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- Operations Manual - Quality Assurance and Research Compliance
Operations Manual - Part 12
Quality assessment (QA) is an evaluation of whether or not activities meet defined standards. Quality improvement (QI) is a process initiated to improve a practice or procedure and to institutionalize the practice. QA/QI activities comprise a critical component of the Human Research Protections Program (HRPP) and play a vital role in protecting the rights and welfare of human subjects. They assist in the institutionalization of sound, ethical research design and procedures; promote compliance with laws, regulations and institutional policies governing the conduct of research; and are critical in the development of a culture that promotes and rewards ethical behavior.
To assist with both quality assessment and quality improvement activities the University established the Office of Research Compliance Review (ORCR). ORCR’s mission is to facilitate safe, ethical, efficient, and high quality human subjects research. ORCR activities include conducting compliance reviews of research studies and Institutional Review Boards (IRBs), developing education and outreach initiatives for individuals and groups engaged in the research enterprise, and participating locally and nationally in committees (e.g. Public Responsibility in Medicine and Research (PRIMR)) and scholarly endeavors related to human research.
The various University units and functions responsible for operation of the HRPP identify and communicate legal and regulatory standards and best practices applicable to human research. These are reflected in and communicated throughout the University community through Regents Bylaws and proceedings, the University's Standard Practice Guide, this Operations Manual, IRB Standard Operating Procedures, policies and procedures implemented at the individual unit level, mandatory educational modules, and a variety of ad hoc communications.
Performance measurement and self-assessment is an ongoing process and includes the following formal and informal activities:
- Continuing review of regulatory developments and industry standards, analysis of their application to University research, and integration as appropriate into the HRPP;
- Solicitation, review and analysis of research participant, researcher, HRPP staff and other stakeholder feedback;
- Data collection (for example, through eResearch) and analysis;
- Initial and continuing IRB review and monitoring;
- Not-for-cause inspections and for-cause audits;
- Receipt, investigation and response to complaints;
- Risk assessment; and
These activities help identify opportunities for improvement and prioritize quality improvement initiatives.
Quality improvement occurs at all levels of the HRPP and includes the following activities:
- Education of the research community through in-person programming, web site development and dissemination of formal and informal guidance;
- Data collection and analysis to identify the cause and determine remediation of identified performance gaps;
- Development and implementation of corrective action plans in response to internal and external investigations and inspections;
- Policy development;
- Significant investment in technological improvements that facilitate work flow integration among and between HRPP entities and that provide "control points" for regulatory compliance; and
- Training and mentoring to provide qualified and experienced IRB staff and IRB membership, compliance and auditing staff, and research team personnel.
These activities have resulted in dedication of significantly increased resources to HRPP activities, creation of interdisciplinary, cross-functional policy and planning committees including the IRB Council, and their respective workgroups, implementation of the Program for Education and Evaluation in Responsible Research and Scholarship (PEERRS) and other educational initiatives, development of eResearch and additional technological improvements, establishment of a comprehensive HRPP description, and more.
Effectiveness of the HRPP's quality improvement initiatives is measured both at the local level (for example, through monitoring of corrective action plans) and system-wide (through audit, accreditation and similar activities).
The HRPP promotes an organizational culture that encourages a commitment to compliance with the legal, regulatory, and ethical principles that govern human subjects research. The program relies on a system of self-regulation and integrated oversight to accomplish this objective and reflects an emphasis on the high ethical standards and values demanded of the most outstanding research institutions. The Vice President for Research (VPR) strives to promote and enforce the program consistently throughout the organization and ensure its acceptance. This is achieved by maintaining the utmost respect for individuals, clearly communicating expected behaviors, fostering principled reasoning based on shared values, and recognizing shared responsibilities.
The following section describes the circumstances under which allegations of noncompliance may and must be reported and the process for reporting, the protections afforded individuals who make reports, and the process for investigating and responding to reports. Although all complaints and concerns related to the HRPP or to the conduct of individual studies are reviewed, they will not all involve noncompliance.
Complaints or allegations of noncompliance may be made by subjects or their representatives, or by faculty, staff, or others engaged in research or responsible for related University oversight activities. Written consent documents provide a contact phone number that research subjects or their representatives may call to discuss concerns or complaints regarding research studies. The University's HRPP web site also provides the telephone numbers and email contacts for IRB staff members and for the U-M Office of Research. In addition, the University provides anonymous reporting through the Compliance Hotline. As described in detail in Section C below, faculty and staff are obligated to report noncompliance concerns.
Noncompliance and Academic Misconduct
If the complaint or allegation of noncompliance contains facts that suggest there may have been serious academic misconduct as described in the University Policy Statement on the Integrity of Scholarship (SPG 303.03 and the "research misconduct" policy), the information about the case must be forwarded promptly to the U-M Office of Research or to the Office of the Vice President and General Counsel. The University Integrity policy incorporates by reference the Federal Research Misconduct Policy (65 CFR 235), which defines research misconduct as "fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results." Research misconduct does not include honest error or honest differences in interpretations or judgments of data.
Typically, reviews of noncompliance in human subject research do not trigger the University's research misconduct policy even if there is a finding of "serious" or "continuing" noncompliance as described below, unless there are also indications or allegations of fabrication or falsification of research data. However, the academic misconduct policy may be applicable subsequent to a noncompliance review in unusual situations where there may have been egregious, intentional disregard of the rules (i.e., "flagrant and repeated failure to adhere to or to receive the approval required for work under research regulations of Federal, State, local, or University agencies").
- Noncompliance: The failure of a person or organization to act in accordance with the requirements of a law, regulation, policy, or the requirements and/or determinations of an IRB;
- Serious Noncompliance: Noncompliance that materially increases risks or causes substantive harm to research participants or materially compromises the rights or welfare of participants, including consideration of the following:
- Harm to participants;
- Exposure of participants to a significant risk of substantive harm;
- Compromised privacy and confidentiality of participants;
- Willful or knowing misconduct on the part of the investigator;
- A violation of ethical principles; or
- Damage caused to the scientific integrity of the data collected.
- Continuing Noncompliance: Noncompliance that reoccurs after an investigator has been notified of a similar or related noncompliance concern pertaining to one or more protocols.
- Allegation of Noncompliance: An unconfirmed report of noncompliance.
Generally, allegations of potential noncompliance related to specific research projects are first reviewed by the responsible IRB. IRBs may take interim actions as noted in their SOPs - including suspension of research - to protect human subjects while a concern is under review. Any suspension or termination of research is reported immediately to the U-M Office of Research (UMOR; i.e., the HRPP Director or the Deputy Institutional Official [DIO]), so that UMOR may make the required external reports. If, after initial review, the IRB decides that the concern may represent serious or continuing compliance, it reports the case to UMOR. UMOR, at its discretion, may conduct additional fact-finding and adjudication using an ad hoc faculty review panel and/or the resources of ORCR. If the IRB makes a final determination of serious or continuing noncompliance, it immediately reports the determination to UMOR, so that UMOR may make the required external reports. A flow diagram illustrates this process.
For situations reported to UMOR for additional review and/or reporting, the VPR makes the final determinations, reports the institutional conclusions, and imposes any institutional sanctions or remediation requirements. External reporting procedures are described in Section III below.
IRBs may, themselves, take corrective action, as described in Section II(G) below, if noncompliance is determined to be neither serious nor continuing.
Summaries of non-serious/continuing concerns are reported by IRBs to OVPR at the monthly IRB Council meetings as a way of monitoring the need for attention to policy or to education.
The University recognizes that due process is critical to the investigation of and response to noncompliance allegations. Providing appropriate due process in an internal investigation, like carefully following a scientific protocol, helps ensure that the resulting report is valid, reliable, and respected. Upon receipt of an allegation of noncompliance, the reviewing authority should provide the following information to that individual or entity that is the subject of the allegation:
- Notice of the general nature of the complaint, with sufficient detail to facilitate preparation of a response;
- Access to evidence gathered supporting the complaint;
- An opportunity to be heard, i.e., a chance to respond to the complaint, dispute the factual basis of the complaint, present evidence, or offer an explanation or justification for the conduct in question, and a chance to review and respond to substantive final reports before they are widely distributed;
- Assistance of a colleague, advisor or other advocate in communications with the review body; and
- An objective fact finding process that avoids conflicts of interest among those reviewing allegations and among those empowered to determine the outcome of a case.
These standards do not apply to the initial fact finding activities undertaken to evaluate the credibility of a complaint and the need for further investigation; or to preliminary actions, such as protocol suspension, necessary to protect subjects from potential harm. Nor do they represent a mandate for any specific process or procedure. Rather, they impose on a reviewing authority the obligation to incorporate basic principles of fairness and transparency into its procedures to promote a fair and objective outcome.
Maintaining confidentiality is essential to assuring an open and honest process and assuring due process to any individuals against whom allegations of wrongdoing may have been made. Accordingly, identification of individuals reporting noncompliance concerns, and other information collected or created in connection with noncompliance investigations, particularly prior to the issuance of a final report, should be shared internally only on a "need-to-know" basis and should not be disclosed externally except as required by applicable regulations or contracts. In addition, it is important to protect the identity of individuals reporting noncompliance concerns.
Consistent with the requirements and spirit of the Michigan Whistleblowers Protection Act, a University employee may not be discharged, threatened, or otherwise discriminated against (with respect to compensation, terms, conditions, location or privileges of employment) because the employee made a report (or is preparing to make a report) of a violation or suspected violation of applicable human subjects research laws or regulations, University policy, or IRB requirements, unless the employee knew the report was false or materially misleading. Any violation of this policy must be reported to the University's Compliance Hotline.
All researchers and research review units and their staffs are responsible for maintaining the integrity of the HRPP. Accordingly, all are expected to report identified compliance concerns, including concerns of coercion or undue influence.
Allegations of noncompliance are normally reportable directly to the IRB with jurisdiction over the relevant research protocol but may be transmitted directly (and anonymously, if desired) to UMOR, the Provost, ORCR, the Office for the Vice President and General Counsel, the Director of University Audits, or to other institutional officials (such as the appropriate dean, director, or department head). The recipient of any allegation, complaint, not for cause observation, or other concern must forward this information (excluding the identity of the reporter, if anonymity has been promised) to the IRB with jurisdiction over the study or studies. If the concern relates to the conduct of an HRPP subsystem that is not affiliated with a specific IRB, the concern should be forwarded to the VPR or their designee. The IRB SOPs will contain, at a minimum, expected timeframes for addressing allegations of noncompliance and provisions for exceptions to these timeframes in extenuating circumstances
Allegations of noncompliance may also emerge through internal or external audits of the IRBs or ORCR, or site visits or audits by regulatory agencies, such as FDA or research sponsors or their agents. If a complaint or allegation is received by any of these methods, it must be forwarded promptly to the responsible IRB for immediate initiation of established IRB-level review procedures. UMOR will decide on the appropriate initial review location for concerns about noncompliance by the IRBs themselves or by other HRPP components.
Any complaint or concern identified by the U.S. Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) about human research conducted at or by the University will, in accordance with OHRP policy, be directed in the first instance to the VPR, who is the Institutional Official (IO). The DIO is delegated primary responsibility for assuring appropriate internal investigation and response to any such report and will seek the assistance of the IRBs, through their established IRB-level review procedures, in fulfilling this responsibility.
The IRB, through appropriate members and/or staff (and consistent with locally adopted SOPs, if any), will initiate a fact-finding review. The IRB Director determines whether the complaint or allegation of noncompliance is reportable immediately to the IRB Chair(s) for a determination of serious or continuing noncompliance. If the IRB Director concludes that the concern clearly is without merit or that the conduct in question (i) clearly does not constitute serious or continuing noncompliance; and/or (ii) can be addressed through minor corrective action agreed to by the Principal Investigator (PI) or other involved parties, the matter may be closed.
Potential noncompliance, particularly if the conduct in question might constitute serious or continuing noncompliance, is referred to the IRB Chair(s) for additional review. The IRB Chair(s) must perform or make arrangements for any additional fact finding necessary to make an initial determination. In reviewing the alleged noncompliance, the Chair may request a meeting with the PI and others to discuss the allegations and provide an opportunity for the study team to answer any questions. In reviewing the alleged noncompliance, the Chair may request a meeting with the Principal Investigator and others to discuss the allegations and provide an opportunity for the study team to answer any questions.
While the investigation is taking place, the Chair(s) may request an investigator to voluntarily "hold" new subject accrual or research-related interventions during the fact-finding period, unless to do so would place subjects at risk of immediate harm or otherwise jeopardize their course of treatment. Such a voluntary hold does not constitute a suspension of approval for purposes of the HRPP. A Chair, consultant, IRB member, or staff person with an actual or apparent conflict of interest associated with the research or individual(s) that are the subject of the concern must recuse him or herself from involvement in the matter.
After reviewing any relevant information gathered about the alleged noncompliance, the Chair(s) must make a preliminary assessment as to whether or not it has caused injury to a subject, represents an unanticipated problem involving risks to subjects or others, or whether or not it constitutes serious or continuing noncompliance with IRB determinations, applicable regulations, or HRPP policies. If the Chair determines that the conduct does not represent serious or continuing noncompliance, the Chair(s) may work with the relevant parties to develop an appropriate corrective action plan.
If the Chair(s) determines that the conduct represents serious or continuing noncompliance, the matter (together with sufficient background to facilitate an informed discussion and decision) must be referred to the convened IRB for review and discussion of the findings, recommendations regarding corrective actions (examples described below), and vote to approve the recommended actions. The results of the convened IRB meeting will be provided to UMOR within one month, absent extenuating circumstances.
When the VPR receives a report from an IRB (or from another source regarding an issue not within a U-M IRB's jurisdiction ), he or she will review the report and determine whether additional investigation is needed. If so, the VPR will, directly or through a designee, conduct the investigation, or will require that one be completed through the relevant academic unit, research review unit, or the ORCR . Upon completion of such an investigation, a report must be drafted (with specific recommendations for corrective action, if merited) within a time specififed by the VPR. Upon receipt of the report, the VPR may determine that no further action is needed; or may convene a faculty advisory committee to assist in any further investigation and in drafting recommendations for a response; or may take any other action appropriate under the circumstances in consultation, as appropriate, with the relevant IRB and other interested parties. UMOR will make any required external notifications as described in Section III below.
Each IRB, as well as the VPR and other institutional officials, has the authority at any time to suspend or terminate approval of human subjects research that is not being conducted in accordance with applicable laws and regulations, institutional policy, or an IRB's requirements, or that has been associated with unexpected serious harm to subjects or others, or that for any other reason is believed to impose unreasonable risks on subjects or others.
Other sanctions may be imposed in response to findings of noncompliance, depending on the severity and nature of the noncompliance . Examples include the following:
- Development and implementation of case-specific corrective action and mitigation plans;
- Protocol modification or termination;
- Notifications of former subjects or others or re-consenting of current subjects or others;
- Recommended or mandatory education or mentoring requirements;
- One-on-one mentoring;
- Regular or remedial IRB courses;
- Additional on-line training modules;
- Additional professional certification;
- Attendance at regional/national meetings/seminars;
- Increased monitoring or oversight; and
- Random or targeted audits.
The VPR may institute any or all of the following additional sanctions:
- Embargo or destruction of research data;
- Refunding improperly billed/incurred costs;
- Notification to publishers with present or past submissions of circumstances of noncompliance and status of data;
- Faculty or staff suspension from engagement in University research; and
- Other disciplinary sanctions up to and including dismissal (in consultation, where required by University policy, with other appropriate institutional officials and subject to any additional University due process requirements).
In the event the IRB votes that the alleged noncompliance constitutes serious or continuing noncompliance, the VPR must report this information to government authorities with jurisdiction and to sponsors to the extent required by any relevant regulations, grants, or contracts.
Where the IRB does not determine that the alleged noncompliance is serious or continuing, the VPR may accept the IRB determination, may reject the determination and report externally as required, or conduct an additional investigation of the allegation.
III. Other Reportable Events (Adverse Events, Unanticipated Problems and Suspension and Termination of IRB approval.
It is a condition of the University of Michigan Federalwide Assurance of Compliance (FWA) that the institution have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, the head (or designee) of any federal department or agency conducting or supporting the research, and any applicable regulatory bodies, including the HHS OHRP or the FDA for research subject to FDA oversight, of any:
- Unanticipated problems involving risks to subjects or others;
- Serious or continuing noncompliance with the federal regulations or the requirements or determinations of the IRB(s); and
- Suspension or termination of IRB approval.
The PI of any research project is responsible for reporting adverse events (AEs) and other reportable information or occurrences (ORIOs) to the IRB overseeing that project, as required by that IRB. These include unanticipated problems involving risk to research subjects or others (referred to as “unanticipated problems”). Guidance and reporting procedures for AE and ORIO reporting are posted on the IRBMED web site. This web site is also referenced within the help feature in the eResearch IRB application system.
Investigators should understand the nature and significance of unanticipated problems. Although all unanticipated problems are either AEs or ORIOs, not all AEs and ORIOs are unanticipated problems.
An unanticipated problem is an occurrence or a data point that has all of the following characteristics:
- It is “unexpected” in terms of its nature, severity, or frequency given 1) the procedures described in the study documents or 2) the characteristics of the subject population being studied;
- It is “related” to the research; meaning there is a reasonable possibility that the event may have been caused by the procedures involved in the research;
- It suggests that the research places subjects or others at greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
Because an individual event cannot be readily concluded to represent an unanticipated problem, investigators should assess and report:
- Events that were not just isolated occurrences and were significant to subjects' rights and welfare.
- Expected AEs that occur at a greater frequency or severity than expected.
Investigators must report serious and non-serious unanticipated problems. Investigators must report unanticipated problems occurring in or related to studies under the direction of University faculty, staff, or students and reports of unanticipated problems occurring elsewhere ("external" unanticipated problems) that potentially impact a study under University IRB oversight, including all unanticipated problems about which the investigator receives notice from the FDA, a sponsor, a data and safety monitoring board, other oversight entity or source. Serious unanticipated problems must be reported to the IRB within seven (7) days and non-serious unanticipated problems in fourteen (14) days of their occurrence or notice to the investigator.
PIs engaged in research involving investigational devices for which the FDA has issued an investigational device exemption must inform the IRB and sponsor of any unanticipated adverse device effect (UADE) during an investigation. The IRB report must be submitted within seven (7) days. The sponsor must receive the report within ten (10) days. A UADE is defined as any serious adverse effect on the health or safety or any life-threatening problem or death caused by, or associated with, a device, if that problem or death was not previously identified in nature, severity or degree of incidence in the investigational plan.
PIs must report adverse events (AEs) occurring at the University or under the direction of University faculty or staff to FDA or sponsors, as applicable, in accord with and within timelines required by those agencies and in accord with the IRB's posted guidelines or a study-specific plan approved by the IRB.
PIs must forward to the IRB any inspection, audit or investigation reports issued by internal or external sponsors or oversight authorities as required by IRB policies or by a study-specific plan approved by the IRB.
Each IRB must require, through SOPs or other policies or guidelines, the reporting of specified adverse events and other reportable information and occurrences in accordance with a defined process and timetable.
The IRB SOPs explain the timing and methods by which all reports submitted by investigators are reviewed. IRB staff members conduct the initial review of a report to ensure completeness, assess whether the report may represent an unanticipated problem (including those reports not characterized by the investigator or sponsor as an unanticipated problem), and route serious unanticipated problems and serious, unexpected, and related adverse events for prompt review. The IRB Chair may act on behalf of the IRB with regard to such a review.
The IRB Chair is authorized to take immediate action to protect the health and safety of research subjects. Such action may take the form of: (i) asking the investigator to voluntarily impose a hold on the recruitment of subjects to facilitate further inquiry by the IRB and/or institutional officials; (ii) asking the investigator to voluntarily impose a hold on the recruitment and research intervention to facilitate further inquiry by the IRB and/or institutional officials; (iii) suspending recruitment or enrollment; (iv) altering or suspending current interventions; or (v) suspending the project.
Any such action of the IRB chair will be documented in the IRB research record immediately. If the IRB chair imposes a partial or complete suspension, the IRB chair will immediately report the suspension to UMOR. The IRB chair shall report to the convened IRB at its next regularly scheduled meeting of any such action taken.
A convened board will review serious and non-serious unanticipated problems occurring on studies under the direct oversight of a University IRB, and external serious unanticipated problems. The IRB may endorse interim action by the chair, if any, or may take a different action or additional actions. In the event immediate action is not required to protect the health and safety of research subjects, any of the above actions must be approved in advance by a vote of the IRB.
If a majority of IRB members vote that a submitted report is an unanticipated problem, the following steps will be taken:
- The chair or chair's designee will notify UMOR;
- The board will vote on further actions;
- The investigator will be notified;
- The study records and IRB minutes will document the findings and actions of the board.
The HRPP Director informs the VPR (the IO designated on the University’s FWA) of potential serious or continuing noncompliance. Within three (3) business days of its receipt of such a report, UMOR will communicate its receipt to relevant parties, including the PI, the IRB, and the ORCR. UMOR will immediately take any institutional actions required to protect the health and safety of research participants or others or to comply with other regulatory or institutional policy requirements.
Upon receipt of a report of IRB suspension or termination of research, a report of an unanticipated problem involving research subjects or others, or a report of serious or continuing noncompliance with IRB requirements or directives, applicable regulations, or HRPP policies, the IO or designee will take additional action, as appropriate, as described in Section II.C.
UMOR will evaluate any external reporting already made and consider additional external reporting. For studies supported by HHS or other federal agencies requiring reporting to the HHS OHRP, UMOR will notify OHRP of the IRB’s receipt of a University unanticipated problem in a timely manner. For studies under FDA oversight, UMOR will provide any additional required notification to the FDA of a University unanticipated problem, serious and/or continuing non-compliance, or suspension or termination of research. Initial reports may be made by phone or email. Additional and complete information will be provided in writing to applicable oversight authorities as appropriate.
When making a report to OHRP, the following information will be included:
For Unanticipated Problems Involving Risks to Subjects or Others:
- Title of the research project and/or grant proposal in which the problem occurred;
- Name of the principal investigator on the protocol;
- Number of the research project assigned by the IRB and the number of any applicable federal award(s) (e.g., grants, contracts, or cooperative agreements);
- A detailed description of the problem; and
- Actions the University is taking or plans to take to address the problems (e.g., revise the protocol, suspend subject enrollment, terminate the research, revise the informed consent document, inform enrolled subjects, increase monitoring of subjects, etc.)
For Serious or Continuing Noncompliance:
- Title of the research project and/or grant proposal in which the noncompliance occurred;
- Name of the PI on the protocol;
- Number of the research project assigned by the IRB and the number of any applicable federal award(s) (e.g., grants, contracts, or cooperative agreements);
- A detailed description of the noncompliance; and
- Actions the University is taking or plans to take to address the noncompliance (e.g., educate the investigator, educate all research staff, suspend the protocol, suspend the investigator, conduct random audits of the investigator or all investigators, etc.).
For Suspension or Termination:
- Title of the research project and/or grant proposal that was suspended or terminated;
- Name of the PI on the protocol;
- Number of the research project assigned by the IRB that were suspended or terminated and the number of any applicable federal award(s) (e.g., grants, contracts, or cooperative agreements);
- A detailed description of the reason for the suspension or termination; and
- Actions the University is taking or plans to take to address the suspension or termination (e.g., investigate alleged noncompliance, educate the investigator, educate all research staff, require monitoring of the investigator or the research project, etc.).
Generally, the report to OHRP will be made within one month, absent special circumstances, such as the need for extensive data gathering or analysis.
ORCR is responsible for conducting the for-cause and not-for-cause post-approval reviews, remediation, and reporting.
Not-for-cause reviews are conducted according to SOPs developed by ORCR, in consultation, as appropriate, with the IRB and others and approved by UMOR. In the event a not-for-cause review uncovers serious situations reportable to the IRB or UMOR under the guidelines above, ORCR will provide such notice to UMOR and the IRB. UMOR and the IRB will proceed pursuant to the guidelines articulated above.
ORCR will conduct for-cause reviews as requested by UMOR in fulfillment of the institutional obligation to review, remediate, and report.