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Operations Manual - Quality Assurance and Research Compliance

Operations Manual - Part 12

[Operations Manual Table of Contents]

References to the HRPP Director in Part 12 of the  Operations Manual also encompass any qualified individual designated in this role during the unavailability of the HRPP Director.

I. QUALITY ASSESSMENT AND IMPROVEMENT

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, Institutional Review Boards (IRBs) and other HRPP components, developing education and outreach initiatives for individuals and groups engaged in the research enterprise, and participating locally and nationally in committees and scholarly endeavors related to human research.

A. Performance Measurement and Quality Assessment

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 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
  • Accreditation.

B. Quality Improvement

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 the dedication of resources to HRPP activities, such as interdisciplinary policy and planning committees including the IRB Council and its 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, and the establishment of a comprehensive HRPP description.

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).

II. Reportable Events: Adverse Events, Unanticipated Problems, Noncompliance, Suspensions, and Terminations of IRB approval

A. Background

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 U.S. Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) or the U.S. Food and Drug Adminstration (FDA) for research subject to FDA oversight, of any:

  • Unanticipated problems involving risks to subjects or others;
  • Serious and/or continuing noncompliance with the federal regulations or the requirements or determinations of the IRB(s); and
  • Suspension or termination of IRB approval.

B. Definitions

1.  Adverse Events (AEs)

OHRP defines an AE as "any untoward or unfavorable medical occurence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject's participation in research, whether or not considered related to the subject's participation in the research." (OHRP, Unanticipated Problems Involving Risks & Adverse Events Guidance, 2007

The FDA defines an AE as "any untoward medical occurence associated with the use of a drug in humans, whether or not considered drug related."  (21 CFR 312.32)

2.  Unanticipated Problems

OHRP considers unanticipated problems, in general, to include any incident, experience, or outcome that meets all of the following criteria:

  • It is “unexpected” in terms of its nature, severity, or frequency given 1) the research procedures described in the protocol-related documents, such as IRB-approved research protocol and informed consent documentation; and 2) the characteristics of the subject population being studied;
  • It is “related” or "possibly related"to the particpation in the research; meaning there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research; and
  • 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.  (OHRP, Unanticipated Problems Involving Risks & Adverse Events Guidance, 2007)

The FDA indicates an AE observed during the conduct of a study should be considered an unanticipated problem involving risk to human subjects, and be reported to the IRB, only if it were unexpected, serious, and would have implications for the conduct of the study (e.g., requiring a significant, and usually safety-related, change in the protocol such as revising inclusion/exclusion criteria or including a new monitoring requirement, informed consent, or investigator's brochure).  An individual AE occurence ordinarily does not meet with tese criteria because, as an isolated event, its implications for the study cannot be understood.  (FDA, Guidance for Clinical Investigators, Sponsors, and IRBs - Adverse Event Reporting to IRBs, 2009)

3.  Unanticipated Adverse Device Effect (UADE)

The FDA's investigational device exemption (IDE) regulations define an UADE 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 or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects." (21 CFR 812.3(s)

4.  Suspension

Suspension of an IRB approved protocol is when an approved protocol is partially or completely stopped by the IRB pending future action by the IRB or other regulatory entity in order to protect human subjects.  If the IRB is underatking further inquiry, a voluntary "hold" during this fact-finding period does not constitute a suspension of IRB approval for purposes of the HRPP reporting to external agencies or sponsors.

5.  Termination

Termination of an IRB approval is defined as a permanent halt in IRB approval of all research related activities as a result of direct action by the IRB.  A request from a principal investigator (PI) to terminate IRB-approval at the end of a study's defined approval period, or at any other earlier point during the approval period, does not constitute a termination of IRB approval for the purposes of the HRPP reporting to external agencies or sponsors.

6.  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 determination of an IRB.

7.  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 research misconduct on the part of the investigator;
  • A violation of ethical principles for human research; or
  • Damage caused ot the scientific integrity of the data collected.

8.  Continuing Noncompliance

Noncompliance that recurs after an investigator has been notified of a similar or related noncompliance concern pertaining to one or more protocols.

9.  Allegation of Noncompliance

An unconfirmed report of noncompliance.

C. Roles and Responsibilities for Required Reporting of Reportable Events 

1. Researchers

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.  Information that must be reported to the IRB, along with the timelines for reporting, is posted on each IRB's website.  All reportable information is submitted by researchers through the eResearch Regulatory Managment (eRRM) 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.  In addition, 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.

2. The IRBs

IRBs must require, through SOPs or other policies or guidelines, the reporting of specified AEs and ORIOs 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. Generally, IRB staff members conduct the initial review of a report to ensure completeness and to make a preliminary assessment of whether the report meets the OHRP's or FDA's definition of unanticipated problem (including those reports not characterized by the investigator or sponsor as an unanticipated problem), or when the report represents a serious, unexpected, and related adverse event.  Reports of concern are forwarded for prompt review by an IRB member with expertise for assessment or to the IRB Chair, who 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) terminating the IRB's approval of 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 the HRPP Director. The IRB chair shall report any such action taken to the convened IRB at its next regularly scheduled meeting.

While the IRB is undertaking further inquiry, any voluntary "hold" during the fact-finding period does not constitute a suspension of IRB approval for purposes of the HRPP reporting to external agencies or sponsors.

A convened IRB will review reportable events occurring on studies under its direct oversight as well as external unanticipated problems. The IRB may endorse the 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.  

3.  Reporting Process

If the IRB determines that a submitted report is an unanticipated problem, the IRB will follow the methods for prompt reporting described in their SOPs.  Generally, reports to federal agencies for unanticipated problems will be made promptly (i.e., not to exceed one month, absent special circumstances, such as the need for extensive data gathering or analysis).

If the IRB makes a determination of serious noncompliance, continuing noncompliance, suspension, or termination, it will promptly (i.e., no later than three business days) inform the HRPP Director.  The HRPP Director will promptly (i.e., not to exceed one month, absent special circumstances, such as the need for extensive data gathering or analysis) notify federal agencies and sponsors as required by regulations or agreements and provide notification to the insitutional official (IO), the IRB, the Associate Vice President for Research, the principal investigator (PI), and other institutional entitites as indicated.  See Section II. D for detailed information regarding the procedures associated with these determinations as they relate to noncompliance.  The IRB will evaluate any external reporting already made and consider additional external reporting after notification of University leadership.

The following information will be included when making required reports to federal agencies:

  • Title of the research project and/or grant proposal in which the problem occurred;
  • Name of the principal investigator (PI) on the protocol;
  • Number of the research project assigned by the IRB and the number of any applicable federal awards (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 problem (e.g., revise the protocol, suspend subject enrollment, terminate the research, revise the informed consent document, inform enrolled subjects, increase monitoring of subjects, etc.)

D.  Compliance Oversight

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.

1. Response to Complaints or Allegations of Noncompliance

Complaints or allegations of noncompliance may be made by subjects or their representatives, faculty, staff, or others engaged in research or responsible for related University oversight activities. Written informed 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 and individual IRB websites 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 D.3 below, faculty and staff are obligated to report noncompliance concerns.

Noncompliance and Research Misconduct

If the complaint or allegation of noncompliance contains facts that suggest there may have been serious research misconduct as described in the University Policy Statement on the Integrity of Scholarship (SPG 303.03), 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 of Scholarship 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. 

2. Noncompliance Review Procedures

a. Process Summary

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 to the HRPP Director, so that the U-M Office of Research (UMOR) may make the required external reports.  If, after initial review, the IRB decides that the concern may represent serious and/or continuing noncompliance, it reports the case to the HRPP Director.  The HRPP Director may conduct additional fact-finding and adjudication using an ad hoc faculty review panel and/or the resources of the Office of Research Compliance Review (ORCR).   When the IRB makes a final determination of serious and/or continuing noncompliance, it reports the determination to the HRPP Director, so that the HRPP Director may make the required external reports. 

b. Rights of Faculty, Staff or Others Accused of Noncompliance

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 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 the 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.

c. Assurances of Appropriate Confidentiality

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.

d. Policy Against Retaliation for Reporting

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.  The University's Compliance Hotline is one option that permits confidentiality to be maintained.

3. How Compliance Concerns are Brought Forward

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 the HRPP Director, the Provost, ORCR, the Office for the Vice President and General Counsel, the Director of University Audits, the Compliance Hotline, or to other institutional officials (such as the appropriate dean, director, or department head). The recipient of any allegation, complaint, 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 HRPP Director. 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. The HRPP Director 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 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 HRPP Director 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.

4. Receipt and Initial Handling of Allegations of Noncompliance

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 potential serious and/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 and/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 appropriately addressed and closed.

5. Chair and Board Considerations and Determinations

Potential noncompliance, particularly if the conduct in question might constitute serious and/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(s) 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. 

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 IRB approval for purposes of the HRPP reporting to external agencies or sponsors. 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 potentially serious and/or continuing noncompliance with IRB determinations, applicable regulations, or HRPP policies.  If the Chair(s) determines that the conduct does not represent serious or continuing noncompliance, the Chair(s) may determine the relevant parties to develop an appropriate corrective action plan. 

If the Chair(s) determines that the conduct represents potentially serious and/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 convened IRB may request additional information for consideration before proceeding to a vote.  The results of the convened IRB meeting will be provided to UMOR within one month, absent extenuating circumstances.

6. Actions of the HRPP Director as Delegated by the Institutional Official (IO)

When the HRPP Director receives a report from an IRB (or from another source regarding an issue outside a U-M IRB's jurisdiction), he or she will review the report and determine whether additional investigation is needed. If so, the HRPP Director 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 HRPP Director. Upon receipt of the report, the HRPP Director together with the IO 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. 

7. Response to Determinations of Noncompliance

Each IRB, as well as the IO and other institutional authorities, 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 to former subjects or others or re-consenting of current subjects;
  • 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 IO 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 authorities and subject to any additional University due process requirements).

8. Institutional Notification and Reporting Requirements

In the event the IRB votes that the alleged noncompliance constitutes serious and/or continuing noncompliance, the IO must ensure the prompt reporting of this information to government authorities with jurisdiction and to sponsors to the extent required by any relevant regulations, grants, or contracts.  The HRPP Director will provide notification of reporting to the IO, the IRB, the Associate Vice President for Research (VPR), the principal investigator (PI), and other institutional entities as indicated. 

Where the IRB determines that the alleged noncompliance is not serious and/or continuing, the IO may accept the IRB determination, may reject the determination and report externally as required, or conduct an additional investigation of the allegation.