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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Tchekmedyian, N. Simon, M.D. 07-Aug-02

Department of Health and Human ServicesDepartment of Health and Human Services            Public Health Service


Food and Drug Administration

Center for Biologics Evaluation and Research

1401 Rockville Pike

Rockville, MD 20852-1448

August 7, 2002

By Certified Mail ? Return Receipt Requester

And by Facsimile Transmission

CBER-02-014

Warning Letter

N. Simon Tchekmedyian, M.D.

Pacific Shores Medical Group

1043 Elm Avenue, Suite 104

Long Beach, California 90813

Dear Tchekmedyian:

During the period from March 25 through April 5, 2002, Diane C. Van Leeuwen and Vien Q. Le, investigators with the Food and Drug Administration (FDA) reviewed your conduct of a clinical study entitled Phase 1 Study of Anti-tumor-Associated Glycoprptien 72 (TAG-72) Bispecific Antibody (MDX-220) in Patients with Advanced Adenocarcinomas Expressing TAG-72. The inspection was conducted under the FDA?s Bioresearch Monitoring Program, which includes inspections designed to review the conduct of clinical research involving investigational drugs. A Form FDA 483, Inspectional Observations, was issued to you and discussed with you at the conclusion of the inspection.

We have reviewed your written response dated May 13, 2002, and addressed to Mr. Alonza Cruz, to the FDA Form 483. Although your letter provides a response to some of the study deviations and provides supporting documentation and corrective actions, we request that you specifically respond to the items designated with the symbol "® ® " that are included below.

We have determined that you violated regulations governing the proper conduct of Clinical studies involving investigational new drugs, as published in Title 21, Code of Federal Regulations (CFR) Parts 50 and 312 (available at www.access.gpo.gov/nara/cfr/index.html). The applicable provisions of the CFR are cited for each violation.

  1. You failed to ensure that the investigation is conducted according to the investigational plan (protocol). [21 CFR 312.60].
  1. You did not follow the protocol for reporting serious adverse events. The protocol required that serious adverse events be reported to the sponsor within [redacted] followed by a written report within [redacted] working days. Written reports of grade 4 or fatal toxicities were required to the reported to the Institutional Review Board (IRB) within [redacted] working days. The following table summarizes serious adverse events that were reported within the time frames established by the protocol.
  2. Subject

    Serious Adverse Event

    Date of Serious Adverse Event

    Date Sponsor Notified

    Date IRB Notified

    # [redacted]

    Cellultis

    9/24/98

    *

    Not notified

    # [redacted]

    Death

    [redacted]

    10/27/98

    2/6/02

    # [redacted]

    Death

    [redacted]

    *

    2/6/02

    # [redacted]

    Fluid Overload

    10/15/98

    *

    Not Notified

    # [redacted] Event 1

    Shortness of breath Grade 4

    11/16/01

    *

    12/4/01

    # [redacted] Event 2

    Shortness breath Grade 4

    11/21/01

    *

    12/4/01

    # [redacted] Event 3

    Death

    [redacted]

    *

    12/4/01

    *Serious adverse event report issued within protocol-required time frame.

    In you response letter you acknowledge that serious adverse events were not reported to the sponsor and/or the IRB in a timely manner for subjects # [redacted], # [redacted], # [redacted] attributing the failures to report to administrative delay or administrative error. You state that you have implemented procedures for tracking and documenting adverse event reports in order to improve the accuracy and timeliness of your adverse event reporting in clinical trials.

    ® ® As described in the table above, subject # [redacted experienced Grade 4 shortness of breath on November 16, 2001 and November 21, 2001. Subject [redacted] died on [redacted]. Although these events were tinely reported to the sponsor, you did notify the IRB of these three events until December 4, 2001. These failures to report were not specifically listed in the 483. We now request that you respond to them.

  3. The protocol requires the administration of [redacted] of acetaminophen prior to infusion of the test article. You failed to follow the protocol by administering [redacted] of acetaminophen prior to infusion of the test article to the following subjects: #[redacted] (before each of [redacted] infusions); # [redacted] (before each of [redacted] infusions); # [redacted] (before each of [redacted] infusions); and [redacted] and # [redacted] before [redacted] infusion each). Subject # [redacted] also received doses of [redacted] respectively, before each of [redacted] infusions.
  4. Your response letter acknowledges the administration of [redacted] of acetaminophen instead of [redacted] prior to test article infusion.

  5. You failed to perform study evaluations required by the protocol.

  1. Screening tests, specifically urinalysis, TAG-72, and Human Anti-Bispecific Antibody (HABA), were not completed for subject # [redacted]
  2. The screening urinalysis test was not completed for subjects #[redacted] and # [redacted]
  3. Day 0 physical examination for subject #[redacted] as not performed.
  4. Day 0 and Day 14 vital signs were required to be monitored every [redacted] during infusion of study drug. Only one temperature was recorded for subject # [redacted] during Day 0 infusion that was adminstered from 1045 to 1500.
  1. You failed to conduct test procedures at intervals required by the protocol. The protocol requires screening tests be performed after the consent form is signed and within [redacted] prior to Day 0. The following tests were not performed within the timeframe required by the protocol:
  2. Subject

    Screening Test

    Date consent signed

    Date of test

    Day 0

    # [redacted]

    Chest X-ray and CT scans

    8/31/98

    8/18/98

    9/8/98

    # [redacted]

    ECG

    4/27/00

    4/13/00

    5/11/00

    # [redacted]

    CT scans

    5/2/00

    4/24/00

    5/11/00

    # [redacted]

    ECG

    3/21/00

    5/31/00

    5/31/00

    Your response letter acknowledges these deviations.

  3. You failed to record all data on the Case Report Forms (CRF) as specified by the protocol.
  1. The following abnormal laboratory values were not recorded as adverse experiences on the Adverse Experience Case Report Forms as required by the protocol:
  2. Subject

    Test

    Study Day

    Result

    Grade

    # [redacted]

    Hemoglobin

    Day 0

    7.3 g/dl

    3

    # [redacted]

    Total Bilirubin

    Day 10

    15.7 mg/dl

    4

    # [redacted]

    Glucose

    Day 10

    414 mg/dl

    3

    Your response letter acknowledges these deviations.

  3. The following adverse events were not recorded on the Adverse Experience Case Report Forms as required by the protocol.
  4. Subject

    Event

    # [redacted]

    Depression on 7/23/98, 7/24/98, and 7/25/98

    # [redacted]

    Emesis on 7/15/98

    # [redacted]

    Depression 8/14/98-8/24/98

    # [redacted]

    Decrease L4-L5 sensory distribution and complaints of radiating hip pain with numbness

    # [redacted]

    Multiple episodes of emesis, anorexia, severe nausea, and severe fatigue

    # [redacted]

    Deep tendon reflexes 5/22/00

    Your response letter acknowledges these deviations.

  5. The following concomitant medications were not recorded on the Concomitant Medication Case Report Form as required by the protocol:
  1. Ciprofloxacin for subject [redacted] for urinary tract infection on 6/20/98.
  2. Lactulose, Kytril, and Zofran for subject #[redacted] prior to treatment with the study drug.
  3. Robitussin with Codeine for subject # [redacted] on 2/26/01.

Your response letter acknowledges these deviations.

  1. You failed to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation, and failed to retain investigational records. [21 CFR 312.62(b) and (c)].
  1. The Case Report Form states that flow cytometry and cytokine tests were performed for Subject # [redacted] on 11/16/01, but subjects case history does not report the results of these tests which are pertinent to the investigation and required by the protocol.
  2. Your response letter states that flow cytometry and cytokine testing were no longer being performed. You included a facsimile transmission stating that flow cytometry and cytokine testing should end, yet the protocol required that the tests be performed and the Case Report Form says they were performed when they were not ® ® . Please explain why the Case Report Form states that these tests were performed, yet there are no test results showing that the tests were performed.

  3. We note that you failed to retain the IRB approved protocol that was in effect when you enrolled subjects # [redacted]. While you showed the FDA investigators another sponsor?s policy that requires that an outdated protocol version be destroyed when superceded , that policy was not in effect for this particular protocol. You must retain these superceded protocol versions for the period of time required by 21 CFR 312.62(c). In your response letter, you state that you keep older versions in the study binder clearly identified as "no longer applicable".

Your response letter describes procedures you have implemented to improve the completeness, accuracy, and timeliness of your adverse event reporting. You also have instituted procedures to re-verify that all eligibility criteria are met and that no exclusion criteria are present before drug protocol therapy or intervention is started.

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 and to protect the rights, safety, and welfare of subjects under your care.

Please respond to the items designated by "® ® " in writing, within fifteen (15) business days of receipt of this letter. Your response should include any documentation necessary to show correction has been achieved.

The Warning Letter is issued to you because of the serious nature of the observations noted at the time of the FDA inspection. Please be advised that the failure to effectively put into practice the corrective actions you have described in your response letter, and/or the commission of other violations may result in the 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:

Christine Drabick

Division of Inspections and Surveillance (HFM-664)

Office of Compliance and Biologics Quality

Center for Biologics Evaluation and Research

Food & Drug Administration

1401 Rockville Pike, Suite 200N

Rockville, MD 20852-1448

Telephone: (301) 827-6221

We request that you send a copy of your response to the FDA District Office listed below.

Sincerely,

/s/

Steven A. Masiello

Director

Office of Compliance and Biologics Quality

Center for Biologics Evaluation and Research

Cc: Alonza E. Cruse

Food and Drug Administration

19900 MacArthur Blvd. Suite 300

Irvine, CA 92612-2445