Marin Kollef, M.D.

Washington University School of Medicine, St. Louis, MO, Jan. 28 (Kansas City)

During an inspection conducted at this clinical site Aug. 7-15, an investigator from FDA's Kansas City District Office observed "objectionable conditions" and "serous violations" of regulations concerning IDES and protection of human subjects.

The purpose of this inspection was "to determine whether activities and procedures related to your participation in the clinical study complied with applicable federal regulations" concerning use of a medical device.

The inspection was conducted under a program designed to ensure that data and information contained in requests for IDE, PMA applications and 510(k)s are scientifically valid and accurate, and to ensure that human subjects are protected from undue hazard or risk during the course of scientific investigations.

Kollef failed to obtain informed consent in accordance with the regulations regarding the protection of human subjects, FDA charged.

An investigator must ensure that informed consent is obtained and maintain accurate, complete and current records, including documentation of in formed consent. The Institutional Review Board (IRB)-approved informed consent documents for six subjects lacked dates and signatures of study participants. There was no evidence that subjects were legally consented prior to enrollment in the study and no written concurrence of a licensed physician and brief description of the circumstances justifying the failure to obtain informed consent.

The study sponsor notified Kollef of the above stated deficiencies on May 12, 2003; however, the investigator continued to fail to obtain informed consent from later subjects or legally authorized representatives.

The IRB-approved informed consent document included a study flow sheet, which was included for subjects given the IRB-approved revision of the informed consent document. However, the informed consent forms used with subjects prior to March 28, 2003, lacked the flow sheet referred to in both the original and revised IRB-approved consent documents. Nineteen subjects were enrolled prior to March 28, 2003, and were consented using consent forms that lacked the flow sheet.

In some cases, FDA wrote, "you attribute the lack of legally effective informed consent to oversights by study personnel. In the summary section of your response you stated, 'To address this concern going forward we will require the entire study team to go through an additional training program specific to the process of obtaining and documenting informed consent. This program will also focus on obtaining consent in. . .'Your response is inadequate in that it does not state a timeline for this training."

An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, investigational plan, applicable FDA regulations and any conditions of approval imposed by an IRB or FDA. The agency concluded that Kollef failed to adhere to these regulations.

"You allowed personnel to perform study-related functions they were not authorized to perform under the investigational plan. The study personnel identification list clearly identifies who is authorized to consent individuals for participation in the study and includes their title, signature and date of authorization. Ten subjects were consented by individuals not listed on the study personnel identification list."

The investigator indicated that he supervised training of all study personnel who obtained informed consent for the study, and attributed the missing signatures on the delegation of authority logs to an oversight. "You indicated that you will ensure that all individuals trained under the protocol also will have documentation, through proper completion and signing of the delegation of authority log. Your response is inadequate in that you have not indicated when this training will be completed," FDA wrote.

In addition, "Your response describes cases in which you obtained 'verbal consent.' However, informed consent must be documented by the use of a written consent form unless the IRB waives the requirement or finds that the requirements for an exception from informed consent are met. No verbal consent was approved by the IRB."

FDA requested that the investigator "work with your IRB to develop a plan for notifying subjects for whom informed consent was not obtained and documenting notification, as well as a plan for obtaining informed consent to prevent future recurrences of this problem." The agency requested documentation of a corrective action plan that addresses each of the violations noted above, including:

* written procedures for ensuring study protocol compliance

* written verification of staff training on study procedures and requirements, and/or

* internal study reviews or audits. BiM0