Inspections, Compliance, Enforcement, and Criminal Investigations
Ochsner Clinical Foundation 05-Mar-02
DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration
Center for Devices and Radiological Health
2098 Gaither Road
Rockville, MD 20850
via Federal Express
MARCH 5, 2002
Patrick Quinlan, M.D.
Chief Executive Officer
Ochsner Clinical Foundation
15 14 Jefferson Highway
New Orleans, Louisiana 70121
Dear Dr. Quinlan:
The purpose of this letter to inform you of objectionable practices and activities found
during a Food and Drug Administration (FDA) inspection of the Clinical Investigations
Committee (UC), an Institutional Review Board (IRB), of Ochsner Clinical Foundation
and to request corrective actions. The inspection took place during the period of
November 5-28,2001, and was conducted by Ms. Dana M. Daigle, an investigator from
FDA New Orleans District Office, and Ms. Marian Linde-Serge, a Nurse Consultant from
FDA? s Center for Devices and Radiological Health, Office of Compliance, Division of
The purpose of the inspection was to determine whether the IRB?s activities and
procedures for the protection of human subjects complied with applicable federal
regulations. These regulations and observations apply to clinical studies of all products
regulated by the FDA.
We reviewed the observations, documents, and records contained in the establishment
inspection report (EIR) resulting from this inspection. Our review of the information
reveals violations of FDA regulations contained in Title 21, Code of Federal Regulations
(2 1 CFR), Part 50 - Protection of Human Subjects and Part 56 - Institutional Review
Ms. Daigle listed her observations on the form FDA-483, "Inspectional Observations,"
which, at the conclusion of the inspection was presented to and discussed with Dr. Carl
Kardinal, CIC Chair, at the conclusion of the inspection. Dr. William Pinsky, Dr.
Richard Re, Dr. George Pankey, Ms. Wendy Portier, Dr. Claire Dunne, and Ms. Denise
Pinkston were present during the presentation and discussion of the FDA-483. A copy of
the FDA Form-483 is enclosed for your reference.
We acknowledge receipt of copies of two letters from Drs. Re, Kardinal, and Dunne
(letters were dated December 17,2001, and January 21,2002) that were sent to the New
Orleans District Office in response to the inspectional observations. These letters will be
made a part of our official files. The letters describe the following: the contract with
Western Institutional Review Board (WIRB) to perform initial and subsequent review of
all future externally funded trials and some intramural generated protocols; that Ochsner
Clinical Foundation CIC will perform review of already approved research and selected
new intramural protocols; and the CIC will review all standard operating procedures.
These activities are inadequate given the extent of the noncompliance at the institution,
The corrective action plan neither addresses the review of previously approved
investigations nor the positive steps that the CIC must put into practice to comply with all
pertinent federal regulations for the protection of human subjects in research.
This letter informs you of the violations found during the recent inspection. Many of
these violations were observed and brought to Ochsner?s attention during past FDA
inspections. Previous commitments to correct these violations have not been
implemented. For your review and reference, we have enclosed copies of previous FDA
Form 483? s for the following dates: May 3,1994; November 20, 1997; September 21,
1999; and November 28, 2000.
The violations listed below are not intended to be an all-inclusive list of deficiencies. As
the parent institution, the Ochsner Clinical Foundation is responsible for ensuring that the
CIC adheres to each requirement of all pertinent federal regulations.
1. Failure to have adequate written procedures for conducting initial or continuing
review of research per 21 CFR Part 56, Subpart C.
The regulations require IRBs to adopt and follow written procedures for conducting their
review of research. The institution? s procedural manual entitled "The Alton Ochsner
Medical Foundation, Division of Research Policy Manual," revised July 2001, does not
meet all regulatory requirements.
The manual does not adequately describe the criteria for review of research and
information. For example, it does not adequately, 1) cover all required functions and
operations of the CIC, 2) address how the institution is notified of CIC findings and
actions, and 3) describe expedited review or emergency research.
Also, the manual does not contain written procedures delineating the role and
responsibilities of CIC members assigned as primary and secondary reviewers or the role
and responsibilities of CIC members on specialized institutional or CIC review
committees. The manual does not contain work instructions or directives, including
maintaining reports and records necessary in the performance of the Biosafety, Radiation,
Gene Therapy, and other specialized groups, whose review precedes CIC review. In
addition, there are no procedures describing the responsibilities of Chairperson as a
The manual does not adequately describe how the CIC support staff prepares and
maintains records of all IRB activities, including meeting minutes, records and reports
associated with investigations, and archiving. The manual does not describe how data
and information are gathered, stored, and analyzed to prevent research misconduct. Also,
the manual does not describe how electronically stored data and information are
safeguarded and maintained.
In addition, the manual does not have procedures for how the CIC determines whether an
investigational medical device study is a significant risk or non-significant risk device
study as required in 21 CFR 8 12 - Investigational Device Exemption (IDE) regulations.
The CIC manual must accurately describe the functions and operations of the CIC. The
procedures must provide all information that employees need to perform their tasks
correctly. Terminology used in written procedures should approximate as closely as
possible regulatory terms in order to avoid confusion. For example, laypersons should
not be described as "anyone other than physicians," administrative review should not be
used to describe expedited review, and compassionate use should not be used to describe
In addition, all procedures in the manual should be reviewed on a regular basis for needed
changes and to ensure the CIC is properly implementing all procedures. The CIC should
ensure there are standard operating procedures for continuous quality assurance of the
review of the manual. Outdated procedures in the manual should be updated or replaced,
but historical copies of all manuals should be maintained by the CIC and accessible
during internal audits and FDA inspections.
2. Failure to conduct review of research as described in the written procedures and
required by 21 CFR 56 Subpart C.
The manual states alternate members may participate in the meeting only when it is
necessary to maintain a quorum. A quorum is defined by the institution as 50 percent of
the CIC (regular) membership plus one more regular member. A review of your meeting
minutes reveal alternate members participated contrary to this procedure at the following
nine meetings: February 19; April 23; May 28-29; June 26; July 23; August 27; and
September 24-25, 2001.
It is not apparent that the CIC conducts full review of research at their convened
meetings. The CIC does not review, discuss, and vote on individual continuing review
research projects, including protocol amendments, changes, and adverse events. At the
September 24,2001, CIC meeting 93 studies were reviewed within 55 minutes. The
record for this CIC meeting indicated 25 continuing reviews, 30 local adverse events, and
21 study changes were reviewed, discussed, and voted on during the convened
meeting. However, a substantive and meaningful review (discussion and vbte on each
protocol) apparently did not occur for each continuing research project.
Our review of other CIC meetings minutes noted similar review time frames, that is, the
reviews of numerous studies completed within a span of one hour. For example, the
August 27,200 1, meeting minutes recorded the review of 2 10 studies in 50 minutes; the
May 28,2001, minutes recorded the review of approximately 200 studies in 60 minutes;
and the February 19,2001, minutes recorded the review of approximately 200 studies in
Our review of the CIC records revealed that the CIC apparently does not review complete
study files when significant protocol changes and safety information are submitted to the
,example, during the January 22, 2001, meeting, the CIC approved [redacted] for another year without discussing numerous Investigational New Drug (IND) Safety Reports, including [redacted], and which the minutes recorded that the CIC had "No Comment." The sponsor terminated this study two months later.
3. The IRB fails to prepare and maintain adequate documentation of IRB activities
as required by 21 CFR 56 Subpart D.
Documentation of the CIC membership and its roster is inadequate in that it does not
identify those who are knowledgeable in regulations, institutional commitments,
applicabIe law, and standards. The CIC MEMBERSHIP roster does not identify the
primary member(s) for whom each alternate member may substitute. Also, training
records of members are not available.
The CIC meeting minutes do not accurately reflect the activities of its meetings. Votes
and discussions at convened meetings do not occur as documented. For example, none of
the 68 studies listed under the Major Revision, Minor Revision, Ongoing Reviews, and
Adverse Events section of the meeting minutes were reviewed, discussed, and voted on
individually as reported in the September 24, 2001, meeting minutes.
The vote on the CIC reviews is inconsistent with regulations and often fails to record the
number of members voting for, the number voting against, and the name of the
member(s) who abstains.
The CIC correspondence to the clinical investigator does not accurately reflect the review
and approval activities that take place during the CIC meetings. Also, the CIC?s review
of IND Safety Reports and non-local adverse events is inconsistent and not accurately
reflected in correspondence to the institution and the clinical investigator. For example,
the CIC notified the clinical investigator that it reviewed 35 IND Safety Reports during
the September 24,200l meeting, when in fact, there is no record that these safety reports
were discussed at the meeting.
The CIC fails to maintain all regulatory information related to a research project. For
example, the CIC approved a research project even though there were concerns among
institution officials that an Investigational New Drug Application (IND) may be needed.
For examole. there are no records that document that Dr. Steven Ramee submitted an
IND for jis study that the CIC approved. The title of the research project is [redacted].
The Division of Cardio-Renal Drug Products, Center for Drug Evaluation and Research,
determined that the above study requires an IND. Therefore, it is necessary that an IND
be obtained from FDA in order for this study to be legally conducted. An IND
application for this study must be sent to the Food and Drug Administration, Center for
Drug Evaluation and Research, Central Document Room, 12229 Wilkins Avenue,
Rockville, MD 20852-l 833. Information on the preparation and submission of an JND
are available online at http://www.fda.gov/cder/forms/l57l-l572-help.html. Copies of
the IND regulations, further guidance regarding IND procedures, and additional forms
are available from the FDA Center for Drug Evaluation and Research, Drug Information
Branch (HFD-210), 5600 Fishers Lane, Rockville, Maryland 20857, telephone (301) 827-
4573 or toll free at I-888-INFOFDA.
During the inspection, Ms. Daigle and Ms. Linde-Serge inquired whether Ochsner was
conducting gene therapy research. Dr. Kardinal informed them that the institution does
not conduct gene therapy research. As CIC chairperson, Dr. Kardinal reviews all
submissions to the CIC regardless of the nature of the study and presides over the CIC
convened meetings. However, the Division of Clinical Trials, Designs, and Analysis,
Office of Therapeutics Research and Review, Center for Biologics Evaluation and Research at the FDA advised this office that the [redacted] an example of gene therapy research.
FDA?s administration actions
The FDA holds the parent institution accountable for the CIC?s functions and operations
with respect to review and approval of biomedical research regulated by the FDA and for
the protection of the rights and welfare of human subjects in research. We are concerned
that the CIC?s activities and operations are not adequate to protect the rights and welfare
of human subjects in research.
Because of the serious noncompliance with FDA?s regulations, we request you
immediately contact this office to arrange a meeting or telephone conference to discuss
corrective actions. You should be sufficiently represented at the meeting by members of
your institution? s human subject protection programs, including responsible institutional
advisory members, or consultants of your choosing.
Your failure to arrange this meeting may result in alternative administrative action, under
the authority of regulations at 21 CFR 56.120 (b), (l), and (2), including the immediate
suspension of Ochsner Medical Foundation CIC?s authority to:
- approve new research studies of FDA-regulated products subject to 21 CFR Part 56 (This includes all studies regulated by the FDA under sections 505(l) and 520(g) of the Food, Drug, and Cosmetic Act as well as any clinical investigations that support applications for research a n d marketing permits.) See 21 CFR 56.101 and 56.102;
- add new research subjects to ongoing FDA regulated studies (21 CFR Part 56); and
- continue ongoing studies subject to 21 CFR Part 56 when doing so would not endanger the subject.
During the meeting, Ochsner Medical Foundation representatives must be prepared to
discuss a corrective action plan that includes at a minimum the following items:
- a satisfactory plan to ensure that all previously approved investigational studies are adequately reviewed in accordance with FDA requirements, including the applicability of an IND or IDE submission
- revision of current CIC policies and procedures so that the functions and operations in the manual comply with all pertinent federal regulations (include the date of revision, and signatures of approval officials, and the date of implementation )
- a satisfactory plan to ensure that all CIC members and staff are appropriately educated, on a continued basis, about the regulatory requirements for review of research projects and the protection of human subjects
- a satisfactory plan to ensure that the CIC (or the institution) prepares and maintains adequate documentation of the CIC activities
- full disclosure of any use of non-approved therapies or approved therapies used for indications other than approved (off-labeled use). Identify the product, the physician, the patient medical record number, the reason for the use of product, and any adverse events including deaths that occurred after use of the product(s) regardless of causality and in any patients who received the product(s)
Further, in order to comply with your DHHS Assurance, you must also include all
requirements found in 45 CFR 46 in the UC?s policy manual. For assistance with these
regulations you should call a representative in the Office for Human Research Protections (OHRP) at (301) 402-5552.
Within fifteen (15) working days of receipt of this letter, you must contact Mr. David R.
Kalins, Branch Chief, Division of Bioresearch Monitoring, Office of Compliance, Center
for Devices and Radiological Health at (301) 594-4723 to arrange for a meeting. Failure
to respond may result in regulatory action without further notice as previously described.
Larry D. Spears
Office of Compliance
Center for Devices and Radiological Health