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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Kim, Hyun S. (Kevin), M.D. 30-Jul-04

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration

 

Center for Devices and Radiological Health
2098 Gaither Road
Rockville, MD 20850

 

WARNING LETTER

VIA FEDERAL EXPRESS

Hyun S. (Kevin) Kim, M.D.
Johns Hopkins Hospital
600 North Wolfe Street
Blalock 544
Baltimore, MaryIand 21287-4020

Re:[redacted]

Dear Dr. Kim:

This Warning Letter informs you of violative conditions found during a Food and Drug Administration (FDA) inspection of your clinical site at Johns Hopkins Hospital. This letter also discusses your written response to the noted violations and requests that you implement prompt corrective actions. Ms. Stephanie Shapley and Ms. Anastasia Piliafas-Brown, investigators from the FDA, Baltimore District Office, conducted the inspection during the period of March 8-9, 11-12, 16, and 19, 2004. The purpose of the inspection was to determine whether your activities as a clinical investigator of the [redacted] investigator of the [redacted] manufactured by [redacted] complied with applicable FDA regulations. [redacted] is a device as defined in Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 321 (h)].

FDA conducted the inspection under a program designed, in part, to ensure that data and information contained in requests for Investigational Device Exemptions (IDE), Premarket Approval Applications (PMA), and Premarket Notification [510(k)] submissions are scientifically valid and accurate. The program also ensures that human subjects are protected from undue hazard or risk during the course of scientific investigations.

Our review of the inspection report prepared by the district office revealed serious violations of Title 21, Code of Federal Regulations (21 CFR), Part 812-Investigational Device Exemptions, and Part 50-Protecticn of Human Subjects. At the close of the inspection, Ms. Shapley and Ms. Piliafas-Brown presented a Form FDA-483 "Inspectional Observations" to you for review and discussed the listed deviations. The deviations noted on the FDA 483 and our subsequent inspection report review are discussed below:

Failure to submit a report of two unanticipated adverse device effects to the sponsor and the IRB [21 CFR 812.150(a)(1)]

Pursuant to 21 CFR 812.150(a)(1) an investigator shall submit to the sponsor and to the reviewing IRB a report of unanticipated adverse device effects occurring during the investigation as soon as possible but no later than 10 working days after learning of the event.

You failed to adhere to this regulation. Examples include, but are not limited to the following:

  • Subject [redacted] reported an event of dysuria requiring catheterization in the emergency room to the site on January 30, 2003, but this event was not reported to the sponsor and the reviewing IRB in accordance with the above-stated regulation.

In response to this observation, you state, "Since the event that occurred in this patient was not device related, not life threatening and did not adversely affect the rights, welfare or safety of this subject it was not reported as an UADE." However, the only documentation of the event in the subject's records is her notification to the site of the event. There is no information documenting that you obtained or reviewed the subject's hospitalization record relating to this event.

Failure to obtain informed consent from eight out of [redacted] subjects prior to their participation in the study [21 CFR 50.20, 812.100, and 812.140(a)(3)(i)]

Investigators are responsible for ensuring that informed consent is obtained in accordance with FDA regulations at 21 CFR Part 50 and section 812.100. In addition, clinical investigators must include in each subject's case history documents evidencing informed consent and that such consent was obtained prior to the subject's participation in the study. [21 CFR 812.140(a)(3)(i)].

You failed to adhere to these regulations. Examples include, but are not limited to the following:

  • The consent form for subject [redacted]  is not dated by the subject and is dated three months post treatment by the study coordinator.

  • Study assessments (medical history, inclusion/exclusion screening, completion of SF-36, and completion of quality of life screening questionnaire) were conducted for eight subjects [redacted] before they signed the consent form.

Failure to maintain records on the condition of each subject upon entering and during the course of the investigation [21 CFR 812.140(a)(3)(ii)]

According to 21 CFR 812.140(a)(3)(n), the investigator is responsible for maintaining information and data on the condition of each subject upon entering, and during the course of, the investigation.

You failed to adhere to this regulation. Examples include, but are not limited to the following:

  • It cannot be determined if subjects' records were screened or physical exams were conducted for fifteen out of [redacted] subjects prior to treatment.

  • It cannot be determined if the investigator conducted physical exams for [redacted] out of [redacted] subjects at the following completed study visits: one week, three months, six-months, and twelve months.

Failure to conduct the clinical investigation in accordance with the investigational plan (21 CFR 812.100)

An investigator is responsible for ensuring that an investigation is conducted according to a signed agreement, investigational plan, and applicable FDA regulations. [21 CFR 812.100].

You failed to follow the investigational plan. Examples include, but are not limited to the following:

  • Unanticipated adverse device effect was not reported to the IRB within the required two business days for subject [redacted] as required by the investigational plan. This subject suffered [redacted] on October 21, 2002; however, the event was not reported to the IRB until October 30, 2002.

  • For two out of [redacted] subjects, the volume of [redacted] treated was greater than the maximum volume of 33% of the total [redacted] volume, as specified in the investigational plan.

  • Treatment volumes greater than 33% of [redacted] size as specified in the investigational were intentionally prescribed in four [redacted] in three subjects.

  • Total time from first to last sonication for four out of [redacted] subjects was greater than the maximum time of 120 minutes, as specified in the investigational plan.

  • There is no documentation in the subjects' records for sixteen out of [redacted] subjects that compression hose (TED stockings) were worn to prevent deep venous thrombosis, as required by the investigational plan.

  • A completed Quality of questionnaire and SF-36 was not obtained on treatment day for subject [redacted] as required by the protocol.

Failure to maintain records of device receipt, use, and disposition [21 CFR 812.140 (a)(2)(ii) and (iii)]

Pursuant to 21 CFR 812.140 (a)(2)(ii) and (iii); the investigator is responsible for maintaining records of the names of all persons who received, used, or disposed of each device, as well as records relating to why and how many units of the device have been returned to the sponsor, repaired or otherwise disposed of.

You failed to adhere to these regulations. Examples include, but are not limited to the following:

  • Your site lacked records documenting your receipt of the shipment of the investigational device sent to you from on March 9, 2002.

  • Your site failed to maintain a device repair log.

Failure to maintain adequate case histories [21 CRF 812.140(a)(3)]

Pursuant to 21 CRF 812.140(a)(3), an investigator is responsible for maintaining accurate, current, and complete records of each subject's case history and exposure to the device, which include the case report forms, and supporting data.

You failed to adhere to this regulation. Examples include, but are not limited to the following:

  • For sixteen of the [redacted] subjects, one or more pages of the Quality of Life questionnaires, the primary efficacy measurement, do not have patient identifiers.

The above-described deviations are not intended to be an all-inclusive list of deficiencies that may exist in this clinical study. It is your responsibility as a clinical investigator to assure adherence to each requirement of the Act and all applicable federal regulations.

FDA acknowledges your written response, dated April 13, 2004, to the inspectional observations noted on the Form FDA 483. While the submission provides an explanation for events that occurred at your site and discusses how you personally intend to address the deficiencies observed at your clinical site, it does not provide a detailed explanation of system-wide corrective actions that will be taken to prevent these deficiencies from occurring in the future. Simply stating in response to the inspectional observations that, "In the future, I will ensure.. ." doe's not address the system failures at your site from a research compliance perspective. It is recommended, at a minimum, that additional staff training be provided that includes retraining on Good Clinical Practice (GCP) guidelines with emphasis on safety. This will assist you and your staff in the protection of human subjects as it relates to the informed consent process and the federal regulations for device research. In addition, we recommend that you establish specific Standard Operating Procedures (SOPS) for your research activities. In your response, you indicate that your overall corrective action plan will include the formulation of a set of SOPS. Please include copies of these SOPS when you respond to this letter.

Within 15 working days after receiving this letter, please provide written documentation of the additional, specific steps you have taken or will take to correct these violations and prevent the recurrence of similar violations in current and future studies. Any submitted corrective action plan must include projected completion dates for each action to be accomplished. Failure to respond to this letter and take appropriate corrective action could result in FDA initiating regulatory action without further notice to you. Send your response to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Division of Bioresearch Monitoring, Program Enforcement 1, HFZ-311,2094 Gaither Road, Rockville, Maryland 20850. Attention: Doreen M. Kezer, CSO .

We are sending a copy of this letter to FDA's Baltimore District Office, and request that you also send a copy of your response to that office. If you have questions, please contact Doreen M. Kezer by phone at 301-594-4720.

Sincerely yours,

/s/

Larry D. Spears for Timothy A. Ulatowski

Director

Office of Compliance

Center for Devices and Radiological Health

 

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