External IRB Review What Does it Mean for Your Institution

External IRB Review What Does it Mean for Your Institution Wesley G Byerly, Pharm.D. Associate Vice President for Research Integrity and Regulatory Affairs University of Connecticut and UCONN Health HCCA Research Compliance Conference June 5 8, 2016 Baltimore, MD What are IRBs Charged to Do? Notify investigators and the institution in writing of its decision to approve or disapprove the proposed research activity, or of modifications required to secure IRB approval of the research activity Conduct continuing review of research at intervals appropriate to the degree of risk, but not less than once per year Have the authority to observe or have a third party observe the consent process and the research Have the authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected serious harm to subjects. Maintain adequate documentation of IRB activities 45 CFR 46 1

What are IRBs Charged to Do? Approve, require modifications in (to secure approval), or disapprove research activities Require that information given to subjects as part of informed consent is in accordance with regulation May require that additional information be given to the subjects when in the IRB's judgment the information would meaningfully add to the protection of the rights and welfare of subjects Require documentation of informed consent or may waive documentation 45 CFR 46 What are the Institutions Responsibilities? Designation of one or more IRBs Ensure designated IRBs have: A list of IRB members Written procedures Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of Any unanticipated problems involving risks to subjects or others Any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB Any suspension or termination of IRB approval Ensuring all other institutional and regulatory requirements are met 45 CFR 46 2

Process Submission IRB Review Require Modifications Approve Disapprove Return to Investigator Notify Investigator Notify Investigator Other Institutional or Regulatory Requirements Begin Study Research Study Models Single site Multi site Sites conducting the same protocol Multi site Multiple sites recruiting and involved in study interventions Coordinating center Statistical / data center Lab/ Reading / Bio specimen analysis 3

Why Rely on Another IRB? The federal system for protecting research subjects was designed decades ago, when most research studies took place at a single institution. These days, if a study is conducted at multiple sites, an ethics review by an institutional review board (IRB) may be repeated many times. This practice has been criticized for both wasting resources and leading to inappropriate delays in the conduct of research. Jerry Menikoff, Director OHRP Variability in Multi IRB Review Academic Medicine, Vol. 87, No. 12 / December 2012 4

Variability in Multi IRB Review Design: Descriptive analysis of survey information and informed consent forms from 16 IRBs from the institutions participating in a multicenter trial comparing lower vs. traditional tidal volume ventilation in patients with acute lung injury. Results: Surveys and IRB approved consent forms were obtained from all of the contacted IRBs (n = 16). Variability was observed among several of the research practices; one IRB waived the requirement for informed consent, five IRBs permitted telephone consent, and three IRBs allowed prisoners to be enrolled. Three consent forms contained all of the basic elements of informed consent outlined in the federal regulations, and 13 forms had varying numbers of these elements absent (six forms without one element, four without two, one without three, and two without four). Reading levels of the consent forms ranged from grades 8.2 to 13.4 (mean 6 SD was 11.6 1.2 grade level) Crit Care Med 2001;29: 234 41 Variability in Multi IRB Review Design: 82 investigators from 44 US medical centers were surveyed regarding their local IRB (e.g., frequency of meetings, membership), IRB queries and concerns related submission of a multicenter, randomized, double blind, placebo controlled trial of outpatient therapy for acute asthma. Results: Both surveys had 100% response rate. Investigators submitted applications a median of 58 days (interquartile range [IQR], 40 83) after receipt of the protocol, and IRB approval took an additional 38 days (IQR, 26 62). Although eight applications were approved with little or no changes, IRBs requested an average of 3.5 changes per site. Changes involved study logistics and supervision for 45%, the research process for 43%, and the consent form for 91%. Despite these numerous requests, all eventually approved the basic protocol, including inclusion criteria, intervention, and data collection. Academic Emerg Med 2001; 8:636 641 5

Variability in Multi IRB Review Design: a systematic review of the empirical literature evaluating IRBs included an analysis of 16 published studies located that evaluated variation in the processes and/or outcomes of review by different IRBs for multicenter studies. Results: The studies demonstrated variation in: Type of review required Time required to review the proposed research Designation of risk level Acceptable methods for recruitment of subjects Number and type of IRB concerns expressed or changes required J Empir Res Hum Res Ethics. 2011 March ; 6(1): 3 19 Challenges and Barriers to Non Local IRB Review Review quality Local context Regulatory and legal liability Control and accountability Logistics Loss of income BMC Medical Ethics 2011, 12:13 Using Central IRBs for Multicenter Clinical Trials in the United States. 2013 PLoS ONE 8(1): e54999. doi:10.1371/journal.pone.0054999 6

Common Rule and FDA regulations provide for External IRB and other cooperative IRB review arrangements OHRP Cooperative research projects are those projects which involve more than one institution. [An] institution participating in a cooperative project may enter into a joint review arrangement, rely upon the review of another qualified IRB, or make similar arrangements for avoiding duplication of effort. FDA institutions involved in multi institutional studies may use joint review, reliance upon the review of another qualified IRB, or similar arrangements aimed at avoidance of duplication of effort. 21 CFR 56.114 45 CFR 46.114 To Rely on a Non Institutional IRB Must document arrangement in a written agreement that outlines [the] relationship and includes a commitment that the IRB will adhere to the requirements of the institution s FWA (OHRP s Terms of FWA #6) IRB Authorization Agreement (IAA), also called Reliance Agreement, negotiated and executed Policies and procedures to delineate responsibilities implemented External IRB ensures process and ability to addresses local issues OHRP 7

NPRM Why Now? Any institution located in the United States that is engaged in cooperative research must rely upon approval by a single IRB for that portion of the research that is conducted in the United States. The reviewing IRB will be selected by the Federal department or agency supporting or conducting the research or, if there is no funding agency, by the lead institution conducting the research. Federal Register /Vol. 80, No. 173 /Tuesday, September 8, 2015 / Proposed Rules Why Now? Request for Comments on the Draft NIH Policy on the Use of a Single Institutional Review Board for Multi Site Research Release Date: December 3, 2014 Response Date: January 29, 2015 Purpose: The National Institutes of Health (NIH) is seeking public comments on a draft policy to promote the use of a single Institutional Review Board of record for domestic sites of multi site studies funded by the NIH. http://grants.nih.gov/grants/guide/notice files/not OD 15 026.html#sthash.pb6R5AAT.dpuf 8

Why Now NIDDK: Type 1 Diabetes TrialNet Clinical Centers (U01) Posted June 18, 2013 http://grants.nih.gov/grants/guide/rfa files/rfa DK 13 010.html Central Institutional Review Board (IRB) NIDDK will give preference to Clinical Centers agreeing to use a central IRB of record to accelerate IRB approval in multi center trials. To that effect, the network will use a federated" IRB model. This model gives participating institutions the option to choose one of three tiers of IRB review: Tier 1 indicates reliance on a central IRB as IRB of record; Tier 2 indicates designation of a central IRB as IRB of record in addition to involvement of a local IRB; Tier 3 indicates reliance on a local IRB. Why Now? 21st Century Cures Act Independent versus Institutional IRB Review Calls for rule changes that reduce delays, updates language to accommodate multi site studies, and acknowledge any local concerns Requires that all research allow the possibility for central review, whether that is by independent IRB, joint review, or another institution s IRB Requires that new guidelines address concerns over local liability for decisions made elsewhere. Calls for continued local review by incorporating community values through the use of local institutional review boards. Could complicate IRB review across multiple sites, possibly by requiring a shared review of any research Central IRB Review for Devices Changes device regulations to match corresponding drug research guidelines and allow central IRB review of device studies 9

Non Institutional IRB review models Facilitated Review A shared responsibility between central and local IRB The central IRB makes initial decisions, and then a local IRB rereviews the decisions and possibly amends them Example: National Cancer Institute s CIRB used a facilitated model until 2012. Reliance Model IRBs share SOPs, informed consent documents and other information that allows IRBs to pool resources, compare best practices, facilitate work on multi site studies and sometimes accept each other s decisions Example: IRBChoice Quorum IRB 2016 National Conference on Alternative IRB Models, Nov 19 21, 2006 Non Institutional IRB review models Lead IRB or IRB of Record A model common to NIH funded studies. In a multi site study, the sponsor of a multi site study establishes one institution s IRB to oversee the study. The other locations can accept that jurisdiction, or opt to review the research themselves.. Example: NeuroNEXT Consortium/Regional A group of research sites, universities or hospitals share form a new entity to manage, audit and monitor research, and provide IRB oversight Example: BRANY Quorum IRB 2016 National Conference on Alternative IRB Models, Nov 19 21, 2006 10

Non Institutional IRB review models Independent IRBs Free standing review committees which have no direct or permanent affiliation to a research organization conducts review on behalf of one or more research sites, which accept the independent review (no local review by each site). Independent IRBs can have review authority over one, some, or all of the sites in one protocol, over some portion of an institution s research such as all clinical trials, or over a single protocol. Examples: Quorum, Western IRB (WIRB), Schulman, New England and others Quorum IRB 2016 National Conference on Alternative IRB Models, Nov 19 21, 2006 Decoupling Responsibilities Organizational Considerations Who decides Process for institutional Review Who can execute an IAA Scope of Review Single Protocol Multiple Protocols By type of research Specific group of institutions By funding All Protocols 11

Decoupling Responsibilities Organizational Considerations How does the institution determine the IRB it will be relying on meets its standards for the protection of human subjects Oversight of reviewing IRB Study monitoring /audit /oversight Agency specific or other review requirements State / local laws Check / Uncheck the box Decoupling Responsibilities Organizational Considerations Metrics How are non local reviewed studies counted Insurance Advertising approval Use of name FOIA Sponsored Programs / Financial Systems Secondary reliance (you rely but others rely on you or VA) 12

Decoupling Responsibilities IRB related considerations Scientific review Unanticipated Problems and Noncompliance determination and reporting Who investigates Who reviews Who determines corrective actions Who drafts correspondence Who reports Decoupling Responsibilities IRB related considerations Conflict of Interest Investigator, Institutional, IRB member Grant congruence Suspension and Terminations Lapses of approval Training and qualification of study team Adequacy of resources 13

Decoupling Responsibilities Clinical Trials Considerations CTMS Clinical trials coverage analysis Subject injury terms Clinicaltrials.gov Contract congruence Decoupling Responsibilities Ancillary Organizational Considerations HIPAA Covered, hybrid or uncovered entities Waiver to recruit/screen Authorization Review Compounded or Stand Alone Authorizations FERPA Radiation Safety Biosafety Pharmacy / Device Sponsored Programs / Financial Systems Departmental or Unit review 14

Institutional Responsibility Acceptability Determine if the proposed research study is acceptable or appropriate for its investigators to conduct Is the disease, condition, or issue to be studied acceptable to the organization? Is the organization supportive of the proposed methods or expected outcomes of the study? Are there procedures proposed in the research that differ from the standard of practice in the institution? Are the investigator and staff qualified to conduct the study? Using Central IRBs for Multicenter Clinical Trials in the United States. PLoS ONE 8(1):e54999. doi:10.1371/journal.pone.0054999 Institutional Responsibility Acceptability Does the organization and/or investigator have the resources available to carry out the study? Does the proposed research violate any organizational policies or local laws/regulations? What will community reactions be to the research? Are there any funding issues associated with the research? Do the investigators, staff or the institution have a financial conflict of interest related to the research? Using Central IRBs for Multicenter Clinical Trials in the United States. PLoS ONE 8(1):e54999. doi:10.1371/journal.pone.0054999 15

Institutional Responsibility Accountability Provide oversight of the research study Conduct institutional reviews such as conflict of interest, radiation safety, biosafety reviews, and facility Ensure ICF, recruitment materials and other documents include local information and adaptations Establish a process to receive, review, manage and report to reviewing IRB local unanticipated problems, adverse events, noncompliance, complaints Conduct study monitoring or audits Maintain accountability of investigators and study staff Using Central IRBs for Multicenter Clinical Trials in the United States. PLoS ONE 8(1):e54999. doi:10.1371/journal.pone.0054999 Reviewing IRB Responsibility Review of the ethics of the study Review of the study design Confirm the competency of the investigator Review proposed research according to applicable regulatory criteria Ensure the quality of ICFs, recruitment materials and other documents, and inclusion/adaption of local information Review, manage and report unanticipated problems, adverse events, noncompliance, and complaints submitted by sites Determine that institutional oversight and accountability is appropriate and acceptable Using Central IRBs for Multicenter Clinical Trials in the United States. PLoS ONE 8(1):e54999. doi:10.1371/journal.pone.0054999 16

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