The FDA determined that a researcher in Medtronic’s CoreValve pivotal trial failed to adequately address what inspectors had identified as “objectionable conditions.” The agency requested “prompt corrective actions” and warned that it could initiate disqualification proceedings.

In a letter dated Jan. 14, the FDA described violations observed during an inspection between July 24 and Aug. 23, 2012, at the clinical site led by Michael R. Ring, MD, of Providence Spokane Heart Institute in Spokane, Wash. Those included:

• Failure to ensure trial participants’ informed consent was obtained as required under federal regulations;
• Failure to conduct the investigation in accordance with the signed agreement with the sponsor, the investigational plan, the FDA and the Institutional Review Board (IRB); and
• Failure to maintain accurate, complete and current records.

FDA inspectors cited two specific incidents in which patients underwent research-specific tests such as CT angiograms before signing screening informed consent documents, with one person never signing the document. The FDA said Ring responded by adding a checklist to the standard operating procedures and retraining study personnel, which the FDA deemed as adequate.

Inspectors also identified three incidents in which patients were randomized for the study to either receive transcatheter aortic valve replacement or surgical aortic valve replacement without signing the procedure informed consent document that detailed the procedure and risks.

“Your response is inadequate because, although you state that you will create a unified ICD [informed consent document] that will explicitly state that high-risk patients will be randomized and receive either the CoreValve device or a standard, commercially available surgical aortic valve replacement, which does not involve an experimental device, you do not explain how you will ensure that you will obtain informed consent prior to randomization,” according to the letter.

The letter noted that as the investigator, Ring was obligated to ensure that the sponsor and reviewing IRB are informed within five days of deviations from the study plans’ protocol on protecting the life and well-being of patients in an emergency. Inspectors reported several cases of late reporting to the sponsor and IRB.

It described Ring’s response as inadequate: “Although you state that you will implement a study‑site work practice for tracking all study patients in which the study coordinator will come to the operating room before the end of every surgery and meet with the investigator to determine whether any protocol deviations occurred during surgery, you failed to describe how you will ensure that protocol deviations are reported.”

The investigation cited two deaths that were not reported to the IRB within five days, which the letter said was adequately addressed with retraining of study staff.

The FDA charged that Ring failed to adhere to regulations designed to ensure records are accurate, complete and current, citing incidents of unsigned documents, worksheets, an electronic form and missing data. The letter emphasized that such information is important for ensuring patient care and the validity of the data collected from the study site.

The letter described Ring’s response, which included a commitment from the hospital to provide sufficient resources and staff retraining, as inadequate because it failed to assess how the violations occurred and what actions were needed to prevent a recurrence. It also noted that records of monitoring reports were not complete or current.

The FDA requested a response in writing within 15 days that describes corrective and preventive action plans with projected completion dates. The agency warned that it could take regulatory action and begin disqualification proceedings if it did not receive a response.

Ring confirmed to Cardiovascular Business that statements attributed to him in other publications were accurate and declined to elaborate on them. He had said that his group replied to the FDA and they thought their response addressed the concerns. He added that improvements had been made to procedures, staffing and training, and emphasized that none of the cited violations had an impact on patient safety or study data integrity.

He also clarified that the two deaths cited in the FDA letter involved patients who signed the screening informed consent document but who died before enrollment in the study.