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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Tellez, Juan L., M.D. 23-Oct-02

Food and Drug Administration

Center for Biologics Evaluation and Research

1401 Rockville Pike

Rockville, MD 20852-1448

 

By Certified Mail - Return Receipt Requested

And by Facsimile Transmission

 

CBER-03-002

Warning Letter

October 23, 2002

 

Juan L. Tellez, M.D.

Illinois Center for Clinical Trials

737 N. La Salle St., 3ti Floor

Chicago, Illinois 60610

 

Dear Dr. Tellez:

 

During an inspection ending on November 16, 2001, Ms. Alicia Mozzachio, an investigator with the Food and Drug Administration (FDA}, reviewed your conduct of the clinical study entitled [redacted]? is the sponsor of the clinical study. The inspection was conducted under FDA?s Bioresearch Monitoring Program, which includes inspections designed to review the conduct of research involving investigational products. At the close of the inspection, a Form FDA 483, List of Inspectional Observations, was issued to and discussed with you.

 

We have determined that you violated regulations governing the proper conduct of

clinical studies involving investigational new drugs as published under Title 21,

Code of Federal Regulations (CFR), Part 312 [21 CFR 312] (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. You failed to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the Investigation. [21 CFR 312.62(b)].

 

A. Several laboratory reports supporting one of the study?s endpoints show that the sample ?collected? and ?received? dates were altered without explanations. It is not clear when and by whom these changes were made. These changes cast doubt on whether the pre-infusion and post-infusion blood samples were actually collected at the time points

required by the protocol. Please explain these discrepancies and provide complete documentation of the actual dates that these samples were collected and received.

 

The following table describes the alterations made on the lab reports:

Subject

Laboratory Accession No.

Original lab report

Altered lab report

 

 

Collected date

Received date

Collected date

Received date

[redacted]

[redacted]

07-07-00

07-07-00

06/27/00

06/27/00

[redacted]

[redacted]

07-07-00

07-07-00

06/27/00

06/27/00

[redacted]

[redacted]

07-07-00

07-07-00

06/27/00

06/27/00

[redacted]

[redacted]

07-03-00

07-04-00

06/30/00

06/30/00

[redacted]

[redacted]

07-07-00

07-07-00

06/27/00

Not altered

 

The protocol requires that corrections of data on the case report form ?can only be made by crossing out the incorrect data with a single line and inserting the correct values next to those crossed out. Each correction must be initialed and dated by the individual authorized to make data changes.?

 

B. You did not always document whether laboratory reports and other test results required during the screening and pre-infusion phase were reviewed prior to subject treatment. There is no documentation that study personnel reviewed several laboratory reports for safety analysis, as described in the table below. During the inspection, you acknowledged that several lab reports were not reviewed in a timely manner.

 

Subject

Visit Date

Lab Tests

Clinical Investigator Review

[redacted]

6/16/00

Serum Chemistries

Signed but not dated

[redacted]

6/16/00

[redacted] Lewis Type, DAT, HIV

Not signed or dated

[redacted]

6/27/00

[redacted] haptoglobin HGB,

DAT

Not reviewed until10/31/00

[redacted]

6/16/00

Serum Chemistries [redacted] Lewis Type, DAT, HIV

Signed but not dated

[redacted]

6/16/00

[redacted] haptoglobin. HGB,

DAT HIV

Not signed or dated

[redacted]

6/27/00

[redacted] haptoglobin, HGB, DAT

Not reviewed until10/31/00

[redacted]

6/16/00

Serum Chemistries [redacted] Lewis Type, DAT, HIV

Not reviewed until10/31/00

[redacted]

6/16/00

[redacted] Lewis Type, DAT, HIV

Not signed or dated

[redacted]

6/27/00

haptoglobin, HGB, DAT

Not reviewed until

[redacted]

6/16/00

Serum Chemistries [redacted] Lewis type, DAT, HIV

Signed but not dated

[redacted]

6/16/00

[redacted] Lewis Type, DAT, HIV

Not signed or dated

[redacted]

6/27/00

[redacted] haptoglobin, HGB, DAT

Not signed or dated

 

The safety of the individual subject, and potentially ail subjects in the study, is put in jeopardy when safety data such as lab tests are not reviewed and signed off until weeks/months after the tests are performed.

 

C. YOU did not record the following adverse events in the case report form as required.

 

i. Subject# [redacted] experienced shortness of breath during the infusions

of the study product on 6/29/00.

 

ii. Subject [redacted] had a free hemoglobin plasma (hemolysis) value of 6.9 mg/dL (range 0.0-4.0) at the 24-hour post-infusion time point. You determined this to be clinically significant. The protocol requires that [redacted].

 

2. You failed to carry out the general responsibilities of an investigator by not conducting the investigation according to the investigational plan and by not protecting the rights, safety, and welfare of subjects. [21 CFR 312.60]. You also failed to assure IRB review of the clinical study by not promptly reporting to the institutional Review Board (IRB) changes in the research activity and by making changes In the research without 1RB

approval [21 CFR 312.66].

 

The investigational plan approved by the IRB required you to sign, within [redacted] each subject?s signed informed consent form to document your review of each subject?s screening and pre-infusion tests and your agreement that your study staff had? appropriately enrolled that subject. You failed to provide this required signed certification within [redacted] in fact, you did not sign the forms until 12/5/00, more than five months after the subjects signed the informed consent documents on 06/l5/00. This is a violation of 21 CFR 321.60, which States that ?an investigator is responsible for ensuring that an investigation is conducted according to the . . . investigational plan? and ?for protecting the rights, safety, and welfare of subjects under the investigator?s Care.?

 

21 CFR 312.66 requires an investigator to ?assure that he or she will promptly report to the IRB ail changes in the research activity. . . and that he or she will not make any changes in the research without IRB approval.? You made changes in the research by certifying your review of subjects? tests and by your agreement with your staff?s decision to enroll these subjects five months after such tests and decisions, not within [redacted] as provided in the investigational plan and the IRB-approved consent form. Bi failing to report this change to the IRB and by making this change without IRB approval, you have also violated 21 CFR 312.66.

 

The Form FDA 1572 Statement of Investigator did not include two clinical laboratories,

[redacted] and [redacted] used from June 2000 until February 2001. The inspection revealed that the Form 1672 was revised only after completion of the study. We remind you that the Form 1572 requires listing the name and address of any clinical laboratory facilities to be used in the study.

 

This letter is not intended to be an all-inclusive list of deficiencies with your clinical

study. It Is your responsibility to ensure adherence to each requirement of the law and

applicable regulations.

 

Please notify this office in writing, within fifteen (15) business days of receipt of this

letter, of the specific actions you have taken to correct the noted violations, including an

explanation of each step you plan to take to prevent a recurrence of similar violations. If

corrective action cannot be completed within 15 business days, state the reason for the

delay and the time within which corrections will be completed.

 

Failure to achieve prompt correction may result in enforcement action without further

notice. These actions could include initiation of clinical investigator disqualification

proceedings, which may render a clinical investigator ineligible to receive investigational

new drugs, and/or injunction.

 

Please send your written response to:

Jose Javier Tavarez, M.S.

Division of Inspections and Surveillance (HFM-664)

Office of Compliance and Biologics Quality

Center for Biologlcs Evaluation and Research

Food and Drug Administration

1401 Rockville Pike, Suite 200N

Rockville, Maryland 20852-1448

Telephone: (301) 827-6351

 

We request that you send a copy of your response to the FDA office fisted below.

 

Sincerely,

/s/

James Cohen for Steven A. Masiello

Office of Compliance and Biologics Quality

Center for Biologics Evaluation and Research