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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Enforcement Actions

Ochsner Clinical Foundation 05-Mar-02


Public Health Service

Food and Drug Administration

Center for Devices and Radiological Health

2098 Gaither Road

Rockville, MD 20850


via Federal Express

Warning Letter

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

Bioresearch Monitoring.

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

tertiary reviewer.

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

emergency use.

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

55 minutes.

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.

Sincerely yours,

Larry D. Spears

Acting Director


Office of Compliance

Center for Devices and Radiological Health