Medical Device Daily Washington Editor

Doctors have a lot on their minds, and a pair of recent FDA warning letters indicates that sponsors of clinical trials need to bear this in mind when keeping track of what exactly is going on at their clinical study sites.

The first letter, dated Jan. 29, was addressed to David Stern, dean of the University of Cincinnati College of Medicine (UCCM; Cincinnati) for the institution's sponsorship of a clinical study, the name of which was redacted. According to the letter, FDA cleared the investigational device application in 1998, but the name of the principal investigator at UCCM was purged.

The first citation noted failure to perform four diagnostic procedures on one or more patients, but most of the relevant information concerning those procedures was purged from the warning letter. This citation also noted that "one of the approved clinical investigators changed the randomization process and the [redacted] procedure without sponsor approval."

Case histories were also said to be lacking full data for four study subjects, including one patient who contracted sepsis and was treated with three antibiotics, the data from which was not on case report forms. This incident was also not reported to FDA.

The letter said that the unnamed clinical investigator (CI) told FDA that "the current study contains multiple endpoints that are not relevant to the demonstration of safety and efficacy of the investigational device." An unnamed (CI) is also said to have told the agency's investigator that multiple adverse events that are described in the study protocol are not reportable. The warning letter informed UCCM that "because the protocol does not define what events are considered anticipated and does not include a plan to evaluate and report unanticipated events," the institution should "clarify what events are anticipated."

UCCM was also cited for having failed to file yearly reports to the agency on the study, missing reports in 2002 and 2005, and for failing to label the device as an investigational device.

Richard Puff, UCCM's director of public relations, told Medical Device Daily that the institution has implemented "an ongoing comprehensive audit to identify problems and create a corrective action plan" in response to the warning. He said that Kendle International (Cincinnati) is handling the audit and that "we expect the audit work to include a data and systems audit. Officials at UCCM expect the audit report to arrive at FDA this week.

The July 3 warning letter to Michael Janssen, DO, of the Center for Spinal Disorders (CSD; Denver), led with a citation for failing to execute a consent form from an unspecified number of patients prior to screening. The letter noted that the CSD's research coordinator told FDA that CSD discontinued the practice "after the monitor explained [that] screening of the subjects prior to the [signing] the consent form was not permitted."

The clinical investigator apparently saw the screening as not part of the trial, asserting to FDA that "no patients were enrolled in the trial prior to signing the informed consent documents."

FDA also cited CSD for enrolling a patient for compassionate use of the unnamed device with a form that FDA said indicated treatment in the trial rather than outside the trial.

The warning letter indicated that two subjects did not meet inclusion criteria. One subject failed the criterion of age and another a criterion that was redacted. The second patient was the subject of a request for compassionate use of the device, but FDA indicated that the surgery had already taken place by the date of the request.

The response to this finding was that "this subject was erroneously enrolled in the study," but the site reported the situation to both the IRB and FDA in annual reports. Another patient was enrolled despite failing an unspecified criterion, but Janssen told the investigator that the study coordinator entered the initial score incorrectly. However, the warning letter stated "neither your response nor the records available clearly indicates that the scoring error was discovered and corrected prior to enrollment."

CMS issues decision on anticarcinogenic

Manufacturers of expensive-to-make anticarcinogenics known as erythropoiesis-stimulating agents (ESA) got some good news on Monday, but probably not as good as they had hoped. After hearing from FDA on the black box warning it wanted on this class of drugs, the Centers for Medicare and Medicaid Services determined that it would reimburse for the drugs, but with restrictions.

Monday's announcement indicated that the national coverage determination (NCD) will pay for cancer treatments if it is "limited to circumstances in which the treatment is not likely to worsen the cancer and in cases where the beneficiary's anemia is responsive to the ESA."

CMS also stated that the NCD "no longer distinguishes between those cancers that have erythropoietin receptors and cancers without such receptors," and that the agency has not decided on whether to reimburse for treatment of myelodysplastic syndrome, a precursor condition to acute myeloid leukemia. However, the lack of an NCD does not preclude an affirmative coverage decision by local Medicare contractors.

The agency inked its proposed coverage decision in May, followed by the mandatory 60-day open comment period, during which time CMS received "more than 2,600 public comments." Acting deputy director Herb Kuhn said in a prepared statement that the agency sought to "maintain physician autonomy while ensuring the safety of our Medicare beneficiaries in light of the FDA boxed warnings."

Circulatory systems panel slates 2 meetings

FDA has announced that it will hold a two-day meeting of the circulatory systems advisory committee on Sept. 19 and 20, with the first day going toward a discussion of the PMA application for the REPEL-CV, sponsored by SyntheMed (Iselin, New Jersey). FDA accepted the completed application in March (Medical Device Daily , March 29).

On the second day, the panel will discuss clinical trial design for cardiac ablation devices for atrial fibrillation patients who do not respond to medical therapy.