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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Chediak, Juan, M.D. 02-Jan-02

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration

Center for Biologics Evaluation and Research

1401 Rockville Pike

Rockville, MD 20862-1448

BY Certified Mail - Return Receipt Requested CBER -02-007

Warning Letter

Juan Chediak, M.D.

Angelo Creticos Cancer Center

901 West Wellington Avenue

Chicago, Illinois 60657-6708

Dear Dr. Chediak:

During the inspection that ended on August 21, 2001, investigators with the Food and

Drug Administration (FDA) reviewed your conduct of clinical studies of two

investigational blood products. 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. The inspection focused on

the following study protocols:

1 ATC 93-01 -"A Multicenter, Open Label Study to Evaluate the Safety and

Efficacy of [redacted] in the Treatment of [redacted] (hereafter, referred to as Protocol 1).

2. ATC 93-01 -"A Multicenter, Open Label Study to Evaluate the Safety and efficacy of [redacted] in the Treatment of [redacted] (hereafter, referred to as Protocol 2).

The deficiencies noted during me inspection are listed on the Form FDA 483 (enclosed)

that was issued to and discussed with you at the conclusion of the inspection. We

reviewed your response letter dated November 7, 2001, with the attachments.

We 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 http://www.access..gpo.gov/nara/cfr/index.html).

The applicable provisions of the CFR are cited for each violation listed below. These

deviations include, but are not limited to the following items:

  1. You failed to fulfill the general responsibilities of investigators. [21 CFR 312.60 and Part 50 ].
  2. An investigator is responsible for ensuring that an investigation is conducted according to the signed investigational statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator care; and for the control of drugs under investigation. Our investigation revealed that you did not fulfill your obligations as a clinical investigator in the use of investigational new drugs in that you failed to follow the investigational plan and adequately protect the safety and welfare of subjects.

  3. You failed to ensure that an investigation is conducted according to the investigational plan (protocol). [21 CFR 312.60].

FDA documented numerous protocol violations in the review of subject records for Protocols 1 and 2. The violations include, but are not limited to the following.

A. You failed to perform tests to establish that prospective subjects are eligible to be enrolled into the studies.

You failed to perform the required pregnancy test for all nine female subjects enrolled under Protocols 1 and 2.

In your response letter dated November 7, 2001, you explain that, in your judgment, several of these female subjects did not require a pregnancy test and, hence, you did not perform this test. You state that in the future you will follow the protocol and obtain prospective written approval from the sponsor prior to any protocol deviation.

ii. You failed to perform or document the Kamofsky score for all 12 subjects enrolled in the studies. Protocols 1 and 2 require that potential study subjects have a Karnofsky performance score of at least [redacted] to be included in the studies.

In your response letter you state that you will maintain the source documentation for all entry criteria in future clinical trials.

B. You failed to administer the correct dosage of investigational product to eight of twelve subjects as shown in the examples below:

You did not document the volume of [redacted] administered to subject 0103 between 10/14/98 and 10/15/98 for infusions [redacted] as a result of an undetermined

[redacted] to this subject.

ii, Subject 0107 was administered an incorrect volume of [redacted] as a result of inaccurate weight calculations for each of them infusions for surgery number 4 under Protocol 2 Part II b between 5/20/98 and 5/23/98. Your response letter acknowledges this

violation.

iii. Subject 0112 was administered [redacted] instead of [redacted] on 6/9/98, for the first in acknowledge this deficiency in your response letter.

c. You administered a second infusion of the investigational product to subject 0111 on 10/23/96, even though the subject failed to achieve levels of [redacted] activity at or above [redacted] of normal [redacted] after the initial infusion prior to surgery. The infusion log indicates that the sugject’s [redacted] level was [redacted] after the first infusion and, therefore, the subject was ineligible receive additional investigational product.

Your response letter acknowledges that the administration of the second infusion of investigational product on 10/23/96 is a protocol violation.

D. You failed to perform the screening evacuation as required by the protocol,

For subject 0106, under Part la of Protocol 1, the pre-infusion blood chemistry sample was obtained several hours after the infusion was completed on 8/10/93.

Your response letter explains that the sample was obtained prior to the infusion, but there is no documentation to support your claim that the sample was collected before the infusion was begun.

E. You failed to measure the bleeding time a- post-infusion for subjects 0101 (Part Ia and Ib) and 0102 (Part la) under Protocol 1.

In your response letter, you indicate that you contacted the sponsor regarding this protocol directive. However, there is no documentation to confirm that the sponsor authorized this protocol deviation.

F. You failed to save a sample of the [redacted] as required by the protocols under Part la for subjects 0101, 0102, 0103, 0106, and 0108 and under Part IIa for subject 0107.

You acknowledge this deficiency in your response letter, and indicate that you will ensure that study personnel understand the protocol requirements.

G. You failed to draw blood to determine the hemostatic response at baseline

And [redacted] post-infusion, or obtained the sample at inappropriate times

for the following subjects:

Subject

Treatment

Samples not drawn or drawn incorrectly

0101

Part Ib

Not drawn on 11/16/93

0103

Part IIb

Part Iib

Not draw on 10/2/98

Not draw for bleeding episode 8 for infusions [redacted] to [redacted

0111

Part Ib

 

Part IIb

Baseline samples were drawn after the infusion had started

[redacted] post-infusion samples was drawn late, for surgery 1

In your response letter, you explain that in future clinical trials your research staff will be more diligent in adhering to the protocol requirements.

H. You failed to obtain vital signs as required by the protocols. This is not a

complete list, but is provided for illustration.

Part la of the protocols required vital signs to be recorded a [redacted] post-infusion of the study drug. You failed to follow this protocol directive for subjects 0101, 0104, 0105, 0106, 0107, 0108, 0109.

ii. For subject 0103 you failed to obtain vital signs for numerous infusions. Examples include, but are not limited to, the infusions under Part IIa, bleeding episode 7 (infusions [redacted] and [redacted] and Part IIb, surgery 9 (infusion [redacted].

In your response letter, you acknowledge these violations, and commit to train your staff in future studies.

You failed to report all serious adverse experiences (SAES) to the sponsor

as required by protocol 2.

Subject

SAE

Onset date of SAE

Protocol requirement

0111

[redacted]

10/23/96

Within [redacted] working days under version 3.0

0107

Hematuria

1/22/97

Within [redacted] working days under version 3.0

0103

Adenocarinoma of the cervix

Pnumonia and Pulmonary effusion

Hematochezia

Melena, anemia

Polmonary embolism

Deep vein thrombosis

Diarrhea

4/9/98

 

8/10/98

 

9/2/98

10/12/98

10/22/98

 

10/23/98

 

10/27/98

Within [redacted] working days under amendment 3 dated 8/27/97

In your response letter, you acknowledge your deficiency in reporting of SAES to the sponsor in a timely manner and will implement better oversight of study personnel for proper documentation and reporting of SAES to the sponsor.

J. Protocols 1 and 2 require that case report form (CRF) "corrections will be made by a single line stroke through the entry to be corrected, and the correct entry will be made above the deleted entry, initialed and dated." You routinely failed to follow these protocol directives in the following subjects’ records, as illustrated in the following examples: 0101 (CRF page 3.4, dose calculation), 0103 (CRF page 3.1, dated 6/8/93, CRF page 17.1, 9/12/98, infusion [redacted], 0104 (CRF pa 3.3, dose calculation), and

& 0107 (CRF page 24.1, 5/20/98, infusion [redacted].

In your response letter, you acknowledge the inappropriate corrections made by the study staff, and state that you will retrain your staff regarding the proper procedures for correcting errors.

K. Protocols 1 and 2 require the investigator or sub-investigators named on the Form FDA 1572 to review and sign the CRFS, thereby ensuring the completeness, correctness, and timely entry of data relating to the clinical trial. Several CRFS were corrected by an individual not listed on the Form FDA 1572. This is not a complete list, but is provided for illustration.

Subject

CRF page

Date of infusion-Infusion number –data entry

Correction by an individual not infusion number listed on Form FDA 1572

0102

3.2 part 1a

Calculation of dose

Item 3f volume needed

0104

3.3 part 1a

Calculation of dose

Item 7, end of infusion time

0105

3.3 part 1a

Calculation of dose

Item 6b, question regarding same volume as entered in item 3f

0107

24.1, part IIb addendum

5/20/98-5/23/98, infusions [redacted] to [redacted]

Infusion dosage information

0109

3.0 part 1a

7/18/94

Total [redacted] units entry in the infusion log

0111

24.0 part II b

 

24.1, part IIb

10/23/96, infusions [redacted]

10/16/96, infusions [redacted]

[redacted] dose entry under infusion dosage information

3. You failed to obtain informed consent in accordance with the provisions of

21 CFR Part 50. [21 CFR 312.60].

You failed to obtain the written informed consent from the subject or their legally

authorized representative before you initiated study-related procedures. You performed study-related blood tests for subject 0110 on 7/1 1/95 before the subject signed the informed consent document (lCD) on 7/18/95. In your response letter, you acknowledge this protocol deviation. However, you did not provide documentation that the sponsor prospectively agreed to permit this testing without a signed informed consent document.

4. You failed to maintain adequate and accurate case histories. [21 CFR 312.62(b)]

  1. Case report forms contain numerous data entry changes resulting in documentation discrepancies. These changes involve critical data information, such as dates, identification of the subject by number and initials, drug dosage information, drug lot number, concomitant medications, and adverse experiences. The following examples illustrate the type and number of data entry changes found in other records:
  2. Incorrect subject identifiers. The dosing calculation work sheet dated 5/20/97 for subject 0101, the shipping tracking form dated 7/26/95 for subject 0106, and the dosing calculation worksheet under Part la for subject0107 have incorrect subject numbers or

    initials.

    ii. Incorrect dosage information. Them are discrepancies in the volume of investigational product administered to subject 0104 on 10/26/93, under Part la of Protocol 1, between CRF pages 3.2,3.3. and the doctor’s note dated 6/1 3/94 on CRF page 3.2.

    Inconsistent documentation of concomitant medications. Multiple CRFS are discrepant in the listing of concomitant medications. For example, for the infusion on 7/18/94 for subject 0109, CRF page 3.3 did not list any concomitant medications whereas CRF page 3.0 listed the administration of [redacted]. In addition, discrepancies were noted for subject 0111 in the two CRF pages marked 3.0, dated 8/19/96, for the concomitant medications listing.

    iv. In consistent error corrections in adverse experiences. For subject 0103, for the infusion [redacted] between 4/9/98 and 4/12/98, there were multiple discrepant corrections in reporting adverse experiences.

  3. You failed to maintain all supporting source documents for the subjects’ study-related CRF entries. Source documents could not be verified for the CRF entries regarding administration of concomitant medications for the subjects listed:

CRF page 3.3 for subject 0102 reports the administration of Solu-Cortef on 5/19/93. Source documents could not be located during the inspection in the subject’s case history for this medication.

CRF page 3.5 for subject 0108 reports the administration of Benadryi and Hydrocortisone to treat hives on 9/15/93. During the inspection neither written order could be located.

You provided copies of these source documents in your response letter, but you did not explain why these documents were not available during the inspection.

C. You failed to document all pertinent data relating to the study in the subject’s CRF.

The progress notes dated 10/16/96 state that subject 0111 developed nausea and chills as a reaction to the administration of the investigational product, requiring the administration of Hydrocortisone. You failed to record these adverse experiences

(AEs) and the administration of Hydrocortisone on the subject’s CRF.

In your response letter, you explain that the adverse experiences occurred on 10/23/96, not on 10/16/96. You entered the date, 10/23/96, in your progress note for the above-mentioned AEs, subsequently. We note that you entered the AE ‘chills" in the CRF

24.3, on a later date.

ii, For subject 0103 you failed to document the duration of infusion on the following infusion dates: 9/6/98, 10/4/98, 10/6/98, 10/7/98, 10/16/98, 10/17/98, 10/20/98, 10/21/98, 10/22/98, 10/26/98, and 10/27/98.

In your response, you explain that in future studies you will use an infusion pump to correct this deficiency.

D You failed to maintain complete and relevant case histories for the subjects enrolled in the study.

For subject 0106, who was administered investigational product on 8/10/93, you were unable to locate the consent form, signed by the subject or subject’s legally authorized representative, during the inspection.

In your correspondence dated November 7, 2001, you enclosed an ICD signed and dated 8/10/93, by the subject’s representative for subject 0106.

ii You did not have documentation during the inspection to confirm that the sponsor prospective ranted approval to allow you to enroll subject 0109 who was [redacted] age, under protocol 1.

In your correspondence dated November 7, 2001, you enclosed sponsor’s approval letter dated April 25, 1994, agreeing to enroll subject 0109.

5. You failed to maintain adequate records of the disposition of the drug. [21 CFR 312.62(a)].

You failed to maintain adequate records of the disposition of the investigational products including the dates, quantity, and use by subjects. You failed to complete the investigational drug utilization record (IDUR) for the drug lots received by the pharmacy, and could not account for discrepancies in the inventory of the investigational products. Examples include, but are not limited to the following:

  1. Lot [redacted]: You did not record the receipt date, distribution, and the stock verification date in the IDUR. Furthermore, you could not account for distribution of five vials of this lot for recipient [redacted]; no subject with these initials was enrolled in Protocols 1 or 2.
  2. Lot [redacted]: The distribution time and stock verification date are not recorded in the IDUR, and there is an inventory discrepancy of one vial on 9/30/98.
  3. Lot [redacted]: The distribution time, received by, disposition of units, and stock verification are not recorded in the distribution log of the IDUR. The total number of remaining units could not be calculated based on the IDUR.
  4. Lot [redacted]: You failed to record the receipt date in the receipt log, the date and time of the distribution, and the stock verification date in the distribution log of the IDUR. There is an inventory discrepancy of two vials.

In your response letter, you state that you will conduct more extensive training for

study personnel associated with drug distribution and accountability.

6. You failed to promptly report to the Institutional Review Board (IRB) all unanticipated problems involving risk to human subjects. [21 CFR 312.66].

In its approval letter dated 2/25/93, the Illinois Masonic Medical Center IRB required that you immediately report adverse experiences. You failed to report eight of nine serious adverse experiences (SAES) listed in item 2l above to the IRB. In your response letter, you acknowledge that you neglected to report the SAES to the IRB.

In general, your response letter describes several changes you plan to implement to

correct the conditions noted during the inspection. You indicate that in future, study

personnel will be instructed and trained in GCP, the CFR, and the protocol requirements

relating to the conduct of the clinical study. The instructions will include appropriate

ways in sample collection, timing of sample collection, proper methods for collecting,

entering, and correcting data, dosage and volume calculations, and the documentation

of drug distribution.

[redacted]. In your response, please explain the changes you have implemented in ongoing studies.

This letter is not intended to be an all-inclusive list of deficiencies in your clinical study of investigational drugs. These deviations appear to be the result of lack of supervision of

personnel involved in conducting this study. Staff who were delegated the authority to

perform certain functions were not adequately monitored. In addition, there is no

documentation that you actively reviewed the case report forms for accuracy. You, as

the clinical investigator, are responsible for assuring that the data contained in the case

report forms and submitted to the sponsor, are complete and accurate. It is your

responsibility to ensure adherence to each requirement of the law and relevant

regulations.

You should notify this office in writing within fifteen (15) business days of receipt of this

letter of the steps you have taken to correct these violations and to prevent the recurrence of similar violations in future studies. If corrective action, including the measures proposed in your response letters to the FDA-483s, cannot be completed within fifteen (15) business days, state the reason for the delay and the time within which the corrections will be completed. Your response should include any documentation necessary to show that correction has been achieved.

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

notice. These actions could include initiation of investigator disqualification proceedings

which may render a clinical investigator ineligible to receive investigational new drugs.

Your written response should be sent to the following address

Bhanu Kannan (HFM-664)

Division of Inspections and Surveillance

Food and Drug Administration

1401 Rockville Pike

Rockville, Maryland, 20852-1448

Telephone: (301) 827-6221

We request that you send a copy of your response to the FDA Chicago District Office at

the address listed below.

Sincerely,

Steven A. Masiello

Director

Office of Compliance and Biologics Quality

Center for Biologics Evaluation and Research