PRIM&R s At Your Doorstep Program: IRB 250

Transcription

1 PRIM&R s At Your Doorstep Program: IRB 250 Des Moines University 3200 Grand Avenue Des Moines, IA 50312

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3 PRIM&R s At Your Doorstep Program: IRB 250 Des Moines University, Des Moines, IA August 2, 2013 Table of Contents Page Agenda... 1 Continuing Education Information.. 2 Guest Speaker Biography s 3 Presentation Slides Review of Research Beyond Your Backyard. 5 Expedited Review.. 23 Internet Research Research with Children and Adolescents.. 47 Agenda 8 a.m. Registration and Breakfast 8:20 a.m. Welcome and Introduction 8:30 a.m. Review of Research Beyond Your Backyard 9:30 a.m. Break 9:45 a.m. Expedited Review 10:15 a.m. Internet Research 11:15 p.m. Lunch 12:15 p.m. Case Studies 2:15 p.m. Break 2:30 p.m. Research with Children and Adolescents 3:30 p.m. Questions and Answers Session 4 p.m. Adjourn 1

4 Objectives Upon completion of this activity, participants will be able to: 1. Discuss concepts, regulatory requirements, and cross-cultural and ethical considerations that an IRB must consider when the research is conducted beyond the boundaries of its institution, particularly when conducted internationally. 2. Select tools and strategies for acquiring local knowledge of the research setting. 3. Review the federal regulations governing expedited categories, including what types of research are expedited. 4. Review OHRP Guidance on expedited categories, as well as using expedited review. 5. Review recruiting subjects over the Internet, observation of Internet activity, and collecting data over the Internet. 6. Consider IRB review issues, including risk/benefit, consent, participation by minors, and privacy and confidentiality. 7. Discuss electronic data security and IRB review requirements. 8. Analyze the ethical principles as they pertain to subpart D and the regulations. 9. Review what is sufficient pediatric expertise, pediatric risk/benefit assessment and definitions, parental permission and assent, wards of state, and subpart D documentation requirements. Target Audience IRB members and chairs, institutional officials, investigators, research compliance officers, vice presidents of research, and support research staff. Commercial Support Educational grants are not being accepted for this CME activity. Continuing Education Credit M.D.: This activity has been planned and implemented in accordance with ACCME Essential Areas and Elements and Iowa Medical Society (IMS) policies. Des Moines University is accredited by the IMS to provide continuing medical education for physicians. Des Moines University designates this live education activity for a maximum of 6.0 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. D.O.: This activity has been planned and implemented in accordance with the essential areas and policies of the American Osteopathic Association (AOA). Des Moines University is accredited by the AOA and approves this live activity for a maximum of 6.0 hours of AOA Category 2-A CME credits. D.P.M.: Des Moines University is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Des Moines University has approved this activity for a maximum of 6.0 continuing education contact hours. Nursing: Des Moines University (provider #112) is approved by the Iowa Board of Nursing as an accredited provider. This activity has been reviewed and approved for a maximum of 7.2 continuing education contact hours. Other: This live activity was designated for 6.0 AMA PRA Category 1 Credits. 2

5 Guest Speakers George Gasparis is the president of The PEER Consulting Group, LLC. With more than 30 years of experience in the conduct, administration, review, and compliance oversight of research, Mr. Gasparis provides expert consultation for human research protection programs, institutional review boards (IRBs), and principal investigators/research teams. Before starting the consulting company, he served as the assistant vice president and senior assistant dean for research ethics from 2003 to In this capacity, he served as the executive director of the Human Research Protection Program and the IRB Office for Columbia University, Columbia University Medical Center (CUMC), and New York Presbyterian Hospital at CUMC. The Columbia IRB Office managed six IRBs that provided oversight for more than 4,500 total active protocols and more than 1,500 new protocols per year. The office also enhanced regulatory compliance through its Compliance Oversight Team and promoted educational training for researchers through comprehensive training programs. Prior to his arrival at Columbia University in June 2003, Mr. Gasparis was the director for the Division of Assurances and Quality Improvement at the Office for Human Research Protections (OHRP). Prior to his tenure at OHRP from 1996 to 2003, he was the director of the Office of Human Research at The George Washington University (GWU) Medical Center from 1991 to In that capacity he served as the administrator for the GWU Medical Center IRB, director of the Research Pharmacy, and also served on the behavioral IRB for GWU. Mr. Gasparis also has had extensive experience with clinical trials when he was employed at the GWU Lipid Research Clinic (LRC) from 1981 to1991. During his tenure as data manager at the LRC, he managed more than 40 clinical trials, including the National Institutes of Health awards and studies for 10 different sponsors. Mr. Gasparis is a graduate of GWU. He became a Certified IRB Professional (CIP ) in Mr. Gasparis indicated he has no financial relationships to disclose relevant to the content of this continuing education activity. Moira Keane, MA, CIP is the former Executive Director of the University of Minnesota, Human Research Protection Program which includes the Institutional Review Boar d (IRB), and the Institutional Biosafety Committee (IBC). The HRPP oversees the research of all University of Minnesota campuses which encompasses review of basic science, clinical research, and social and behavioral sciences projects conducted by faculty, staff, and students. She is actively involved in subjects protections and served as Chair of the AAHRPP Council on Accreditation, as Vice Chair of the Council on Certified IRB Professionals (CCIP), and as a member of the Secretary s Advisory Committee on Human Subjects Protection (SACHRP) Sub Part A Sub Committee. Ms. Keane indicated she has no financial relationships to disclose relevant to the content of this continuing education activity. 3

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7 Review of Research Beyond Your Backyard George Gasparis The PEER Consulting Group With recognition to Karen Hansen and David Borasky for contributions to some slides and content Learning Objectives Examine IRB review of research outside your institution: international, other U.S. locations, and then your cross-town International codes, regulations, and guidelines and the application of U.S. standards to international research settings Identifying and addressing the challenges of research conducted outside your institution You ve got to be very careful if you don t know where you re going, because you might not get there. Yogi Berra 5

8 International Research Trends More global activity prompted by: Increase in large-scale public health research -Concentrated in developing countries Emerging research markets in China, India, and Eastern Europe/Russia -Large populations of research-ready potential subjects Internet, , telecommunications U.S. Research Trends More research activity prompted by: Industry (Pharmaceutical and Device Manufacturers) Federal Funding Increase in biorepositories/bioinformatics Increase in multicenter studies/collaborations Internet, , telecommunications The application of U.S. research ethics and regulations when reviewing research outside your institution ( beyond your backyard (International or within U.S.) 6

9 Working premise The principles of the Belmont Report are generally an appropriate framework for reviewing overseas research However, often success is gained by referencing international codes -Declaration of Helsinki or CIOMS Belmont Principles and Ethical Basis for U.S. Regulations Respect for Persons Individual Informed Consent Privacy & Confidentiality Vulnerable Populations Beneficence Risk/Benefit Safety Monitoring Vulnerable Populations Justice Subject Selection Vulnerable Populations Respect Overseas Autonomy is a western value -Western researchers must not deny autonomy in subjects anywhere Community (or family or patriarchy) values -must be respected, particularly during consent Autonomy and community can be balanced 7

10 Respect Overseas (cont.) A plausible balance: a study is respectful of persons if it is sensitive to their culture where customs dictate paternal or tribal consent is appropriate, first obtain such consent and, then obtain individual consent Still challenging, however, when enrolling women and such consent is not the norm by local customs Beneficence Minimizing harm to subjects requires -Good information about potential harm, and cultural conditions, norms, and local laws -Objective and accurate information about subjects lives, social conditions, and other local conditions (e.g., standard practice, other potential risks, etc.) May require input from multiple sources -Research staff (both sponsor and host country) -Local IRBs/ethics committees -NGOs, local governmental agencies, other 3rd parties Beneficence (cont.) The special challenge of balancing risk with benefit for those who live dangerous or high risk lives Stigmatized groups sex workers, drug users GLB populations criminals, gang members, etc. Chronically infected persons Impoverished persons 8

11 Justice Who bears the burdens? Should we be in this country in the first place? Objective considerations -Do the subjects come from a group that is affected by the condition being studied? -Assuming the subjects are among those affected by the condition being studies, are they fully representative of all those affected? Justice (cont.) Who bears the burdens? Rational considerations -Would a reasonable person agree to participate? -Would a reasonable third party think it was fair to ask the person to participate? -Is there some unfair incentive or pressure on the potential subjects that makes agreement likely but unreasonable? Justice (cont.) Who benefits from the research? Individual level Community level Post trial access issues 9

12 ABCs of 45 CFR 46 Every institution engaged in DHHS-supported or conducted human subjects research needs: A. Assurance of Compliance Approved by OHRP B. Board Approval (i.e., IRB, REB, ethics cmte.) C. Consent Obtained from Each Subject, Unless Waived by the IRB D. Disclosure: Reporting of Unanticipated Problems/Risks or Noncompliance FDA Regulations Any research involving a drug, device (interventional or diagnostic), or biologic in which the data will be used for supporting marketing approval by the U.S. FDA must comply with the appropriate FDA regulations: A. Investigational Drugs 21 CFR 312 B. Investigational Biologics 21 CFR 600 C. Investigational Devices 21 CFR 812 All of the above must comply with 21 CFR 50 (Informed Consent) and 21 CFR 56 (IRB Review) OHRP Guidance Engagement of Institutions in Research -Provides guidance on when one is or is not engaged in human subjects research. -One area that guidance is provided is when one is conducting research vs. providing a service for research 10

13 Are Agreements Necessary? -IRB Authorization Agreement (IAA) -Individual Investigator Agreement (IAA) -Business Associates Agreement (IIA) -Confidentiality Agreement -Data Use Agreement (DUA) -Materials Transfer Agreement (MTA) -Clinical Trials Agreement What Makes Clinical Research in Developing Countries Ethical? E. Emmanuel, et al., What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research, JID 2004:189, What Makes Clinical Research in Developing Countries Ethical? E. Emmanuel, et al. (cont d) 1. Social Value: research must enhance knowledge or health in the research setting 2. Scientific Validity: research design can answer study objectives; study is feasible within the research setting 3. Fair Subject Selection: vulnerability and privilege are not used to determine who joins the trial. Communities for research and subject selection are based on scientific objectives. 11

14 What Makes Clinical Research in Developing Countries Ethical? E. Emmanuel, et al. (cont d.) 4. Favorable Risk Benefit Ratio: risks are minimized; benefits enhanced; and potential benefits to society and the participant outweigh the risks. 5. Independent Review: unaffiliated individuals review the research and approve, amend, or terminate it. 6. Informed Consent: participants should be informed about the research and provide their voluntary consent. What Makes Clinical Research in Developing Countries Ethical? E. Emmanuel, et al. (cont d) 7. Respect for Participants and Communities: protect privacy, allow withdrawal from the trial, provide new information; monitor well-being; inform them of study results. 8. Collaborative Partnership: respect community s values; benefits participants/communities; develop the capacity of researchers, the health setting, and the community. International Codes, Guidelines and Regulations 12

15 Before we go any further! What does your FWA say you will apply when reviewing research? Ethical codes or standards Belmont? (= should ) Procedural standards 45 CFR 46? All sub-parts? Regardless of funding source? (= must ) You must do what your FWA says you will do regardless of where the research will be conducted! Codes, Guidelines, and Regulations Code: a system that governs procedure or behavior in particular circumstances or within a particular profession Guideline: an official recommendation indicating how something should be done or what sort of action should be taken in a particular circumstance Regulation: an official rule, law, or order stating what may or may not be done or how something must be done; an order issued by a government department or agency that has the force of law Codes, Guidelines, and Regulations The Nuremburg Code A product of the war crimes trials prosecuted following World War II in Nuremburg, Germany. Voluntary consent absolutely essential Now viewed from a historical perspective 13

16 Codes, Guidelines, and Regulations The Declaration of Helsinki Goes further than Nuremburg Numerous revisions Paragraphs on placebo and post-trial access in 2000 and 2002 versions were contested and subsequently revised Available in English Codes, Guidelines, and Regulations CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects Developing country focus Vulnerable populations issues Requires compensation for research related injury Available in multiple languages Codes, Guidelines, and Regulations International Conference on Harmonization Guidelines for Good Clinical Practice (ICH GCP) Developed by US, Europe, Japan Goal = standardize drug development and registration process Available in English and Spanish 14

17 Codes, Guidelines, and Regulations National Bioethics Advisory Committee Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries Developing country focus Viewed through the lens of US requirements Available in multiple languages Codes, Guidelines and Regulations The Common Rule & FDA Regs Indian Council of Medical Research Australia: National Statement on Ethical Conduct in Human Research Procedures and Guidelines for the Conduct of Research in Malawi Guidelines on Ethics for Health Research in Tanzania Terms of Reference for the Regional Committees for Medical Research Ethics, Norway Application of U.S. Regulations OHRP has held the position that HHS-supported international research must comply with 45 CFR 46 and its subparts as its minimum regulatory standards. -Exception can only be granted by Secretarial waiver under 101(h) or 101(i) 15

18 Identifying Codes, Regulations, and Guidelines Practical Approaches: Resources for identifying regulations, policy or law 1. OHRP Website: International Compilation of Human Research Protections 2. Harvard School of Public Health Global Research Ethics Map D=564576&CFTOKEN= CITI International Training Platform, Module 4: International Studies components entitled: An Overview of International Studies (Appendix A) and Comparison of International Guidelines for Research Involving Humans Identifying and addressing the challenges of research conducted at non-us sites (BUT, also applies to research outside of your community) Challenge: Developing Country Settings G2 16

19 Addressing the Challenges Know the environment where the research will be conducted Rural or urban Type of site (clinic, hospital) Site research experience Relevant standards of care Challenge: Study Population Research with Non-traditional Vulnerable Populations Stigmatized communities High poverty Illiterate populations 17

20 Addressing the Challenge Is research in the population justified? Are mechanisms in place to minimize additional risks? Confidentiality Fair compensation Understandable consent / enhancements to the consent process Challenges: Informed Consent The Application of Western Informed Consent Standards Abroad Different beliefs about autonomy Role of elders / community leaders Translation issues Documentation issues Addressing the Challenges Ensure the IRB s understanding of the informed consent process for a study Who will obtain consent? Where will the consent process take place? How long will it take? How are translations handled? 18

21 Addressing the Challenges Ensure the IRB s understanding of the informed consent process for a study Identify local parental permission requirements Understand who can give consent for orphans and other children in unique circumstances Challenges: Research with minors Research with Minors Local definitions of minor (you may get conflicting answers document source) Research on sensitive topics Research with AIDS orphans Research with foster children Challenges: Local Laws Knowledge of local research settings Absence of laws/regulations Local law versus standard practices Varying quality/existence of local IRBs Multi-national research = multiple local norms 19

22 Addressing the Challenges Who will supervise the study when the PI is not there? Are there collaborating investigators? FWAs? Individual Investigator Agreements? Subcontracts? What training will be provided? By whom? Addressing the Challenges How will data be brought back to the U.S.? Does HIPAA apply? Samples brought back? Permit from CDC for infectious agents? (USPHS 42 CFR 71); details on CDC website Data Security Export Control Laws Addressing the Challenges Don t be influenced by stereotypes of a setting or past information that may no longer be true; as demonstrated by the past few slides, the world is changing fast. Obtain current, objective, and accurate information about a setting, its norms, and customs. 20

23 Addressing the Challenges Obtain a consultant from the setting or with experience of the setting Establish dialogue with local IRB Consult with OHRP International Activities staff Additional Strategies Create a supplement to your IRB application Require attendance at IRB meetings by PI Require more rigorous/frequent monitoring Document resources/consultants for review of current study and for future reference Additional Strategies Use the CIA website (CIA World Factbook) Use Google Maps or Google Earth 21

24 References 1. C. Milford, et al., Resources and Needs of Research Ethics Committees in Africa: Preparation for HIV Vaccine Trials, IRB 2006: 28, E. Emmanuel, et al., What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research, JID 2004:189, Office for Human Research Protection (OHRP) International Issues website: 4. National Bioethics Advisory Committee 5. Collaborative IRB Training Initiative International Acknowledgement(s) Karen Hansen, David Borasky Renee Holt, JD, MPH, RN Dawn Fitzgibbons, MPH Wenjin Li, MD, MPH Steven M. Shaber, JD Partnership for Enhancing Human Research Protections in Africa Collaborative IRB Training Initiative - International Questions & Comments 22

25 Expedited Review Moira Keane, MA, CIP Retired, HRPP Executive Director, University of Minnesota August 2, 2013 Learning Objectives To review and understand Federal regulations that govern expedited review OHRP guidance and interpretations Practical tips for using expedited review Underlying Concepts Some research warrants oversight, but is of low-enough risk that a full IRB s attention may be a poor use of resources Federal regulations therefore allow for some research to be reviewed by less than a full quorum an experienced member or a subcommittee The criteria for approval are the same; there s just more flexibility in how review proceeds 23

26 4 Criteria for the Approval of Research 4 Main Criteria (45 CFR / 21 CFR ) (a)(1) Minimization of risks (a)(2) Risk-benefit relationship (a)(3) Equitable selection (a)(4) Consent process (a)(5) Consent documentation (a)(6) Data monitoring (a)(7) Privacy/confidentiality (b) Vulnerable subjects The IRB (or reviewer using the expedited procedure) must determine that criteria delineated in all three boxes are met. Consent Process (45 CFR , 21 CFR 50.20, 50.25) Intro Consent process (a) Required disclosures (b) Additional disclosures (c) Waiver #1 (d) Waiver #2 Consent Documentation (45 CFR , 21 CFR 50.27, ) (a) General (b)(1) Long form (b)(2) Short form (c)(1) Waiver #1 (c)(2) Waiver #2 (Not FDA) Courtesy of Jeffrey Cooper, M.D. Federal Regulations 45 CFR and 21 CFR Carried out by IRB chair or one or more experienced IRB members who must be designated by the chair Reviewers may exercise all of the authorities of the IRB except disapproval i.e., they can either approve or require modifications to secure approval Any other action (including deferral ) is not allowed All IRB members must be advised of research approved under expedited review Federal Regulations 45 CFR (b) and 21 CFR (b) An IRB may use the expedited review procedure to review either or both of the following: (1) some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk, (2) minor changes in previously approved research during the period (of one year or less) for which approval is authorized. 24

27 Caveats Not all minimal risk research is eligible for expedited review Just because research is in one of the eligible categories doesn t mean it is eligible for expedited review In order to be eligible for expedited review, research must be both on the list of eligible categories and meet the three applicability criteria: No more than minimal risk; and Not be classified research; and If identification of the subjects or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects financial standing, employability, insurability, reputation, or be stigmatizing, reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal. Minimal Risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. 45 CFR (i) and 21 CFR (i) Minor Changes Regulations do not define minor change A minor change is something that does not alter the risk/benefit balance in an important way A minor change is something that does not alter the consent burden or the ability to get consent in an important way When in doubt send to full board 25

28 HRPPs should establish criteria for Minor Changes For example: no substantial alteration in the level of risks to subjects; the research design or methodology; the number of subjects enrolled in the research; the qualifications of the research team; or the facilities available to support safe conduct of the research What it is.what it is not Expedited review is a process to review Proposed research Modifications to previously approved research Continuing review of research It is not a process to Handle emergency use of a test article Grant exemption determinations Review serious adverse events/unanticipated problems Evaluate noncompliance Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure Last revised Nov 9, guidance/expedited98.htm 26

29 Federal Regulations Categories Eligible for Expedited Review Clinical studies where IND/IDE NOT required Blood samples (routine methods, small amounts) Noninvasive prospective collection of biological samples Noninvasive collection of clinical data Existing data or specimens, or to be collected for nonresearch purposes Voice, video, digital recordings for research Individual or group behavior, surveys, interviews, oral histories Selected types of continuing review Categories in Federal Regulation (1) Clinical studies of drugs and medical devices only when condition (a) or (b) is met. (a) Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required. (Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review.) (b) Research on medical devices for which (i) an investigational device exemption application (21 CFR Part 812) is not required (includes abbreviated IND devices); or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling. Examples Study comparing Tylenol against Motrin for simple tension headache Study comparing patient satisfaction among three brands of compressive sleeve for lymphedema 27

30 (2) Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows: (a) from healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 times per week; or (b) from other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week. NOTE: OHRP considers withdrawal of blood through an indwelling line to be a venipuncture. OHRP considers each access to an indwelling line to be a venipuncture, not each puncture of the vein. (3) Prospective collection of biological specimens for research purposes by noninvasive means. * Examples: urine (no catheter); saliva (no catheter); sputum; stool; buccal swabs; nail clippings; hair clippings; placenta or amniotic fluid at delivery; spontaneously shed teeth. *nb: this category does not mention intended use of the specimen 4) Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.) 28

31 (5) Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for nonresearch purposes (such as medical treatment or diagnosis). nb: THE COMMA! It is OK to use expedited review if the materials were generated in a previous research study or in routine clinical care; the idea is that they are not being generated without oversight or specifically for the current study (6) Collection of data from voice, video, digital, or image recordings made for research purposes. nb: Subjects might be identifiable from such recordings, so the expedited reviewer must be attentive to confidentiality provisions. (7) Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. nb: SACHRP has recommended that category 7 should be expanded to more clearly accommodate social, behavioral, epidemiologic, health services and educational research and related methods Federal Register notice 10/26/07 29

32 Minimal Risk risk without This sort of research may have hidden or soft risks, like cultural affront or embarrassment The challenge may be recognizing when there is actually greater than minimal risk, despite a seemingly harmless design Conversely, we are not obligated to apply the worst case scenario to every study Expedited reviewer needs some social science insight (8) Continuing review of research previously approved by the convened IRB as follows: (a) where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term followup of subjects; or nb: three applicability criteria still apply e.g., long term follow-up procedures cannot expose subjects to greater than minimal risk and the research cannot be classified (b) where no subjects have been enrolled and no additional risks have been identified; or nb: Research can be greater than minimal risk. Wording is not no subjects have been enrolled since last review (c) where the remaining research activities are limited to data analysis nb: three applicability criteria still apply (9) Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified. nb: This means that Once full board, always full board is NOT a rigid rule the convened IRB can say If no surprises, this one s low enough to be expedited for continuing review. Cannot be used for classified research. 30

33 Guidance on the Use of Expedited Review Procedures Updated August 11, OHRP Guidance As with review by the convened IRB, expedited review must fulfill all the requirements of review found at 45 CFR and subparts B, C, and D, if applicable IRBs are reminded that the requirements for informed consent (or for altering or waiving the informed consent process or the consent documentation) apply regardless of whether research is reviewed by the convened IRB or under an expedited procedure OHRP recommends that documentation include: (a) the specific permissible categories justifying the expedited review; and (b) documentation of the review and action taken by the IRB Chairperson or designated reviewer and any findings required under the HHS regulations; written IRB procedures include a description of policies describing the types of minor changes in previously approved research; and expedited review procedures NOT be used for research involving prisoners. However, if an IRB chooses to use expedited review for research involving prisoners, OHRP recommends that the prisoner representative of the IRB be one of the designated reviewers. 31

34 Practical Tips for Using Expedited Review Procedures Expedited review is not Review Lite All of the regulatory requirements for IRB review at a convened meeting except voting apply equally to expedited review Expedited review must be just as thorough as review by the convened IRB The expedited reviewer must receive all of the information and material that reviewers receive for a convened IRB review Approval under expedited review requires no further review by the IRB The full IRB simply needs to be advised of all expedited approvals Most institutions use a simple listing attached to agendas and/or minutes Some institutions post the list on an internal IRB website Essential Documentation Because there are no minutes, expedited review must be documented in the protocol file, including: the category under which it was approved and the justification for inclusion under that category documentation of review and action by reviewer (e.g., review sheet, checklist, etc.) all findings required in the regulations and protocol-specific findings supporting those determinations 32

35 Summary: Federal regulations allow for expedited review In order to eligible for expedited review research must meet all three applicability criteria and be on the list of eligible categories Expedited review is not review lite References 45 CFR CFR 50 and 21 CFR FR , November 9, Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure OHRP Guidance: Guidance on the Use of Expedited Review Procedures Updated August 11,

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37 Internet Research George Gasparis The PEER Consulting Group Thanks Slide template originally developed by Jeff Cohen, Ph.D. and PRIM&R Staff. Michael Oakes, Ph.D. is also recognized for contributions on a couple of slides. Learning Objectives Types of Research Activities on the Internet IRB Review Issues IRB Review Requirements 35

38 Types of Internet Research Research Activities on the Internet Recruiting Subjects over the Internet Observation of Internet Activity Collecting (or transmitting) Data Over the Internet Experimental Trials Observation of Internet Activity, Survey, or Intervention Observation (disclosed or undisclosed) Gathering information about use of Internet, recording users comments e.g., observation of grieving discussion group, using cookies to track sites visited Mining social networking sites for observational studies Survey Lurking or actively manipulating virtual worlds (avatars, second life, etc.) 36

39 Experimental Trials Internet based intervention such as HIV prevention among MSM Randomize subjects (recruited from net) to experimental conditions Follow subjects and collect data IRB Review Issues Recruiting Subjects Over the Internet IRB needs to review all of the information presented to subjects: invitation and reminder text sender and subject lines Mixed media recruitment materials: -flyers, advertisements, letters, etc. 37

40 Gathering data over the Internet IRB needs to review all plans on how subjects will be approached, observed, and how data will be collected and stored (e.g., data collection forms, instruments, surveys, access to survey web site, details of software, servers, data security plan, etc.) IRB issues: consent, confidentiality and participation by minors, data security Experimental Trials IRB Issues? Recruitment (age?) Consent Sensitive interventions Sensitive questions Data protection Adverse events Bots and other fakes Payment? IRB Review Issues Research on the Internet presents new concerns to traditional IRB issues of: Risk/Benefit Consent Participation by minors Privacy & Confidentiality 38

41 Risk Two sources of harm: participation in the research No direct contact with subjects Can t deal with individual reactions (intervention or debriefing) breach of confidentiality Primary source of harm in most Internet research Challenges of Internet Research and Effect on Benefits Conducting research on the Internet raises concerns about reliability and validity of data skewed subject populations ease with which subjects can mislead investigators difficulty in preventing multiple submissions Invalid research can have no benefit. inappropriate if any risk to subjects Consent IRBs can waive requirement for consent where appropriate [45 CFR (d)]. If consent is required, IRBs can waive requirement for documentation of consent where appropriate [45 CFR (c)]. 39

42 Consent Where consent required but documentation is waived, a portal can be used to provide consent information. Subjects must click on consent page to get to next page. Where written consent required, it is currently not possible to get a signed consent form over the Internet. Can have subjects submit signed consent form and get password for access to web site. Use of electronic signatures for consent or parental permission Consider relevant laws in the jurisdiction where the research is going to be conducted. Unless the IRB waives a signed consent,a written consent which may be an electronic version, must be given to and signed by the subjects or LAR Must be format that signatures must be legally valid within the jurisdiction where the research is to be conducted. OHRP does not mandate a specific method of electronic signature. Use of electronic signatures for consent/parental permission (cont d) IRBs must adopt technologies and consider how the electronic signature is being created, if the signature can be shown to be legitimate, if the consent document can be produced in hard copy for review by the potential subject. Example: use of a secure system for electronic or digital signature that provides an encrypted identifiable signature. If properly obtained, an electronic signature can be considered an original for the purposes of recordkeeping. (based on OHRP Q&A) 40

43 Participation by Minors Where research qualifies for waiver of parental permission, no additional safeguards are required. minors can participate without permission simple statement in consent that participant is over 18 Where parental permission required, use options for consent. Participation by Minors To screen out minors: use Internet Monitoring software (SafeSurf and Internet Content Rating Association ratings) use Adult Check systems None of these are foolproof Since there is no guarantee that minors won t access research, some research may not be appropriate for the Internet. Privacy & Confidentiality New concerns to traditional IRB issues of privacy & confidentiality Privacy concerns Is activity or are data identifiable? Constitutes public or private behavior? Confidentiality concerns inappropriate disclosure of information obtained over the Internet 41

44 Privacy Identifiable vs. Anonymous Online participants usually use pseudonyms (screen names, handles, etc.) Although not publicly linked to actual names, identities can often be readily ascertained (e.g., using search engine) People s online identity may be as important to them as their actual identity Privacy Public vs. Private Behavior Most online activity is open to the public Federal regulations base the definition of private information on the subjects reasonable expectation of privacy In many situations (e.g., chat rooms), participants expect privacy and don t expect their activity to be studied (is there a password?) Determination of privacy more complicated than it seems Anonymity? Are IP addresses identifiable information, like name, address or SSN? IP addresses are often critical for internet researchers (they offer evidence of bot attacks and so forth). An IP address does not generally uniquely identify an individual. In some cases, it uniquely identifies a specific computer on the network (which may or may not be used by multiple individuals). Some IP addresses are used by public access computers or networks in cafes, libraries, etc 42

45 IP Anonymity Solutions Include in the consent process a brief statement that IP address can sometimes identify specific computers or networks, and that individuals concerned about such identification may wish to use public computers or networks such as those at public libraries, internet cafes, etc. Any mapping of IP addresses to survey responses should be destroyed after deduplication, payment, and cleaning of the final data set is concluded. Confidentiality Two potential sources of breach of confidentiality inadvertent disclosure Investigator who sent out research database to entire Listserv Investigator s computer was stolen deliberate attempts to gain access Hacking into research data Technology can provide reasonable security but cannot guarantee absolute security Some survey tools do not have robust security Confidentiality Data transmitted via cannot be anonymous without the use of additional steps. Almost all forms of contain the sender's address. use an "anonymizer" - a third party site that strips off sender's address Web servers automatically store a great deal of personal information about visitors; information can be accessed by others. 43

46 Confidentiality Degree of concern over confidentiality depends on sensitivity of the information Since it is impossible to guarantee absolute data security over the Internet, some extremely sensitive research may not be appropriate for the Internet, but IRBs should weigh risks IRB Approval Criteria Related to Data Security Risks to subjects are minimized by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. IRB Approval Criteria Related to Data Security (cont d) When appropriate, there are adequate provisions to maintain the confidentiality of data. When appropriate, there are adequate provisions to protect the privacy of subjects. 44

47 Data Security How to Minimize Risk Physical Security Locked rooms & locked computers Limited services on computers and up-to-date computer security software Access authentication Control access privileges Strong passwords Data encryption and firewalls Regular secure backups Secure equipment disposal Adequate technical support and regular security audits IRB Review Requirements IRB Review - Key Requirements Investigators must provide technical information on how to deal with these issues IRBs need sufficient expertise (or seek expert consultation) on technical aspects of the Internet to ask appropriate questions and evaluate information provided. IRBs that review Internet research without sufficient expertise are not in compliance with regulations 45

48 Summary Use of the Internet for research is likely to continue to increase Research on the Internet presents different concerns to traditional IRB issues Electronic transmission and storage of data are key areas for risk analysis IRBs need to have sufficient expertise on technical aspects of the Internet in order to ask the right questions and evaluate information provided Resources Association of Internet Researchers- Ethical Decision-Making and Internet Research (2012) American Psychological Association Report of the Advisory Group on the Conduct of Research on the Internet (2003) American Association for the Advancement of Science --Report on Internet Research (1999) 46

49 Research with Children and Adolescents Moira A Keane, MA, CIP Retired, University of Minnesota Human Research Protection Program, Executive Director Learning Objectives Become familiar with Historical context for regulations Ethical principles as they pertain to Subpart D Regulations What is sufficient pediatric expertise? Pediatric risk/benefit assessment and definitions Parental permission and assent Considerations for Wards of State Subpart D documentation requirements Thalidomide Tragedy 47

50 1962: Kefauver-Harris Amendments Drug amendments of 1962 were enacted in response to Thalidomide related birth defects Preclinical testing using animals Required IND submission to FDA for human studies Required Ethical scientific pre-review Not Required Informed Consent of Human Subjects Loosely Required 28 FR 179 (Jan. 8, 1963) The Landmark Willowbrook Hepatitis Study Willowbrook Hepatitis Study Study Site: Willowbrook State School Subjects: Severely mentally retarded children Purpose: Study the natural history of hepatitis Intervention: Subjects were fed viral laden extracts of stool (gg+v and v only). Potential Risk: Chronic liver disease ( v only ) Potential Benefit: Immunity via a sub clinical infection Parental Consent: Coerced by admittance restriction 48

51 Congress Reacts to Willowbrook and Other Ethical Lapses Appointment of The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research marks the beginning of the era of protectionism Public Law , July 12, 1974 Charge: Determine how to best to protect children who participate in research Historical Context early 1970s 1972: Revelations of the Tuskegee Syphilis Study Anti-war movement strong -- war ending 1973 Individual and Civil Rights Movements active with some results 49

52 National Commission Report FR 43 (No. 9), January 13, 1978 The report and recommendations of the National Commission lead to the promulgation of additional protections for children involved in research. HHS Regulations at 45 CFR 46, Subpart D Additional Protections for Children Involved as Subjects in Research FR 48 (No. 46), March 8, 1983 effective June 6, 1983 On April 24, 1979 FDA proposed regulations equivalent to the HHS Subpart D. 1 The regulation was never finalized and was withdrawn December 30, FR 24106, April 24, FR 67440, December 30, 1991 Therapeutic Orphans From , the percentage of FDA approved drugs which contained no pediatric labeling was 71-81%. FDA Status Report to Congress, Jan

53 Congress and FDA Actions 1997 Food and Drug Administration Modernization Act (FDAMA), P.L , Final Pediatric Rule, (63 FR 66632, ) 2002 Best Pharmaceuticals for Children Act (BPCA), P.L , Final Pediatric Rule (overturned by U.S. District Court, District of Columbia) 2003 Pediatric Research Equity Act (PREA), P.L , Pediatric Research Equity Act (PREA) Signed into law December 3, 2003 Mimics the Final Pediatric Rule Requires pediatric studies of certain drugs and biologics Authorizes the Pediatric Advisory Committee FDA Regulations at 21 CFR 50, Subpart D Interim Final Rule FR 66 (No. 79), April 24, 2001 effective April 30, 2001 Final Rule FR 78 (No. 38), February 26, 2013 effective March 28, 2013 The Children s Health Act of 2000 required FDA to ensure that FDA regulated clinical investigations comply with Subpart D by April 17, Title XXVII, Section 2701, Children s Health Act, (Public Law ), 10/14/

54 Current Regulations DHHS- Protections for Children Involved as Subjects in Research (Subpart D, 45 CFR ) Adopted March 8, 1983 FDA- Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products ( 21 CFR 50 and 56) Final rule February 26, 2013 Ethical Principles in The Belmont Report Beneficence Do no harm Maximize possible benefits, minimize possible harms Respect for Persons Recognize the autonomy of persons Protect those with diminished capacity Informed Consent Process Justice Burdens and benefits of research distributed fairly Fair and just subject selection Tension in Belmont Principles Respect for Persons Justice (Equal Moral Force) Protect Those with Limited Autonomy Fair Share Research Benefits Limit Research with Children (Tension) Promote Research in Children 52

55 Definition of Children , 50.3(o), Children " are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted (state, provincial, or tribal law) For NIH inclusion purposes age is 21 Emancipated/mature minors-state law Exemptions (b) (1) and b(3) through (b)(6) are applicable to research involving children (b)(2) Exemption for research involving educational tests is unchanged Exemption for research involving survey or interview procedures or observation of public behavior does not apply to research covered under subpart, exception observations of public behavior when the investigator does not participate in the activity being observed Sufficient Expertise on the IRB FDA 21 CFR HHS 45 CFR If an IRB reviews research that involves a vulnerable population, such as children, consideration shall be given to the inclusion of one or more individuals knowledgeable about and experiences in working with those subjects 53

56 Composition of the IRB Pediatric/child/adolescent expertise (scientific, psychological, social, developmental, emotional) Community/public advocacy specific to pediatrics/children/adolescents Legal expertise (emancipated/mature minors, who is a guardian, state laws pertaining to consent for drug addiction, sexually transmitted diseases, birth control access, foster care, no child left behind) Experts in methods used in pediatric research (blood volume, special pediatric labs, methodology to minimize number of subjects, working within school settings) National Commission: Principles for Guidance Risk/Benefit Sliding scale" for research involving children classified into one of four categories according to the risk and the potential for direct benefit to the child. as risk-benefit relationship of the research become less favorable, additional requirements must be satisfied. Inclusion of Children Minimal Risk [45 CFR , 21 CFR 50.51] Greater than minimal risk; with direct benefit [45 CFR , 21 CFR 50.52] Greater than minimal risk/ no direct benefit/ will yield generalizable knowledge [45 CFR , 21 CFR 50.53] Not otherwise approvable but opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children Federal Review (RARELY USED) [45 CFR , 21 CFR 50.54] 54