Thursday, March 5, 2015

For the Record: Leigh Turner to Office for Human Research Protection - Investigate the University of Minnesota

From Health in the Global Village:

March 4, 2015
Kristina Borror, Ph.D.
Director of the Division of Compliance Oversight
Office for Human Research Protections
Department of Health & Human Services
1101 Wootton Parkway, Suite 200
Rockville, MD, 20852
An Open Letter Requesting an OHRP Investigation of Institutional Protections for Human Research Participants and Psychiatric Clinical Research at the University of Minnesota
Dear Dr. Borror:
An external report commissioned by the University of Minnesota has revealed numerous institutional practices that appear to violate the Common Rule and OHRP Guidance. I request that OHRP investigate apparent violations involving inadequate scientific review of clinical protocols, insufficient attention to risks, and poor documentation of IRB deliberations. The report identifies additional institutional practices and policies that can only be described as alarming because they endanger research subjects. Written by six reviewers selected by the Association for the Accreditation of Human Research Protection Programs (AAHRPP), the report is entitled, “An External Review of the Protection of Human Research Participants at the University of Minnesota with Special Attention to Research with Adults Who May Lack Decision-Making Capacity.”
Despite the gravity of the report’s findings, Eric Kaler, the President of the University of Minnesota, responded to the release of the report by stating that he is “gratified—but not surprised—that the panel found no legal or compliance violations.” What President Kaler failed to acknowledge is that the authors of the report are not federal investigators. While they are familiar with federal regulations governing human subjects research and refer to federal regulations when evaluating institutional policies and research practices, they have no legal authority to make determinations about possible violations of federal regulations. In contrast, OHRP is empowered to investigate allegations of research misconduct and determine whether compliance violations have occurred.
Disturbing findings documented in the report and warranting investigation by OHRP include:
1. Medical IRB lacks members with sufficient expertise to review specific research activities;
2. Violations of IRB policies and insufficient evidence of substantive scientific review;
3. Conflicts of interest and the risk of bias in scientific review;
4. Scientific review, IRB assessment of risks and benefits of research, and inadequate documentation of IRB deliberations;
5. Inadequate IRB documentation and discussion of risks and benefits to research subjects;
6. Inadequate IRB documentation of the discussion of controverted issues and their resolution;
7. Inadequate IRB review of already approved protocols;
8. Inadequate post-approval monitoring of clinical research;
9. IRB Investigative Committees lack sufficient expertise;
10. Investigative Committees fail to adequately interact with complainants and act in a transparent manner;
11. Complaints concerning clinician-investigators in the Department of Psychiatry;
12. Inadequate tools for assessing decision-making capacity of prospective participants in psychiatric clinical trials;
13. Conflicts of interest and the assessment of decision-making capacity;
14. Use of unqualified study personnel to assess capacity to consent and conduct “preliminary consent” discussions;
15. Vulnerability to coercion or undue influence and involuntary commitment orders;
16. Legally Authorized Representatives and apparent noncompliance with the Common Rule and Minnesota Law;
17. Inadequate consideration of challenges in obtaining consent and assessing capacity in studies involving adults with impaired decision-making capacity;
18. Inadequate IRB policy guidance concerning fluctuations in capacity to provide consent;
19. Aggressive recruitment of research subjects;
20. Psychiatric research at Fairview, “A Culture of Fear,” and alleged retaliation against whistleblowers;
21. Inadequate institutional oversight of psychiatric clinical research.
Following this letter I have summarized the 21 specific issues that I believe require investigation by OHRP. I am also providing you with a copy of the full report. If the AAHRPP report is accurate, the University of Minnesota is failing to comply with federal regulations governing the conduct of human subjects research.
Please feel welcome to contact me if you have any questions concerning this request. I am contacting you as an individual faculty member and not on behalf of the institution of the University of Minnesota.
Yours sincerely,
Leigh Turner, PhD
Associate Professor
cc: Jerry Menikoff, Director, Office for Human Research Protections, DHHS
Sean Kassim, Director, Office of Scientific Investigations, FDA
Arne H. Carlson, Former Governor of Minnesota
Terri Bonoff, Minnesota Senator, Chair of the Higher Education & Workforce Development Committee
Carl Elliott, Professor, University of Minnesota Center for Bioethics
Trudo Lemmens, Professor, Faculty of Law, University of Toronto
Michael Carome, Director, Public Citizen Health Research Group
James Nobles, Legislative Auditor for the State of Minnesota
Eric Kaler, President, University of Minnesota
Richard Beeson, Chair of the Board of Regents, University of Minnesota
Brian Herman, Vice President, University of Minnesota
Brooks Jackson, Vice President, Health Sciences & Medical School Dean,
University of Minnesota
Bruce Blazar, Associate Vice President for Clinical & Translational Science,
University of Minnesota
William Donohue, General Counsel, University of Minnesota
Keith Dunder, Legal Counsel, University of Minnesota Academic Health Center
Elyse Summers, President, Association for the Accreditation of Human
Research Protection Programs

According to the report, the Medical institutional review board (IRB) approves many research protocols despite lacking members with sufficient expertise to review particular research activities.
45 CFR 46.107 states, “Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution.” Also, “the IRB shall be sufficiently qualified through the experience and expertise of its members,” and possess “the professional competence necessary to review specific research activities.” 45 CFR 46.107 also states, “If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration should be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects.”
According to the report (p. 24-25), from October 1, 2013 to September 30, 2014, the IRB reviewed 145 adult hematology, oncology and transplant protocols; 60 cardiology protocols; 46 surgery protocols; 34 pediatric endocrine protocols; and 31 neurology protocols. Despite the high volume of studies in these fields, the report states (p. 25), “Of note, there were no individuals on the IRB during this time period with expertise in adult hematology, oncology and transplant, cardiology, surgery, or neurology, although those fields taken together represented over 300 protocols.” It is worth noting that the report examines just one year of protocols and does not address the subject of IRB membership and adequacy of review across all departments in the medical school.
During the one-year period examined in the report, one psychiatrist served on the committee and the IRB reviewed 85 protocols submitted by members of the Department of Psychiatry. However, this psychiatrist rarely attended IRB meetings. The report notes (p.25), “Based on IRB minutes from January through July 2014, the psychiatrist on the IRB roster attended only four of 26 Medical IRB meetings at which new protocols were reviewed. Thus, at 22 of the 26 meetings at which new IRB protocols were reviewed, there was no member present with an expertise in psychiatry.” The report adds (p. 25-26), “Despite the many situations in which psychiatry protocols were reviewed without a psychiatrist present, no other expert was called upon to provide supplemental review.”
At the four IRB meetings the psychiatrist attended, he had to recuse himself from reviewing four protocols due to a potential conflict of interest. The report notes (p. 25), “The recusal in these situations left the IRB without expertise in psychiatry and in three of the four recusals an IRB staff member was required to join the meeting in order to maintain a quorum.”
Summarizing the panel’s assessment of inadequate expertise on the IRB, the Report states (p. 26),
the Medical IRB does not routinely have the requisite number of members or expertise at its meetings to properly handle the number of studies it reviews…. It was clear to the external review team that the membership of the Medical IRBs did not include sufficient members with the scientific expertise necessary      to adequately address the research being reviewed at corresponding meetings. This departure not only contravenes the University’s own policy of having at least one member with ‘primary professional expertise in a scientific field relevant to the type of research reviewed by that panel,’ but also prompts concerns about the quality of review.
Noting the gravity of the problem, the report adds (p. 27), “The failure to have either adequate number of IRB members, or adequate expertise, during IRB deliberations raises profound questions about the IRB’s ability to conduct a robust and reliable protocol review.”
I urge OHRP to investigate whether the University of Minnesota Medical IRB includes members with sufficient expertise to competently evaluate all of the protocols it reviews.  

The responsible review of clinical research requires careful assessment of scientific methods. Rigorous scientific review is an important component of responsible institutional oversight of human subjects research.
Before preparing its report, the review team examined thirty copies of scientific review documents prepared using the University of Minnesota’s departmental review process. Documentation of scientific review is required when protocols are submitted for IRB review.   According to the report, in some instances, scientific review failed to comply with the University’s own policies. The report states (p. 43), “Of the scientific review documents examined, there was only a single documented scientific reviewer for five studies, in clear violation of the University’s policy requiring a minimum of two reviewers for all departmental level review.”
The review team also found that scientific review of research is often superficial and consists of little more than checking a box or providing a signature on standardized forms. The report states (p.43-44),
Twenty-three of the scientific review documents examined included only non-specific statements and thus provided insufficient evidence that a substantive scientific review had been conducted…. Seven reviews were limited to a checked box or signature on the standardized form referenced above with no commentary that outlined the review process or outcome. In fact, only one of the scientific review documents we examined contained substantive commentary.
I urge OHRP to investigate whether research protocols submitted to the Medical IRB are being subjected to substantive scientific review.

The report documents conflicts of interest in which faculty members reviewed scientific protocols prepared by their department chairs. In such circumstances, faculty members are in a hierarchical reporting relationship to the individuals whose study protocol they are evaluating. There is risk that faculty members in such reporting relationships to department chairs might feel pressure to let their chairs’ studies proceed without requiring substantive revisions. The report states (p.46),
Of the 30 protocols examined for scientific review, five cases were identified where the scientific review was completed by a subordinate faculty member for research in which a department chair was the principal investigator. In these cases, a conflict of interest exists and the risk of bias in the review is significant.
I urge OHRP to investigate whether conflicts-of-interest are undermining the quality of scientific review. I recommend that OHRP examine conflicts of interest in which protocols are reviewed by individuals in reporting relationships to the individuals who have prepared protocols for review.
Careful scientific review is connected to informed assessment of risks and benefits of research. However, according to the report, after scientific reviews are submitted to the IRB, there is little evidence that the IRB incorporates these reviews into its deliberations and determinations. The report states (p. 48),
a review of medical IRB minutes that corresponded to 21 of the protocols for which scientific assessment documents were provided, showed little evidence that the merits of scientific design had been discussed in relation to study risks and benefits. In fact, there was no evidence in those minutes examined to indicate that the scientific review had been either evaluated or discussed…. While it is possible that sufficient documentation about the scientific review was made available to the IRB and that the scientific reviews were adequate and sufficiently discussed, there is insufficient documentation to support this. The lack of documentation raises concerns as to whether IRB systematically reviews the scientific assessment documents accompanying the IRB submission and carefully determines whether they contain sufficient information upon which the IRB can rely.
Federal regulations require IRBs to engage in an informed and scientifically grounded process of examining risks and benefits of research. The report states (p.78), “The federal research regulations permit an IRB, in the course of its protocol review process, to exercise broad discretion in determining when research risks are reasonable in relation to benefits and when research risks are minimized.” Commenting upon this federal regulatory standard the report states (p. 78), “The review team found little evidence that the University’s IRB engaged in a meaningful process of evaluating research risk.”
I urge OHRP to investigate whether the Medical IRB sufficiently incorporates scientific review into its deliberative process, including meaningful discussions that address risks and benefits of research, and provides adequate documentation of such deliberations.

Examining risks and benefits to research subjects, ensuring that risks to research subjects are minimized, and confirming that risks to research subjects are reasonable when considered in relation to anticipated benefits are important components of IRB deliberations. Such assessments by IRBs are codified in the Common Rule. 45 CFR 46.111 states, IRBs must determine that “risks to subjects are minimized.” IRBs must also establish that “Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.”
According to the report (p28),
In the majority of the minutes from meetings at which new biomedical research proposals were reviewed, the team found little discussion of the risks and benefits to subjects. Requests for ‘Changes in Protocol,’ for example, which primarily involved modifications of the inclusion/exclusion criteria—changes that may increase or decrease risks to subjects—were almost always approved without any documentation of related discussion.
The report adds (p.30), “The review process, as documented in the minutes, does not reflect a meaningful discussion of the risks and benefits of research protocols and the necessary steps taken to protect human subjects in the face of scientific or ethical concerns.”
I urge OHRP to investigate whether the Medical IRB is adequately discussing, weighing, and documenting deliberations concerning risks and benefits to research subjects.

45 CFR 46.115 states, “An institution, or when appropriate an IRB, shall prepare and maintain adequate documentation of IRB activities.” IRB minutes must contain “a written summary of the discussion of controverted issues and their resolution.”
According to the report, the medical IRB does not adequately document discussion of what federal regulations describe as “controverted issues and their resolution.” These are topics where it is reasonable to expect discussion, possible disagreement, and reasoned argumentation proceeding toward a resolution. The report states (p. 28-29),
A controverted issue usually means that there are questions, or at times disagreements, requiring a more extended discussion about a given protocol. Examples of controverted issues include concerns about placebos, payments to subjects, recruitment methods, risks, etc. In each set of minutes received by the team there is a section titled, ‘Discussion of Controverted Issues Summary.’ Most of the minutes reviewed, however, stated that ‘there were no controverted issues,’ even on those occasions when the required changes would seem to have warranted a more substantive discussion and where the IRB correspondence to the study teams indicated that ‘controverted issues’had in fact been discussed. Accordingly, the minutes did not completely or accurately appear to represent what occurred during the IRB meetings.
The report adds (p.30), “the inadequate documentation of review and the sheer volume of research being reviewed…suggests that the IRB review process may be unacceptable, and that it often contravenes the IRB’s own policies and procedures.”
Given that review of the medical IRB’s activities is limited to examination of meeting minutes, it is unclear whether the problem is confined to inadequate documentation of discussions that are in fact occurring or extends to insufficient discussion of issues meriting discussion and resolution by the IRB.
I urge OHRP to investigate whether the Medical IRB is addressing and documenting discussion of controverted issues in a manner that complies with the Common Rule.

Addressing the subject of continuing IRB review, the report states (p. 29), “the length of time allotted for IRB review was alarmingly inadequate given the number of complex items scheduled for review on many of the IRB agendas reviewed.” For example, at a three-hour meeting on July 30, 2014, the IRB performed continuing review of 57 already approved protocols. Three minutes was the average time allotted for the review of each protocol. Likewise, on September 24, 2014, during a 2.5-hour meeting, the IRB performed continuing review of 46 protocols, with an average of three minutes for the review of each protocol.
I urge OHRP to investigate whether an average of three minutes per protocol is sufficient time for continuing review.

The University of Minnesota, as with peer research institutions, has a monitoring system for post-approval review of human subjects research. At the University of Minnesota this program is known as the Post-Approval Review (PAR) program. Monitoring is supposed to assess the conduct of research after study protocols have been approved by the IRB. According to the report, (p.53)
Although the external review team found evidence of a robust PAR monitoring program, the feedback received during on-site reviews was at odds with these initial conclusions. In fact, during the site visit, we repeatedly heard monitoring cited as a primary area of deficiency and one that had the potential to pose the greatest institutional risk, as the reviews were thought to be infrequent and of poor quality. Although efforts were reportedly underway to increase staffing and resources for monitoring efforts, some high-level staff members expressed their concern that monitoring efforts had not yet achieved the desired standard. Notably, there were specific reports about the lack of monitoring of the research conducted at Fairview (as well as the lack of communication about the need for monitoring) despite the fact that the monitoring function for human subjects research conducted at Fairview is the responsibility of the University under the Master Agreement between the two institutions.
I urge OHRP to investigate the adequacy of post-approval review of human subjects research approved by the University of Minnesota’s Medical IRB. I recommend that OHRP to pay particular attention to post-approval monitoring of psychiatric clinical trials conducted at the University of Minnesota Medical Center at Fairview. 

When possible regulatory noncompliance is identified, the IRB’s Executive Committee is responsible for delegating investigations to three person investigative committees (IC). According to the Report (p.33), “any IC may lack sufficiently relevant expertise to conduct an adequate investigation.” For example, referring to ongoing investigations of psychiatric research at the University, the Report states (p. 33), “The external review team was particularly concerned that, given the nature of the complaints, neither of the active investigations to which it was privy during this evaluation had members with relevant expertise in psychiatry.”
I urge OHRP to investigate whether IRB Investigative Committees tasked with investigating possible regulatory noncompliance possess sufficient expertise.

When research subjects or their loved ones file complaints with the Medical IRB, the IRB is supposed to take reasonable steps to attend to their concerns, investigate, and provide timely responses to complainants. However, there is reason to question whether the Medical IRB adequately responds to complaints, investigates them in a thorough manner, and provides complainants with a report describing the results of their investigation. The report notes the failure of Investigative Committees to engage in meaningful interaction with complainants and report findings upon completion of investigations. Referring to one investigation in progress at the time the research team was conducting its inquiry, the report states, (p.33), “The team was made aware that the IC for Investigation 1 did not meet with the complainant, other than via telephone, and instead focused its review primarily on relevant clinical and study-related records.”
The report also indicates (p. 33) that inadequate transparency is an issue. “During its evaluation, the external review team learned of a general concern regarding the lack of transparency of IC findings, particularly as they relate to following-up with complainants to inform them of the progress and outcomes of the investigations.”
I urge OHRP to investigate whether the Medical IRB and its Investigative Committees adequately respond to complaints, investigate them, and communicate their findings to complainants.

After the research team submitted its report to University of Minnesota, senior administrators redacted the names of the individuals who have been at the center of allegations of psychiatric research misconduct. According to the report (p.82),
In the course of our interviews, many concerns were voiced about the commitment to human subjects protection of [NAME REDACTED] and [NAME REDACTED]. While anecdotal, the clear pattern that emerged was of two investigators whom faculty and staff do not trust and who fail to communicate a set of priorities that align their own research agenda with the best interests of patients and patient care. Similarly, administrative staff involved in IRB review voiced criticisms of the care taken by [NAME REDACTED] in protocol submissions and in interactions with the IRB. Documentation of IRB review provides some additional support for these statements and an example of resistance by [NAME REDACTED] to IRB efforts to introduce the use of an independent consent monitor.
The report adds (p. 83),
In other ways, it appears that [NAME REDACTED] does not take a sufficiently active role in efforts to promote higher ethical standards with the Department. For example, by emphasizing human subjects protections in the department’s strategic plan, [NAME REDACTED] could have communicated the priority of this work and make a compelling statement to the Department and beyond. For a department as embattled as the Department of Psychiatry with regard to the ethics of research, the omission of ethics from the strategic plan indicates an insensitivity to matters of paramount concern within the Department, the    University, and the community.
The report notes (p.84) the importance of addressing widespread skepticism toward the activity of one unidentified faculty member. “There is a need on the part of the University, Fairview, and the Department to acknowledge, understand, and remedy the evident distrust of the work of [NAME REDACTED].”
Vice President for Research Brian Herman has an unredacted copy of the report. I urge you to investigate whether the psychiatrists identified in the report violated the Common Rule.

Assessing decision-making capacity is a delicate undertaking requiring professional expertise, suitable assessment tools, good clinical judgment, and integrity. At the University of Minnesota, researchers in the Department of Psychiatry use a six-item “evaluation to sign consent” form when “assessing” decision-making capacity of prospective research subjects. According to the report (p. 79), a member of the clinical research team completes and signs the form, certifying that “the above subject is alert, able to communicate, and able to give acceptable answers to the items above.” The report notes (p. 79), “While this approach has the advantage of requiring some discussion between the investigator and the potential subject, in the review team’s judgment, it is insufficient.”
Although this point is not mentioned in the report, there are allegations that duplicate (photocopied) evaluation to sign consent forms have been deposited in patients’ medical records. More specifically, there are concerns that a single pre-completed and photocopied evaluation to sign consent form has been used in the context of psychiatric clinical trials. While the veracity of such allegations could easily be resolved by publicly disclosing documents already sought through Data Practices Act filings, to date university administrators have refused to release such documents.
I urge OHRP to investigate how “evaluation to sign consent” forms are used to assess decision-making capacity of prospective research participants. This document does not appear to be a sufficient tool to evaluate whether individuals are competent to make informed decisions about whether they wish to enroll in psychiatric research studies. I also urge OHRP to investigate whether members of clinical research teams are placing in patients’ medical records pre-completed “evaluation to sign consent forms.”

When assessing individuals’ decision-making capacity, it is imperative that conflicts-of-interest not influence the integrity of the assessment process.
At the University of Minnesota, treating psychiatrists who are also clinician-investigators sometimes assess the decision-making capacity of prospective study participants. In some instances, components of the assessment process are delegated to members of the clinical research team. Such arrangements can create conflicts-of-interest that compromise the integrity of the assessment process.
The report states (p.79),
It is the external review team’s opinion, that, in the context of the many concerns raised about recruitment and enrollment in Departmental Research, the University, IRB and investigator should have introduced an independent assessment of capacity for relevant research. For example, some institutions require (for defined categories of research) that an assessment of capacity be made by a trained individual who is not a member of the research team and who does not report to the principal investigator. In this manner, neither the investigator nor his/her paid staff are responsible for determining whether the prospective subject meets a reasonable standard for capacity to consent; such separation of responsibilities between the investigator and prospective subject helps ensure that real and perceived conflicts of interest are mitigated or even     eliminated.
The failure to adequately separate such roles and responsibilities appears to be a longstanding problem associated with the recruitment of prospective study subjects for psychiatric clinical trials.
I urge OHRP to investigate whether members of clinical research teams are assessing decision-making capacity of prospective research participants rather than obtaining independent assessment of capacity.  

Assessing decision-making capacity of prospective research subjects requires specialized clinical skills. The Report notes (p.80), “The decision that a prospective research subject can or cannot make a consent decision for herself or himself is one that requires considerable training or expertise.” Despite the necessity of such expertise, the Report adds (p. 80),
Boilerplate language inserted in many of the IRB protocols reviewed by the team state, ‘All study personnel have completed University of Minnesota HIPAA and CITI training. Study personnel will be trained and certified by the sponsor to administer rating scales. Research coordinators may conduct the preliminary consent discussion, but consent will be obtained by the Principal Investigator or Co-Investigator.’ This is inadequate, though, since neither HIPAA, CITI, nor sponsor training…address the relevant details of consent and capacity to consent. The question as to whether an investigator (and his or her coordinator) is appropriately trained and able to devote the time required to the consent process is one that the IRB should consider in its review and monitoring efforts.
I urge OHRP to investigate whether inadequately trained members of clinical research teams sometimes play a role in assessing the decision-making capacity of prospective research participants and conducting “preliminary consent” discussions.
Some prospective and actual research subjects are highly vulnerable to coercion or undue influence. Addressing this important issue, the Report states (p. 66),
Federal regulations require that an investigator ‘shall seek such consent only under circumstances that minimize the possibility of coercion or undue influence.’ Further, ‘When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as…mentally disabled persons, additional     safeguards have been included in the study to protect the rights and welfare of these subjects.’ Neither University policies nor practice distinguish between vulnerability to coercion or undue influence when it could occur with subjects who are limited in their understanding of the research. This area of concern is     heightened in psychiatric setting situations where there is a prospect of civil commitment (i.e., involuntary hospitalization), since that threat can increase a prospective subject’s vulnerability to coercion or undue influence.
Describing the University of Minnesota’s troubled record in this area, the report adds (p. 66),
Despite a history that includes legislative intervention by the State to protect subjects perceived to be in potentially coercive situations (i.e., those under a stay of an involuntary mental health commitment order), the external review team found no evidence that the University, Fairview, and its investigators have taken steps to ensure a broader understanding of the implications of this very fraught situation. When patients with severe behavioral disorders are in the medically unique circumstance of facing legal compulsion to receive treatment against his or her will, that prospect can affect their decision-making. Simply put, the fear of being subjected to an involuntary legal process for perceived noncooperation, even if there is no direct threat of such legal compulsion, is an overwhelming barrier to voluntariness. Yet none of the studies examined by the external review panel referenced, or distinguished among potential subjects based upon, civil commitment status, apart from verifying compliance with the state law.
According to the report (p.67),
The above problem, i.e., the risk of coercion or the appearance of coercion, is further exacerbated when the principal investigator is also the treating physician and thus has the power to initiate the individual’s involuntary confinement. We found only a single instance where consideration of the dual and potentially conflicting role of treating psychiatrist/investigator was addressed.
Noting “a recent investigation that addressed a complaint related to a subject who was recruited for a study and in fact provided consent to research while under a temporary involuntary hold,” the report notes, “the potential impact of that status (i.e., being held involuntarily) on the subject’s ability to provide consent was not referenced.”
Summarizing the importance of ensuring that consent is not sought from research subjects vulnerable to coercion or undue influence, the report states (p. 68),
The University should directly and thoughtfully address the specific issues related to the context in which acutely ill psychiatric patients are identified, recruited, and asked to consent to research. Policies are needed that reflect the imperative to refrain from seeking consent when there is situational impairment as a result of an acute physical or psychological event.
I urge OHRP to investigate allegations that individuals with mental illnesses and who are vulnerable to coercion or undue influences have been recruited into psychiatric clinical trials in a manner that is not compliant with federal regulations. I also urge OHRP to investigate whether the university’s research protection program has provided adequate institutional oversight of psychiatric clinical trials including this vulnerable study population.

According to the report (p.71), “The University’s interpretation of the regulatory term ‘applicable law,’ and therefore its policies defining who may serve as a legally authorized representative in federally funded research, do not appear to adequately conform to federal regulations and related guidance.”
Describing the research team’s review of study protocols, the report notes (p.72),
The review team also observed inconsistencies with regard to the planned inclusion of subjects who lack the capacity to consent. Often, within the same protocol, it would state that only subjects with the capacity to consent would be included, and then might later state that LARs would be used when potential subjects lacked capacity. Many of these conflicting messages were contained in applications from the Department of Psychiatry, despite the fact that members of that Department told the external review panel that they do not use LARs for any studies.
In a footnote, the report notes (p. 72), “This statement by the Department was directly contradicted by a protocol submitted in September that was explicit about the intended use of LARs when subjects lacked decision-making capacity.” Drawing attention to the apparent lack of discussion of these issues by the IRB, the report states (p.72), “The IRB minutes reviewed by the team did not address these discrepancies.”
Addressing whether university policies concerning LARs are compliant with Minnesota state law, the report states (p.71),
University policy and IRB protocols reflect inconsistencies and, in some cases, appear to be at odds with Minnesota Law…. Also, the prohibition against research consent by a legal guardian without a specific court order does not appear to be applied consistently, as guardians are sometimes referenced in research protocols as fulfilling the LAR’s function without mention of any authorization by the court.
Despite these inconsistences and reports of protocols failing to comply with state law (p. 71), “none of the IRB minutes reviewed by the team reflect discussion about who may serve as a LAR.”
According to the report, problems related to LARs extended to both clinical protocols and IRB deliberations. It notes (p. 73),
The policies and practices adopted by the IRB do not yet provide adequate guidance for investigators on the best means of identifying and educating those individuals who are permitted to function as a LAR in a given situation. Protocols and other information reviewed by the team indicate wide disparities and failures in understanding the definition and appropriate selection of LARs. Only a few sets of the IRB minutes that were assessed by the external review team commented on these discrepancies, and none addressed the question of legal authority. This evidenced a lack of appreciation for the gravity of replacing an individual’s autonomous consent with that of a surrogate in the research context. It should be well understood by all those involved in research with prospective subjects with limited decision-making capacity that the use of a surrogate for research consent calls for heightened levels of scrutiny.
I urge OHRP to investigate whether the University’s policies, practices, and protocols addressing and involving legally authorized representatives (LARs) are compliant with federal regulations.

Researchers and institutional review boards must be particularly sensitive to issues of capacity assessment and informed consent when conducting clinical trials involving research participants with impaired decision-making ability. According to the report, psychiatrists and the IRB have not addressed these topics with the sensitivity required to conduct clinical trials involving adults with impaired decision-making capacity. From a sample of 89 studies that (p.61) “posed more than minimal risk and that included subjects from diagnostic groups that may include adults with impaired decision-making capacity,” the review team selected for review “a cross section of 20 protocols.” The majority of protocols reviewed by the team predated a 2014 revision to the Institutional Review Board’s consent policy. According to the Report (p. 62),
These earlier protocols contained little or no information about the consent process and virtually no details as to how capacity would be assessed, regardless of whether a targeted population was likely to include prospective subjects with impaired decision-making capacity and regardless of the level of risk. The corresponding IRB meeting minutes similarly failed to reflect a review of these issues by the IRB.
The report describes several protocols that do not appear to comply with contemporary standards for the responsible conduct of human subjects research. The report notes (p. 62),
a number of practices described in the examined documents reflected a departure from recognized standards designed to support autonomous decision-making (with appropriate protections) for those who cannot make decisions for themselves regarding participation in research. For example, the team noted the arguably inappropriate use of a LAR when the subject’s disability was physical rather than related to consent capacity. In one such protocol, the IRB required the addition of a signature line for surrogate consent because ‘some subjects may not be able to sign their name when enrolling in this trial.’ In still other cases, the internal policy was to ‘err on the side’ of obtaining consent by a LAR, even when the individual may be able to make a consent decision on his or her own.
The report notes (p. 63) the recent development of a new IRB policy entitled, “Adults Lacking Capacity to Consent.” This policy states (p. 63), “prospective adult subjects with impairments to functional abilities are presumed to be capable of providing consent unless there is substantial evidence otherwise.” This standard is problematic because the presumption that subjects are capable of providing informed consent to participate in research could have the unintended effect of seeking consent from individuals lacking decision-making capacity. According to the report (p. 63),
this major change eliminated the requirement that a researcher must proactively ensure that prospective subjects possess the capacity to consent to participate in research. While the University’s IRB reported having had discussions about the important balance between protection and autonomy when discussing and enacting these revisions, the external review team questions whether the new approach aligns with current guidance and best practice.
Questioning the IRB’s new policy, the report (p. 63) refers to OHRP Guidance that states, “the informed consent process should ensure…that prospective subjects or their legally authorized representatives adequately understand the research so that they can make informed choices.” With this approach, the Report notes (p. 63), “The process of obtaining consent for research thereby requires the researcher to affirmatively establish that a prospective subject understands the risks and benefits of the proposed study, as well as the available alternatives to participation.” According to the Report (p. 63), “University policy, which assumes capacity to consent to research absent ‘substantial evidence’ to the contrary, is inconsistent with the principles underlying the OHRP guidance.”
The report also notes (p.65),
studies examined by the team seldom showed the IRB to be engaged in a substantive discussion of the potential tools that might be utilized in an assessment of consent capacity. These could include, among other practices: 1) the use of a decision tree that outlines the different potential requirements for assessment of consent capacity, starting from a universal informal subject assessment for consent capacity for all subjects and moving to more formal and validated independent assessments when impairment is more likely to be present, capacity fluctuations are likely, anticipated benefits are fewer, and foreseeable risks are greater; or 2) the use of independent consent monitors to oversee and assist with the assessment of capacity. In the protocols reviewed following the implementation of the new policy changes, the external review team found no evidence that these types of tools had been considered or implemented.
I urge OHRP to investigate whether psychiatric clinical studies including research subjects with impaired decision-making capacity complied with federal regulations governing human subjects research. I also urge OHRP to investigate whether past and present IRB Policies concerning adults lacking capacity to consent and IRB deliberations addressing this subject comply with federal regulations.

Assessing circumstances in which there is potential for fluctuations in decision-making capacity, the report states (p. 69), “The team found a lack of robust guidance and consistent application of policy in situations in which fluctuations in capacity can be reasonably anticipated as a component of a subject’s condition.”
I urge OHRP to investigate whether the university has adequate IRB policy guidance concerning research subjects and prospective research subjects with fluctuations in capacity to provide consent.

Fairview staff members interviewed by the research team described (p. 81-82)
a ‘pervasive lack of trust’ specific to ‘behavioral’ research at Fairview. Others reported a perception of the Department’s ‘overly aggressive’ approach to subject recruitment, which is seen as being at odds with patient-centered clinical priorities. A review of records of complaints and concerns submitted via the Fairview Research Helpline by Fairview staff has provided additional support for these perceptions.
I urge OHRP to investigate whether the alleged “aggressive recruitment” of research subjects violated the Common Rule.

Whether engaged in clinical research activities or providing care outside the context of clinical research, physicians, nurses, pharmacists, social workers and other health care providers as well as research subjects and their loved ones should not have to function in an institutional “culture of fear.” Nonetheless, the report states (p.88), “Faculty and staff in Psychiatry repeatedly characterized the climate of work as a ‘culture of fear.’ They provided stories of intimidation by researchers and fear of retaliation should staff voice opposition to practices that were of concern.”
According to the report (p.88),
concerns were also raised with regard to University policies on whistleblowing that include the language ‘no one will retaliate against individuals who acted in good faith in reporting.’ The external review team was told a story by a longstanding University employee about another who was terminated after having expressed concern about a research study involving the elderly, and further, that the concerns were ignored.  Again, the external review team cannot conclude that this indicates a problem with the institution’s response to ‘whistleblowers,’ rather, that there is such a perception. True or not, the potential impact of such concerns is considerable.
I urge OHRP to investigate whether the alleged “culture of fear” in the Department of Psychiatry has made individuals fearful of reporting allegations of noncompliance. I also urge OHRP to investigate whether any whistleblowers or prospective whistleblowers have suffered retaliation or threat of retaliation as a result of reporting allegations of wrongdoing or revealing their intention to file such reports. In addition, I recommend that OHRP investigate whether the university’s research protection program has taken adequate steps to protect whistleblowers and ensure that individuals reporting or indicating their intention to report complaints about clinical research have not suffered retaliation or been threatened with retaliation.

Fairview administrators and clinical staff members reportedly play no role in approving clinical studies at Fairview or monitoring ongoing trials. In addition to expressing concerns about inadequate institutional oversight, they appear to have observed an alarming discrepancy between approved psychiatric clinical studies and prospective research subjects available for recruitment. According to the report (p.81),
the Fairview leadership and staff reportedly have no input in the approval process for human subjects research, and no program for monitoring or quality assurance of ongoing research. According to the Fairview leadership, one specific consequence of this inability to participate in the vetting of protocols by their staff is that studies are often approved for which the subject population required is simply not among the patient populations available for recruitment, or are not available in the numbers required.
I urge OHRP to investigate the University of Minnesota Medical Center, Fairview’s institutional oversight of psychiatric clinical research conducted at that institution, the adequacy of institutional oversight the University of Minnesota Medical IRB provides for psychiatric research at Fairview, and whether the relationship between these institutions sufficiently promotes protections for psychiatric research subjects.

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