research example 2 (cont): – The selection of the samples, the survey questions, and the blood and urine analysis are designed to enable the officials to test the hypothesis that the nausea/diarrhea syndrome is caused by the identified contaminant for the people who did suffer from the condition, and to rule out any other plausible explanations of how they might have gotten the condition.

57. Clinical Care and Research

58. Case reports and case series in general are not research. Clinical care and research are frequently intertwined and occur together. Separating the research activities from non-research activities can be challenging.

59. Clinical Care and Research The Belmont Report: “…when a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is ‘experimental’ …does not automatically place it in the category of research. Introduction of innovative interventions solely for clinical purposes are not research, even if data about the intervention is collected from medical records for research purposes in a retrospective or prospective manner.

60. Conclusions Reviewed why lines need to be drawn. Reviewed the three key lines: definition of research, definition of human subject, and the exemptions. Reviewed errors commonly made when drawing the lines. Discussed drawing the lines in the setting of QI/QI, public health, and clinical practice activities.