Welcome

1. Welcome The University of Texas at Arlington Office of Research Integrity and Compliance Human Research Protections Program (HRPP) Tier II Training Responsible Conduct in Human Subject Research

2. The Principal Investigator and the Key Personnel are required to complete compliance education . . . So who are the Key Personnel ? • Members of the Institutional Review Board; • The listed Principal Investigator; • Sub- or Co-Investigators named on an Application for Research; • All listed investigators on FDA Form 1572 for FDA-regulated investigations; • A member of the group of key personnel on a Grant Application (e.g. NIH); • A subcontractor or consultant associated with a federally-sponsored study;

3. More key personnel . . . • A Clinical Research Coordinator, Graduate Research (GRA) or Teaching Assistant (GTA) involved in any direct interactions with research subjects, including involvement in the process whereby Informed Consent is acquired from potential research subjects; • Departmental Administrative and/or support staff directly involved with the completion of required forms or the support of thesis and doctoral students.

4. If it isn’t documented, it did not happen

5. The Tuskegee Tragedy IRBs…doing their best to insure history does not repeat itself! • In 1932 the American Government promised 399 men – all had Syphilis, all residents of Macon County, Alabama, all poor, all African American – free treatment for Bad Blood. It lasted until 1972. [Syphilis Study Ad Hoc Panel (1973)] • Although the study was initially planned for 6 mos., it was allowed to continue for 4o years. The men were never told they were being enrolled as research subjects; they were promised free medical care (treatment for bad blood) and $100 burial money. • Treatment was withheld even after Penicillin became available. • The researchers referred to these lives as, expendable!

6. The Nuremberg Code (1947) Click here to learn more: http://www.ushmm.org/research/doctors/ • In the name of research, numerous atrocities were conducted on civilian prisoners held in WWII camps. • As part of the verdict in the Nuremberg War Crimes Trials of 23 German doctors, the Court enumerated some rules for “permissible Medical Experiments”, now known as the Nuremberg Code. These rules include: • Voluntary consent • Benefits outweigh risks • Ability of the subject to terminate participation • The Nuremberg Code was never legislatively enacted. Although it is not a law, researchers around the world follow its standards for ethical reasons.

7. Jesse GelsingerSeptember 17, 1999University of Pennsylvania Institute for Human Gene Therapy Jesse died at the age of 18, on September 17, 1999. Read Jesse’s Intent, written by Paul – his father. http://www.guineapigzero.com/jesse.html

8. The Belmont Report • (Foundation document) Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The three main sections will be reviewed on an upcoming slide. • Authors: The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The report was released on April 18, 1979.

9. “IRB” History • Nuremberg code (1947) • Public Health Service (PHS) Policy and the National Institutes of Health (NIH) Clinical Center (1966) began Independent Ethics Committees (early IRB-type reviewing committees) • Syphilis Study (revealed) – AD Hoc Panel assigned to review the case (1973) • National Research Act, July 12, 1974 (PL94-348) • 45 CFR 46 (Codes of Federal Regulation [CFR] federal laws) under section 491 PHS Act (1974) • National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974-1978) • 1979 – National Commission’s Belmont Report • 1981 – Major revisions to federal regulations (e.g., 21 CFR 56) • 56 FR 28803, June 18, 1991 • The Common Rule (Federal Policy), Subpart A, 45CFR 46 (latest revision June 18, 1991)

10. This institution is an approved research institution by a DHHS Federalwide Assurance (FWA).What is an Assurance? • A type of contract between us and the federal government. • A promise to conduct ethical research in compliance with the Department of Health and Human Services (DHHS) regulations for the protection of human subjects of research as found in 45 CFR 46. • Establishes a partnership to protect the rights and welfare of the human subjects of research. • Identifies a signatory official. • Ronald L. Elsenbaumer, PhD Vice President for Research

11. What Constitutes Ethical Human Research? According to 45 CFR 46 • A valid and important question • Valid methodology • Balance between risks/benefits • Independent ethical review • Informed consent

12. Beneficence “an obligation” (do no harm, and maximize benefits/minimize harms) Justice (who ought to receive the benefits of the research and bear its burdens) Respect for persons (individuals should be treated as autonomous agents and those with diminished autonomy are entitled to protection) #1 Fundamental Ethical Constructs A Guide for Human Research: The Belmont Report #2 #3

13. The Buck Stops here! • Principal Investigator (PI) • Faculty, student or staff • Conduct of study • Personnel supervision • Protecting the rights, safety and welfare of research subjects . . . Any number of research team members may be delegated certain research related duties BUT the PI is ultimately responsible (federally and ethically) for the conduct of the research.

14. What Regulations Apply? • Common Rule 56 FR 28003 (Subpart A, 45 CFR 46) • 45 CFR 46 • 45 CFR 160, 164 • 38 CFR 16 (Veteran Affairs) • DHHS Office for Human Research Protections (OHRP) regulations are applied for the sake of consistency in many non-FWA institutions • Institutional policies • Statutes • Ethical codes • State and local law • Any many more! It depends on the research focus.

15. Scientific Misconduct • Public Health Service (PHS) regulations • Official Definition: Misconduct in science means fabrication, falsification, plagiarism or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducing and reporting research. It does not include honest error or honest differences in interpretations or judgments of data. • Retaliation against a “whistle-blower” who made an allegation of misconduct in good faith, may itself, be construed as an act of misconduct.

16. Compliance MonitoringConducted by any of the following and more! • The Office of Research Integrity and Compliance Quality Improvement Program for Human Subject Research (QIP) • FDA • OHRP • NCQA or AAHRPP • Sponsor/Cooperative Group Monitoring • Internal Auditing Mechanisms These visits are not always announced. The research conduct of the individual investigator represents and affects all of us. . .

17. Investigator RecordsMost common findings during monitoring of site records • Missing original signed ICDs • Documentation lacking of initial date of subject pre-screening (for those who do not meet inclusion criteria) or patient enrollment • Documentation of the initial procedure or treatment date for each subject or patient • Refer to the Quality Improvement for Human Subject Research (QIP) program guidelines located on the IRB Website for program description and the specific documentation required for compliance and to achieve successful program audits Visit OHRP to learn some surprising facts! http://www.hhs.gov/ohrp/references/findings.pdf

18. What Counts as Research? • Quest for generalizable knowledge • (The research data will be shared in public venues: publication, thesis, dissertation, invited presentation, etc. • Organized data gathering • Non-standard therapeutic or diagnostic approach • Decisions made by computer or protocol, rather than by patient or caregiver • Presence of risk (even “soft” risk) beyond that of standard care

19. OHRP Definition of Researchin Regs 45 CFR 46.102(e) • 45CFR46.102(d) “Research” means a systematic investigation designed to develop or contribute to generalizable knowledge. • Activities which meet this definition constitute “research” for purposes of these regulations, whether or not they are supported or funded under a program which is considered research for other purposes.

20. OHRP Definition of Human Subjectin Regs 45 CFR 46.102(f) “Human subject” means a living individual about whom an investigator (whether professional or student) conducting research obtains • data through intervention or interaction with the individual, or (2) identifiable private information.

21. Risk/Benefit • Risk - A probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study. • Minimal Risk – where the probability and magnitude of harm or discomfort in the study is not greater than those ordinarily encountered in daily life, in performance of routine physical or psychological testing.

22. Vulnerable Subjects • Additional protections are required (45CFR46, Subparts B,C,D) • Children (e.g., <18 yrs, unemancipated minors) • Cognitive disorders • Prisoners • Pregnant women • Minorities This is not an all inclusive list. Consider, for example, that under certain circumstances, a specific socio/economic population could represent a vulnerable population.

23. Are “Soft Risks” Important? • Risks re: confidentiality, stigmatization, embarrassment, social/legal risk are explicitly mentioned in FDA and OHRP documents as potential exclusions from categorization as “minimal risk” • Once in awhile, the consequences can be severe Do not assume “no physical risk” means no risk.

24. Deception • Deception interferes with the subject’s ability to give informed consent • Ethical concerns are increased whenever the protection of informed consent is compromised • Use of deception must be scientifically AND ethically justified AND approved by the IRB • It is not permissible to use deception to obtain enrollments

25. What is an IRB? • An Institutional Review Board (IRB) is a board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct continuing review of biomedical and behavioral research involving the participation of human subjects in accordance with the regulations of the DHHS, FDA and OHRP.

26. IRB ResponsibilitiesCriteria for IRB approval of research • Risks to subjects are minimized; • Risks are reasonable in relation to anticipated benefit; • Selection of subjects is equitable; • Informed consent is sought from each subject; • Informed consent is appropriately documented. The responsibilities of the IRB are mandated by 45 CFR 46.111

27. Levels of IRB Review • Exempt • Little to no risk involved • Expedited (Short Review) • Research that does not exceed minimal risk • (See 45 CFR 46.102(i) for the definition of minimal risk) • Full Review (Convened Meeting) • Research that exceeds minimal risk

28. Exempt Review Does not mean do NOTHING! When the PI determines that the research involves little to no risk, someone other than the PI must agree (in writing) with the determination. That someone is the IRB Chair (or the designee of the IRB Chair).

29. Exempt Review Risks to subjects are minimized; Review is performed by IRB chairperson or designated experienced reviewer. Example: anonymous survey of a healthy adult population. No signed consent document is required!

30. When *IRB Review Not Needed?45 CFR 46.101(EXEMPT) • Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as (i) research on regular and special education instructional strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods. • Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless: (i) information is recorded in such a a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) and disclosure of the human subjects’ responses outside the research could reasonable place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, or reputation. *The IRB mentioned here refers to the convened Board.

31. When IRB Review Not Needed?45 CFR 46.101(EXEMPT) • Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement) survey or interview procedures, (if no identifiers and no confidentiality risk) or observation of public behavior that is not exempt under paragraph (2 above), if (i) the human subjects are elected or appointed public officials or candidates for public office; or (ii) Federal statutes(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter. • Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.

32. When IRB Review Not Needed?45 CFR 46.101(EXEMPT) • Research and demonstration projects which are conducted by or subject to the approval of Department of Agency heads, and which are designed to study, evaluate, or other examine: (i) public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs. • Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the FDA or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Dept of Agriculture.

33. Expedited (Short Review) Minimal risk to human subjects and involves only procedure in the categories: 1. Research on drugs for which an new investigational new drug application is not required. 2. Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture from (a) healthy, non-pregnant adults weighing at least 110 pounds, not exceeding 550 ml in an 8 week period, and no more than 2 times per week.

34. Expedited (Short Review) (b) Other adults and children, considering the age, weight, and health of subjects. Amount drawn may not exceed the lesser of 50 ml or 3ml per kg in an 8 week period, with collection no more than 2 times per week. 3. Biological specimens by noninvasive means: Hair and nail clippings, excreta, saliva, placenta after delivery, amniotic fluid obtained at time of rupture, subgingival plaque, mucosal and skin cells by scraping, swabbing, sputum.

35. Expedited (Short Review) 4. Collection of data through noninvasive procedures, excluding x-rays or microwaves. Examples: physical sensors on the body surface; moderate exercise; testing of sensory acuity. 5. The study of existing data, documents, records, pathological specimens.

36. Expedited (Short Review) • Collection of data from voice, video, digital, or image recordings made for research purposes. • Research on individual or group characteristics or behavior. • Continuing review of research previously approved by the convened IRB where (a) project is closed to accrual (b) the research remains active only for long-term follow-up. (c) remaining research activities are limited to data analysis.

37. Expedited (Short Review) 9.Continuing review of research that is not greater than minimal risk, but had to undergo initial review by a convened IRB because it did not meet the criteria of categories 2 through 7. Special Note: Related grant protocol packet must be included in the original submission.

38. Full Review (Convened Meeting) • If a study does not fit in the short review scenario, it exceeds minimal risk and must, by default, undergo full review. • Requires the attention of an official meeting of the IRB with an operating quorum. • Investigator(s) must attend the meeting to present the project parameters, explaining the subjects’ involvement.

39. Types of Review • Initial Review • Continuing Review of ongoing research • (required for periods not to exceed 12 months) • Study Closure • notification of closure is required from the PI • Amendment Review (Minor Modifications) • Includes any deviation from the original approval: amendments, revisions & modifications and requires IRB approval prior to implementation • Adverse Event / Unanticipated Problems Review

40. Adverse Events • Unanticipated Problems • Information that impact on the risk/benefit ratio should be promptly reported to, and reviewed by the IRB to ensure adequate protection of the welfare of the subjects. (FDA (1998) Information Sheets) • All investigators are required to report to the IRB any injury (harm caused by involvement in research), deaths and unexpected serious adverse experiences. • When reporting, the Investigator must determine the relationship between the event and the study (definite, possible, probable, doubtful, unknown, not related)

41. InformedConsent • Informed consent is not a document, it is a process. The informed consent document (ICD) provides documentation of the process. • Telephone Consenting requires careful documentation • Confidentiality • Consider Data/Safety Monitoring • Use 2nd person (you), rather than 1st person (I). • Use of “I understand…” on the research ICD is prohibited. • Use well defined headings for each section.

42. The Process of Informed Consent • An exchange of information between the subject and the investigator (or qualified designee) before, during and sometimes even after participation.

43. Formatting the Consent Document • Instructions available on the ICD templates located at http://www.uta.edu/ra/RC/Forms/InternalForms/ICD_Sample_-_Full_Review.doc Document must be written non-technical terms, understandable by a 7th grade reading level. • Format: includes header with project title and investigator name, version date mm/dd/yyyy • Footer must include page number in # of total and an area for initial of subject for each page. • No less than 12 pt. font • Written to the potential subject • Use of standard format is required unless a waiver has been granted.

44. When Can Consent be Waived?45 CFR 46.116 (d)(1)-(4) If the research poses . . . • No more than minimal risk • Research not practicable with consent • Subjects’ rights not adversely affected, AND • Information available later, if practicable See also 45 CFR 46.116(c)(1)(2) or

45. When Can the Requirement to Obtain Signed Consent be Waived?45 CFR 46.117(c)(1)(2) • The only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject’s wishes will govern; or • That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context. • In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research. Final determination must be made by the IRB . . .

46. When is Consent Needed?45 CFR 46.116 • Except as provided elsewhere in this or other subparts, no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative.

47. Required Elements of the Consent Form • Introductory paragraph stating: 1. Invitation to participate in research 2. Admonishment to read the document and ask questions. 3. Make it clear that it is his decision to become involved.

48. Elements of Consent Form • Purpose Specific purpose of the project, how it is related to other knowledge. • Duration Subject’s time commitment to the project.

49. Elements of Consent Form • Procedures – Describe what the subject will do, see, where he will go, what equipment will be used and how. If specimens are collected, explain when, where, and how much will be needed for the project. Hold all technical language to a minimum and when used, explain in lay-language the difficult terms.

50. Elements of Consent Form • Possible Risk/Discomforts State in lay-terms any known risk, side effect or inconvenience that this project may cause. Also state there may be unanticipated risk or discomforts that are unknown.