Inspections, Compliance, Enforcement, and Criminal Investigations
Catholic Health Partners 09-Dec-02
Department
of Health and Human Services Public
Health Service
Center for Biologics Evaluation and Research
1401 Rockville Pike
Rockville, MD 20852-1448
December 9, 2002
By Certified Mail - Return Receipt
Requested
And by Facsimile Transmission
Warning Letter
Matthias McGuire
Acting Chief Executive Officer
Catholic Health Partners
2520 North Lakeview Avenue
Chicago, Illinois 60614
Dear Mr. McGuire:
During the period of February 8 to
March 15,2002, Lisa Hayka, an investigator with the Food and Drug Administration
(FDA), conducted an inspection of Catholic Health Partners Institutional Review
Committee (IRB). The purpose of this inspection was to determine if the IRB?s
procedures for the protection of human subjects comply with FDA regulations,
which are published in Title 21, Code of Federal Regulations (CFR), Parts
50 and 56. During the inspection the investigator copied various documents
and records, including, but not limited to, IRB meeting minutes and standard
operating procedures. These documents were later reviewed by the Center for
Biologics Evaluation and Research, Bioresearch Monitoring Branch.
At the conclusion of the inspection
a Form FDA 483, List of Observations, was issued to the IRB Chair, Robert J.
O?Mara, Ph.D. We note that Dr. O?Mara stated at that time the IRB?s policies
and procedures would be revised, and he committed verbally to correcting all
observations discussed at the time of the inspection. As of the date of this
letter, we have not received any further acknowledgment or documentation to
demonstrate the implementation of the promised corrective action.
Based upon the inspectional
findings described in the Form FDA 483, and in the Establishment Inspection
Report (EIR), as well as our subsequent review of documents collected during
the inspection, we have determined that the IRB violated regulations governing
the composition, operation, and responsibilities of Institutional Review Boards
as published under 2 1 CFR 50 and 56.
These regulations are available
at http://www.access.gpo.gov/nara/cfr/index.html.
The applicable provisions of the CFR are cited for each violation listed below.
1. Failure to prepare, maintain,
and follow adequate written procedures for conducting the review of research,
including periodic review. [21 CFR 56.108(a) and 56.115(a)(6)].
A. The IRB?s written procedures, as
described in the Catholic Health Partners Policy ADM 313, are not adequate
because they do not describe in detail the following:
i.
The document
does not establish procedures to enable the IRB to conduct the activities
described in 56.108(a), including initial and continuing review of research.
Specifically, as cited on the Form FDA 483, the procedures do not describe how
the IRB will:
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Assure that
the membership and quorum include at least one member whose primary concerns
are in a non-scientific area;
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Avoid conflict
of interest in its reviews, and how the IRB will consider research proposed by
IRB members;
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Ensure that
research approved by the expedited review procedure involves no more than
minimal risk;
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Determine
which projects require review more often than annually;
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Review
research involving children as subjects;
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Ensure prompt
reporting to FDA, when appropriate, of any instance of serious or continuing
noncompliance with FDA regulations or the requirements of the IRB, and any
suspension or termination of IRB approval;
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Determine when
studies require or are exempt from IND/IDE requirements; and
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Determine when
a study involves a significant risk device.
The following examples of this
violation are based on our review of documents, including the IRB?s policies
and procedures that were copied during the inspection. These documents did not
describe how the IRB will:
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Review adverse
reaction reports;
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Select members
who posses the experience and expertise necessary to review specific research
activities, and who are able to ascertain the acceptability of proposed
research in terms of institutional commitments and regulations, applicable law,
and standards of conduct;
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Assure that
studies "approved" pending modifications are not initiated before the
IRB accepts the modified documents; and
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Allow
alternate members to substitute for absent IRB members.
The following specific violations
are based on our review of documents, including the IRB?s policies and
procedures that were copied during the inspection.
ii. The procedures described in
Article VIII, Investigational Drugs for Emergency Use, are inadequate. For
example, the procedures fail to state that any subsequent use of the same test
article at the institution requires IRB approval, as required by 21 CFR 56.104(c).
Additionally, the Informed Consent
section for emergency use fails to list all the requirements listed under 21
CFR 50.24 for waiving the requirement of obtaining informed consent.
iii. Article VII, General Procedures, part A,
states that IRB approval is for a specific period of time, not greater than one
year. However, the procedures listed under Article VI, IRB Deliberation
Process, Section 3, Post Approval Procedures, part B, allows, or appears to
allow for a study to extend beyond the time initially approved by the IRB,
without being subject to continuing review as long as the investigator submits
a status report to the IRB. 21 CFR 56.109(a)(2)(f) requires an IRB to conduct
continuing review at intervals appropriate to the degree of risk, but not less
than once per year.
iv. Article VII, General Procedures,
part C, states that the IRB may waive the requirement to provide study subjects
with a copy of their signed consent document for a study involving
FDA-regulated test articles. 21 CFR 50.27(a) requires that a copy of the
consent form be given to each subject, and the IRB cannot waive this
requirement.
v. Article V, IRB Review, part B, fails to
state that the primary and secondary reviewers; who are selected by the IRB
Chair to review a specific study and who are not IRB members, are not permitted
to vote on the study they review as required by 21 CFR 56.107(f).
B. The IRB failed to follow its
written procedures for initial and continuing review. The following examples of
this violation are based on our review of documents copied during the
inspection, including the IRB?s policies and procedures, as well as IRB meeting
minutes.
i. The IRB?s procedures state the
new studies will either be "Approved", "Disapproved" or
"Disapproves, can resubmit". However, meeting minutes for 1999, 2000
and 2001 document that on multiple occasions the IRB failed to follow its
written procedures when it granted pre-approvals, approvals pending
modifications, and full approval contingent on revisions to the protocol or
informed consent document.
The following example is provided
for illustration, and is not a complete list.
On l/14/00, the IRB reviewed the
protocol for the study entitled [redacted] and granted full approval for one
year, contingent on revisions of the protocol and consent form. Subsequent
meeting minutes fail to document that the requested modifications were either
submitted or prior approval was rescinded.
ii. Article VI, IRB Deliberation
Process, Section 1, Review of Application, part A, specifically requires the
investigator of a research project to be present at a convened meeting to
review the protocol with the IRB members, and to explain the purpose of, and
need for the proposed research. The IRB commented specifically on this item in
the May 12, 2000 meeting minutes, stating that the physician involved with the study
should attend the IRC meeting to present their study.
However, during the period from
July 1998 to January 2002, for at least 27 separate research projects, someone
other than the physician involved with the study presented the proposed study
to the IRB. Presenters included nurses, study coordinators, and secretaries.
III. Article Ill, Officers, Section 3, Duties of
the Secretary, state the IRB Secretary is responsible for preparing the minutes
of the meeting, and for acting as the Chair in his/her absence. However, on 10/l2/01,
12/14/01, 1l/12/99, and 12/4/98, someone other then the Secretary acted as the
Chair. Additionally, on 11/12199 and 12/4/98, the Secretary, who was not acting
in the capacity of the Chair, voted on proposed research. The procedures do not
grant the Secretary voting rights.
2. Failure to review proposed
research at convened meetings at which a majority of the members of the IRB are
present, including at least one nonscientific member. [21 CFR 56.108(c)].
A. Meeting minutes for 4/14/00,
7/14/00, 6/8/01, 8/10/01, 10/12/01, 1l/9/01, and 12/14/01 document that IRB
members who were not present for the discussion of research protocols granted
their proxies to other IRB members to vote on studies. The IRB does not have
procedures that describe proxy voting. Further, there are no provisions in the
regulations that allow for IRB members to give their proxies to other members.
In addition to the example noted
above, which was cited on the Form FDA 483, the subsequent review of the
meeting minutes copied during the inspection revealed the following violations:
B. During the period of July 1998
through December 2001 the IRB convened at least 36 times. The meeting minutes
for this period fail to specifically identify whether a non-scientific member
was present during these convened meetings when new research proposals were
approved, and when continuing review was conducted. During the FDA inspection,
there were no IRB membership rosters available for this time period.
C. On at least one occasion the IRB
failed to have a quorum present when new research was reviewed and approved,
and continuing review was conducted. At the 619100 meeting there were only 6 of
12 members in attendance. The IRB?s procedures state that a majority of the membership
must be present to establish a quorum.
3. Failure to conduct continuing
review of research at intervals appropriate to the degree of risk. [21 CFR 56.109(f)].
The IRB failed to conduct
continuing review of all prior approved studies on at least an annual basis.
Further, the IRB failed to either suspend or terminate those studies for which
annual continuing review had not been conducted. The following examples, which
were cited on the Form FDA 483, are provided for illustration purposes, and are
not a complete list.
A. [redacted] Initial approval
was granted on 3/30/00, but the
continuing review was not conducted until 8/10/01.
The IRB minutes fail to document
that this study was either suspended or terminated due to lack of continuing
review.
B. [redacted] Initial approval was granted by the IRB on 3/20/00. However,
despite the fact that there were at least two separate instances of serious
adverse events reported for this study within the first six months, there are
no Periodic Review Forms, progress reports, or documentation of continuing
review being conducted for this study in 2001 or as of May 15, 2002.
The IRB meeting minutes fail to
document that this study was either suspended or terminated due to lack of
continuing review.
C. [redacted] initial approval was
granted on 918100, but continuing review was not conducted until 12/14/01.
The IRB minutes fail to document
that this study was either suspended or terminated due to lack of continuing
review.
4. Failure to ensure that
research is reviewed free from conflict of interest. [21 CFR 56.107(e)].
The IRB meeting minutes fail to
document that IRB members always excluded themselves from deliberation and
voting on projects in which they were involved. The following examples, which
were discovered during the review of meeting minutes copied during the
inspection, are provided for illustration and are not a complete list.
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[redacted] is a member
of the IRB and the clinical investigator for the study entitled [redacted]
The meetings minutes for 10/12/01
failed to document that [redacted] did not vote on the study. The meeting
minutes indicated that there were nine members present, with seven votes for
approval and two recusals; however, the minutes did not identify which IRB
members recused themselves from voting.
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The IRB
meeting minutes dated 3/9/01, 6/l3/01, 8/10/01, 9/14/01, and 1 l/9/01, failed
to document that [redacted] either excused herself or abstained from voting
during the continuing review of research projects in which she was the clinical
investigator.
5. Failure to fulfill
requirements for expedited review. [21 CFR 56.110].
During the review of meeting
minutes, which were copied during the inspection, for the dates 6/11/99, 8/l3/99,
and 9/l0/99, it was noted that the Chair used the expedited review process to
approve the use of investigational drugs for subjects based on
"compassionate use."
The term "compassionate
use" does not appear in either FDA or the Department of Health and Human
Services regulations. Expedited review procedures are only to be used for
certain kinds of research involving no more than minimal risk, and for minor
changes in approved research; the uses described in the meeting minutes do not
meet these criteria.
6. Failure to fulfill membership
requirements. [21 CFR 56.107(a) and (f)].
As cited on the Form FDA 483,
meeting minutes for 7/14/00, 9/8/00, and 2/9/01, document individuals who were
not members of the IRB substituted and voted for IRB members in their absence.
The IRB does not have a list of alternate members, and the IRB procedures do
not describe the appointment, function or voting rights of alternate members.
7. Failure to require that
information given to subjects as part of informed consent is in accordance with
the provisions of 21 CFR 50.20, 50.25, and 50.27. [21 CFR 56.109(b) and (c)].
A. The IRB reviewed a safety report
dated 11/9/99, for the study entitled [redacted] which reported on a second case of [redacted]
?The sponsor of the study felt the adverse reaction was related to the administration
of the test article, and recommended that the risk of [redacted] be included in
the informed consent document. The sponsor provided specific phraseology and
stated that other investigational sites had already revised the informed
consent documents to include the specific reference to [redacted].
However, the IRB did not require
the informed consent document to be revised. The IRB failed to ensure the
rights, safety, and welfare of subjects by withholding important information
concerning the possibility of severe neurological side effects associated with
the study.
B. The IRB approved consent forms
that did not meet the requirements of 21 CFR 50.25 and 50.27. For example, the consent
form approved by the IRB for the protocol entitled [redacted] lacks the following required elements:
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A description
of the reasonably foreseeable risks and discomforts associated with androgenic
anabolic steroid therapy, including but not limited to liver cell tumors,
peliosi hepatis, decreased high-density lipoproteins, gynecomastia, insomnia,
and depression;
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An explanation
of whom to contact for answers to pertinent questions about the research and
research subject?s rights, and whom to contact in the event of a
research-related injury to the subject;
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A statement
noting the possibility that the Food and Drug Administration may inspect the
study records;
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A statement
that significant new findings developed during the course of the research which
may relate to the subject?s willingness to continue participation will be
provided to the subject; and
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A statement of
the number of subjects involved in the study.
In addition to the above items,
which were cited on the Form FDA 483, during the review of documents copied
during the inspection, including the IRB?s policies and procedures, the
following deviation from the regulations concerning consent forms was noted.
C. The IRB?s guidelines require a
statement to be included in each consent document which reads in part: "In
the event of injury or illness resulting from research procedures, Catholic
Health Partners...Chicago, Illinois, is not responsible for provision of
medical care nor for compensation of any expenses associated with such injury
or illness.. ... This exculpatory language waives or appears to waive the
subject?s legal rights, and releases or appears to release the clinical
investigator and the institution from liability, despite the prohibition
contained in 21 CFR 50.20.
8. Failure to prepare and maintain adequate
documentation of IRB activities. [21 CFR Part ?56.115(a)(2) and (5)].
A. The minutes of the IRB meetings
are not accurate or in sufficient detail to show all actions taken by the IRB,
and the vote on those actions, including the number voting for, against, and
abstaining.
For example, the meeting minutes
dated 2/12/99, 3/12/99, 4/9/99, 5/14/99, 6/11/99, 8/13/99, 9/10/99, and
11/12/99, do not indicate how many members voted for approval on new studies or
voted on continuing review of ongoing studies.
The dates of meeting minutes listed
above reflect those cited on the Form FDA 483, as well as additional dates
noted during the subsequent review of meeting minutes that were copied during
the inspection.
B. The IRB failed to retain IRB
membership rosters prior to 2002, and the current IRB membership roster as of
May 15, 2002 does not list the Chair, the Secretary, or the non-scientific
member.
The subsequent review of meeting
minutes obtained during the inspection revealed the following additional
deficiency:
C. The meeting minutes for the
period of July 1998 through January 2002, and the current list of "IRC
Open Study Protocols" do not identify the primary and secondary reviewers
assigned to review new studies as required by the IRB?s written procedures.
It is important to include this
information in the meeting minutes to document that the IRB reviewers do not
have a conflict of interest.
This letter is not intended to be
an all-inclusive list of violations. It is incumbent upon you and the IRB to
not only correct the deficiencies cited on the Form FDA 483, and those
described in this letter, but to also conduct a thorough review of the IRB?s practices
and procedures to ensure full compliance with the regulations.
Based on the deficiencies found
during the inspection, as well as our subsequent review of documents collected
during the inspection, we have no assurance that your IRB procedures are adequately
protecting the rights and welfare of the human subjects of research. For this
reason, in accordance with 21 CFR 56.120(b)(2), and effective immediately,
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no new
subjects are to be admitted to ongoing studies that are subject to 21 CFRParts
50 and 56 until you have received notification from this office that adequate corrections
have been made.
This restriction does not relieve
the IRB of its responsibility for receiving and reacting to reports of
unexpected and serious reactions and routine progress reports from ongoing studies.
Please notify this office in
writing, within fifteen (15) business days of receipt of this letter, of the
specific actions you have taken or plan to take to bring the procedures of your
IRB into compliance with the applicable regulations. If corrective actions
cannot be completed within 15 working days, state the reason for the delay and
the time within which corrections will be completed. Your response should
address each item listed, and include any documentation necessary to show that
correction has been achieved. In addition, please submit a copy of the written
notification from the IRB to each of the affected clinical investigators
notifying them of the current restriction.
We will review your written
response and determine whether the corrective actions are adequate to permit
the IRB to resume unrestricted activities. Your failure to adequately respond
to this letter may result in further administrative actions against your IRB, as
authorized by 21 CFR 56.120 and 56.121. These actions may include, but are not limited
to, the termination of all on-going studies approved by your IRB, and the
initiation of regulatory proceedings for disqualification of your IRB.
Should you have any questions or
comments about the contents of this letter or any aspects of the operations and
responsibilities of an Institutional Review Board, you may contact: Robert L.
Wesley at (301) 827-1948.
Please send your written response
to:
Division of Inspections and Surveillance (HFM-664)
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1488
Telephone:(301) 827-1948
We request that you send a copy of
your response to the FDA office listed below.
Sincerely,
/s/
Steven A. Masiello
Director
Office of Compliance and Biologics
Quality
Center for Biologics Evaluation and
Research
