Human Research Protection Program (HRPP)

Office of the Vice President for Research

Part 12 - Quality Assurance and Research Compliance (January 2008)

This section describes the University’s quality assurance, quality improvement and enforcement activities.

QUALITY ASSESSMENT, IMPROVEMENT, AND ASSURANCE

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 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.

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:

These activities help identify opportunities for improvement and prioritize quality improvement initiatives.

Quality Improvement

Quality improvement occurs at all levels of the HRPP and includes the following activities:

In the past several years, these activities have resulted in dedication of significantly increased resources to HRPP activities, creation of interdisciplinary, cross-functional policy and planning committees including the Human Research Coordinating Council, the IRB Council, and their respective workgroups, implementation of 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).

To assist with both quality assessment and quality improvement activities the University established the Office of Human Research Compliance Review (OHRCR). OHRCR’s mission is to facilitate safe, ethical, efficient and high quality human subjects research.  OHRCR activities include conducting compliance reviews of research studies and committees, 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.

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 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. 

This section described the circumstances under which allegations of noncompliance may and must be reported and the process for reporting, protection for individuals who make reports, and the process for investigating and responding to reports.  Although complaints and concerns related to the HRPP or conduct of individual studies all are reviewed, not all of them involve noncompliance.

Response to Complaints or Allegations of 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 human research web site also provides the telephone numbers and email contacts for IRB staff members and for the Office of the Vice President for Research. 

As described in detail in Section C below, faculty and staff are obligated to report noncompliance concerns.

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 http://www.research.umich.edu/policies/um/integrity policy.html, aka, the “research misconduct” policy), the information about the case must be forwarded promptly to the Office of the Vice President for 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 FR 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.  The academic misconduct policy may be applicable, however, subsequent to a noncompliance review in unusual situations where there may have been egregious, intentional disregard of the rules (“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 Review Procedures

Definitions

Process Summary

Generally, reports or concerns about noncompliance related to individual protocols are first reviewed by the responsible IRB.  IRBs may take interim actions as noted in their Standard Operating Procedures – including suspension of research – to protect human subjects while a concern is under review.  Any suspension or termination of research is reported immediately to OVPR, so that OVPR 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 OVPR.  OVPR, at its discretion, may conduct additional fact-finding and adjudication using an ad hoc faculty review panel and/or the resources of the Office for Human Research Compliance Review (OHRCR).  If the IRB makes a final determination of serious or continuing noncompliance, it immediately reports the determination to OVPR, so that OVPR may make the required external reports.  A flow diagram illustrates this process.

For situations reported to OVPR for additional review and/or reporting, the Vice President for Research makes and 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 on a quarterly basis as a way of monitoring the need for attention to policy or to education.

Rights of Faculty, Staff or Others Accused of Noncompliance

The University recognizes that due process is critical in investigating and responding to noncompliance allegations .  Significant internal investigations often stimulate government regulators to conduct their own investigations and the outcome can jeopardize a researcher's livelihood and reputation.  Providing appropriate process in an internal investigation, like carefully following a scientific protocol, helps ensure that the end product is valid, reliable, and respected.  A lack of due process can undermine the integrity of decision-making in an individual case and of the HRPP more broadly.

Accordingly, in conducting an audit or investigation following receipt of an allegation of noncompliance, the reviewing authority should provide the individual or entity about whom the concern is raised the following:

These standards do not apply to the initial fact finding activities undertaken to evaluate the credibility of a complaint and 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.  

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.

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’s Compliance Hotline.

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. 

`over the relevant research protocol but may be transmitted directly (and anonymously, if desired) to the Office of the Vice President for Research, the Provost, the Office for Human Research Compliance Review, 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 ).

Allegations of noncompliance may also emerge through internal or external audits of the IRBs, OHRCR, 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 designated IRB staff member of the responsible IRB, who immediately will initiate the established IRB-level review procedures.  OVPR 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 HHS Office for Human Research Protections (OHRP) about human research conducted at or by the University will, in accord with OHRP policy, be directed in the first instance to the Vice President for Research, who is the Institutional Official.  The Deputy Institutional Official 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.

Receipt and Initial Handling of Allegations of Noncompliance

When a complaint, allegation, or monitoring observation is received by an IRB, the IRB member or staff will immediately initiate a record including the date of the report, the nature of the suspected noncompliance and any supporting evidence that may be offered, and a statement about any immediate measures taken by the IRB to protect research subjects.  The IRB , through appropriate members and/or staff (and consistent with locally adopted SOPs, if any), will initiate a fact-finding review that may involve examination of study records or source documentation, informed consents, and the study protocol ; and as appropriate , discussion with the research team, research participants, the complainant (if known), and others. 

Upon completion of this initial review, the responsible IRB staff member documents and compiles the information in a preliminary report. 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 or quarterly to the IRB Chair and OVPR.  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.

Chair and Board Considerations and Determinations

If the noncompliance activity is brought before the IRB Chair, a preliminary determination is made as to whether or not the alleged activity has caused injury or an unanticipated problem involving risks to subjects or others, or constitutes serious or continuing noncompliance with IRB determinations , applicable regulations , or HRPP policies.

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 . 

If the noncompliance activity is deemed to be serious or continuing by the Chair, a quorum of IRB members will review the activity at the next available convened meeting, discuss the findings, recommend actions, and vote to approve the recommended actions.

The results of the convened IRB meeting will be provided to OVPR within one month, absent extenuating circumstances, If the IRB determines that the noncompliance is either serious or continuing, OVPR will notify as necessary the appropriate federal agency(ies ) and sponsors.  If the IRB determines that the noncompliance is neither serious nor continuing, OVPR may, in its discretion, conduct additional fact-finding or refer the matter back to the IRB.

Detailed Procedures for Investigating Allegations of Noncompliance

The recipient of any allegation, complaint, not for cause observation, or other concern (a "concern") should forward the concern and any relevant information (excluding the identity of the person who first reported it, if anonymity has been requested and promised) to the particular IRB with jurisdiction over the relevant 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 Vice President for Research or his or her designee.

Senior IRB staff with sufficient education and training to initially triage the matter may first assess the concern.  If staff concludes that the concern clearly is without merit or that the conduct in question (i) clearly does not constitute serious or continuing noncompliance; and (ii) can be addressed through minor corrective action agreed to by the Principal Investigator or other involved parties, the matter may be closed.  Any matter disposed of through this process must be identified in a quarterly report transmitted to the relevant IRB Chair(s), oversight authorities (e.g., research associate dean), and the Vice President for Research or his or her designee, and must consist of at least the following information:

In addition to the quarterly report, the IRB must maintain in a secure manner documentation of the source of the complaint (if known) in order to facilitate any necessary follow-up.  

The Vice President for Research or his or her designee may request additional information concerning any matter reported in this fashion and may perform an independent investigation.

If IRB staff determines that there is some basis for the concern, that minor corrective action may not address it appropriately or that the conduct in question might constitute serious or continuing noncompliance, the matter must be 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, including if appropriate a preliminary assessment or detailed audit.  To accomplish this task, 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 with an actual or apparent conflict of interest regarding the individual(s) about whom a concern has been raised, must recuse him or herself from involvement in the matter.  

After reviewing any relevant information and interviewing individuals with information relevant to their decision, the Chair(s) must make a preliminary determination whether or not the conduct in question is potentially serious or continuing .  If the determination is negative, the Chair(s) may work with the relevant parties to develop an appropriate corrective action plan.  If the determination is positive, the Chair(s) must bring the matter (together with sufficient background to facilitate an informed discussion and decision) to the IRB for a vote.  The vote must be promptly reported to the Vice President for Research or his or her designee (who will then report to the Vice President for Research).  

When the Vice President for Research receives a report from an IRB (or from another source regarding an issue not within a UM IRB's jurisdiction ), he or she will review the report and determine whether additional investigation is needed.  If so, the Vice President for Research 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 Office of Human Research Compliance Review .  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 Vice President.  Upon receipt of the report, the Vice President 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.  OVPR will make any required external notifications as described in Section III below.

Response to Determinations of Noncompliance

Each IRB, as well as the Vice President for Research 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:

The Vice President for Research may institute any or all of the following additional sanctions:

Institutional Notification and Reporting Requirements

In the event the IRB votes that the conduct in question constitutes serious or continuing noncompliance, the Vice President for Research must report this information to government authorities with jurisdiction and sponsors to the extent required by any relevant regulations, grants or contracts.  If the IRB votes that the conduct does not constitute serious or continuing noncompliance, the Vice President for Research may accept the IRB determination, reject the determination and report externally as required, or conduct additional investigation.

The next section further describes the obligations of the various HRPP units and the Institutional Official to notify appropriate authorities of suspected or actual noncompliance or unanticipated problems involving risks to subjects or others.  The Vice President for Research makes any required notifications outside the University, for example to government agencies or research sponsors.

Procedures for Review and Reporting of Unanticipated Problems Involving Risks to Subjects or Others, Serious or Continuing Noncompliance, or Suspension or Termination of IRB approval.

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 body of any:

In addition, the University’s FWA requires reporting of such events if they are associated with federally sponsored research to the HHS Office for Human Research; and FDA regulations require similar reporting to FDA for research subject to FDA oversight.

The University’s researchers, Office of Human Research Compliance Review, IRBs, and OVPR have separate but complementary responsibilities for assuring compliance with these reporting requirements.

Roles and Responsibilities

Researchers

The principal investigator of any research project is responsible for reporting to the IRB overseeing that project adverse events (AEs) and other reportable information or occurrences (ORIOs) 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 following web site:
http://www.med.umich.edu/irbmed/ae_orio/.  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 information that has all of the following characteristics:

Because an individual event cannot be readily concluded to represent an unanticipated problem, investigators should assess and report:

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.

In addition, principal investigators engaged in research involving investigational devices for which the Food and Drug Administration 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.  A UADE identified in any study conducted at the University of Michigan Hospitals and Health Centers must also be reported to the Safe Medical Device Act (SMDA) Committee.

Principal investigators must report adverse events 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.

Principal investigators must report potentially serious or continuing noncompliance that comes to their attention to the IRB, pursuant to the guidance in the Section II.C. above.

Principal investigators must forward to the IRB any inspection, audit or investigation reports issued by internal or external sponsors or oversight authorities, according to the schedule articulated in the IRB’s policies or a study-specific plan approved by the IRB.  For projects approved through eResearch, the reports must be forwarded through eResearch.

The IRBs

Each IRB must require, through standard operating procedures 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 conduct an initial review of an application for completeness, assess the applications to see if they 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 OVPR.  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:

Office of the Vice President for Research

OHRP informs the Vice President for Research (the Institutional Official designated on the University’s Federalwide Assurance) potential serious or continuing noncompliance.  Within three (3) business days of its receipt of such a report, OVPR will communicate its receipt to relevant parties, including the Principal Investigator, the IRB, and the Office for Human Research Compliance Review.  OVPR 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 of others, or a report of serious or continuing noncompliance with IRB requirements or directives, applicable regulations, or HRPP policies, OVPR will take additional action, as appropriate, as described in Section II.C.

OVPR will evaluate any external reporting already made and consider additional external reporting.  For studies supported by U.S. Department of Health and Human Services or other federal agencies requiring reporting to the HHS Office of Human Research Protections, OVPR will notify OHRP within one month of the IRB’s receipt of a University unanticipated problem.  For studies under FDA oversight, OVPR will notify the FDA of a University unanticipated problem.  Initial reports may be 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:

The report to OHRP will be made within one month, absent special circumstances, such as the need for extensive data gathering or analysis.

Office for Human Research Compliance Review

OHRCR is responsible for conducting the for-cause and not-for-cause post-approval reviews, remediation, and reporting.

Not-for-cause reviews are conducted in a way and according to a protocol developed by OHRCR, in consultation, as appropriate, with the IRB and others and approved by OVPR.

In the event a not-for-cause review uncovers serious situations reportable to the IRB or OVPR under the guidelines above, OHRCR will provide such notice to OVPR.  OVPR and the IRB will proceed pursuant to the guidelines articulated above.

OHRCR will conduct for-cause reviews as requested by OVPR in fulfillment of the institutional obligation to review, remediate, and report.