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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Koppes, Thomas P 16-May-05

Department of Health and Human Services' logoDepartment 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


By Certified Mail - Return Receipt Requested
And by Facsimile Transmission

May 16, 2005


Warning Letter


Dear Mr. Koppes:

This letter describes the results of a Food and Drug Administration (FDA) inspection ending on January 19, 2005. FDA investigator Lisa Hayka met with Natalie Nickel, Clinical Research Manager, and members of the staff at Howard Brown Health Center to review your conduct of a clinic al study entitled [redacted]. FDA conducted this inspection under the agency's Bioresearch Monitoring Program that includes inspections designed to review the conduct of research involving investigational devices.

At the end of the inspection, a Form FDA 483, Inspectional Observations, was issued and discussed with Natalie Nickel and others at the Howard Brown Health Center.

We have determined that you violated regulations governing the proper conduct of clinical studies involving investigational devices, as published in Title 21, Code of Federal Regulations (CFR), Parts 50 and 812 (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 protect the rights, safety, and welfare of the subjects under your care, and you failed to ensure that the investigation was conducted according to the investigational plan, the signed agreement, and applicable FDA regulations, including Part 50.[21 CFR 812.100].

A. Protocol sections 8.0 and 9.0 require that enrolled subjects be between the ages of 18 and 55 years and able to sustain venipuncture. Subjects with life threatening illnesses [redacted], as well as those with suppressed immune systems, were to be excluded from the study. As the clinical investigator responsible for the study at the Howard Brown Health Center, you were responsible for conducting the study in known [redacted] subjects. You enrolled 202 subjects as known [redacted] subjects in the study, but only 68 of those subjects had medical records on site documenting medical history and [redacted]. You did not document the [redacted] in the other 144 subjects, and it is unclear how you concluded they met this criterion. Furthermore, review of your records showed that you enrolled four subjects not meeting the age requirements. Subjects [redacted] were enrolled although these subjects exceeded the age limit of 55.

B. According to the investigational plan, "each tech [redacted] in the Clinical Trial must perform [Proficiency Panel Testing] independently" in order to establish proficiency with the device. Nevertheless, you and your staff conducted the testing for 202 subjects but failed to perform the required "Proficiency Panel Testing." You allowed this study to be conducted by staff without verifying that they were proficient in performing the assay.

This violation was not included on the Form FDA 483.

C. Protocol section 10.0 directs that "Samples will be shipped to the [redacted] daily." Review of the specimen shipping forms shows that you failed to ship at least 77 samples to the central laboratory on the day they were obtained. Delays in shipping ranged from one to four days.

D. Protocol section 10.0 requires: "if sufficient sample from venipuncture could not be obtained, discontinue the participant and do not perform capillary test." You were unable to obtain venous blood samples on subjects but you nevertheless performed fingerstick tests on those nine subjects.

E. Subject [redacted] did not sign the correct version of the Participant Information and Consent Form. Subject [redacted] provided informed consent on February 5, 2004 when the current IRB approved consent form was Revision 2, Version Date: 10106103. However, the subject was provided with, and signed, an outdated version of the informed consent form: Revision 1, Version Date: 10/21/02.

F. Protocol section 10.0 required you to "obtain one red-top tube and one purple-top tube," and "perform the finger stick once. ""Nevertheless, you developed a study checklist form for use by your staff that contradicted the protocol instructions. The checklist directed you to "draw one red-top and two lavender tubes," and "perform [redacted] on finger stick specimen X3."

2. You failed to maintain accurate and complete records of each subject's case history, including data on the condition of each subject upon , entering, and during the course of, the investigation and you failed to maintain accurate, complete and current records relating to the receipt, use, and disposition of devices. [21 CFR 812.140(a)(2) and (3)].

A. As described in item 1.A above, you failed to document that the enrolled positive subjects met the age and health status enrollment criteria.

B. You failed to maintain device accountability records. Review of shipping records showed that a total of 1200 devices were received at Howard Brown Health Center: 500 [redacted] Lot [redacted] and 700 [redacted] Lot [redacted]. According to the table below, your records show you used 830 devices for testing subjects and controls. At the end of the study it is documented that 325 [redacted] Lot [redacted] were returned to.Therefore, there is no accountability for 45 devices.


  Lot # [Redacted] Lot # [Redacted] Lot # Not Recorded Totals Documentation
Devices Received 700 500   1200  
Devices used for Subjects 340 416 6 761 [Redacted] Results Forms
Devices used for Controls 33 36   69 [Redacted] Controls Forms
Devices Returned 325     325  
Devices not accounted for   45  

This violation was not included on the Form FDA 483.

3. You failed to ensure that the investigation was conducted according to the conditions of approval imposed by the lRB: [21 CFR 812.10(b)].

A. You signed and dated an IRB Continuing Review Application on February 3, 2004, reporting "participants have completed all research activities; remaining activities do not involve participants ." It is noted this form has a stamped received date of February 2, 2004.You received a letter, dated February 2, 2004, from the IRB stating the Continuing Review Application expedited review was conducted and noted that "all remaining research activities do not involve participants. Any modifications to study protocol must undergo IRB review prior to implementation." However, you enrolled an additional 20 subjects between 2/3/05 and 2/15/04.

This violation was not included on the Form FDA 483.

This letter is not intended to contain an all-inclusive list of deficiencies in your clinical study of investigational devices. It is your responsibility as the clinical investigator 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.

You should notify this office, in writing, within fifteen (15) business days of receipt of this letter, of the steps you plan to implement to prevent the recurrence of similar violations in future studies. Your response should include any documentation necessary to show that correction has been achieved.

This 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 failure to implement effective corrective actions and/or the commission of further violations may result in the initiation of enforcement action(s) without further notice. These actions could include injunction and initiation of clinical investigator disqualification proceedings, which may render you ineligible to receive investigational devices.

Please send your written response to:

Janet K. White
Division of Inspections and Surveillance (HFM-664)
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N
Rockville, Maryland, 20852-1448
Telephone: (301) 827-6339

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



Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research