“The FDA inspection of the PPD monitoring site in North Carolina assessed PPD’s role in monitoring the conduct of the ARISTOTLE study. The findings of the PPD inspection indicate there were not significant problems with PPD’s overall monitoring of the ARISTOTLE study that was submitted in support of Eliquis,” FDA spokeswoman Lisa Kubaska, PharmD told Outsourcing-Pharma.com.
“This site represented only 35 of over 18,000 subjects in the ARISTOTLE study; a relative percentage so small the FDA’s Office of New Drugs assessed the data and determined that they did not impact the outcome of the study used in support of Eliquis,” she said.
Accusations of Data Manipulation
Last week we reported on an FDA field report, or “Clinical Inspection Summary,” in which B-MS (Bristol Myers-Squibb) and PPD staff were accused of altering data at one of the sites for the blood thinner in China.
The report, which was published online by the FDA, said the Shanghai site coordinator Dr. Shiyao Wu “admitted that he did not regularly see study subjects – only if there was a special case. In addition to these serious inspectional observations, BMS informed that employees of BMS and PPD had manipulated study records at this site. The extent of data manipulation at this site remains unclear. For these reasons, OSI [Office of Scientific Investigations] finds that the reliability of data from this site could not be verified.”
Kubaska confirmed the oversight issues related to B-MS, but noted that “no evidence was found to suggest that key efficacy and safety endpoints were not properly assessed and reported.”
PPD Response
According to a redacted FDA letter that PPD sent to Outsourcing-pharma.com, an inspection at the contract research organisation’s (CRO) US headquarters revealed that the company’s monitoring of the overall ARISTOTLE trial was adequate.
Jay Dixon, SVP of global quality and compliance at PPD, told us, “In regards to the BMS/Eliquis Aristotle study in China, the FDA did conduct an inspection at PPD. At the conclusion of this inspection, the FDA did not issue any 483s or other findings.”
In addition, the FDA issued a letter to PPD dated July 6, 2012, stating: “From our evaluation of the establishment inspection report and the documents submitted with that report, we conclude that you adhered to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations and the protection of human subjects.”
FDA Investigator’s Report
The FDA approved Eliquis in December 2012 after taking an additional three months to assess whether the alleged misconduct documented in the China field report negated other trial data used in B-MS application.
In documents entitled “Other Review,” and released since the drug’s approval, FDA investigators wrote that one unnamed PPD employee admitted altering data on subject records at the direction of the B-MS site manager “in order to cover-up GCP [Good Clinical Practice] violations which had occurred at the site” in preparation for an FDA inspection.
Another unidentified PPD monitor alleged that documents may have been altered at one of the trial sites in Shanghai. Specifically, the employee “noted that while reviewing a chart which contained records of outpatient visits, she recalled that during an earlier monitoring visit, these same outpatient records contained handwritten comments.”
After the allegations were made, B-MS subsequently investigated and interviewed two PPD monitors, the BMS site manager and several supervisory staff from B-MS. The B-MS site manager who was alleged to have told the PPD monitor to alter records resigned in January 2012 while two other B-MS employees “who had knowledge of the irregularities…were terminated in January 2012,” according to the report.
According to B-MS’ statement in the report, PPD said it would “conduct an investigation of the activities of their staff…and provide refresher training to ‘all PPD operational staff in China.’”
“An audit (by an unidentified party) will be conducted of PPD China and will include an assessment of monitor selection and training, a review of the PPD investigation, and verification of the PPD refresher training.”
Christina Trank, a BMS spokeswoman, told Outsourcing-Pharma.com, “Bristol-Myers Squibb immediately notified FDA and investigated this incident. The investigation included an independent targeted audit of this site and five other sites in China and a review of on-study documentation practices for all sites. It was concluded that the actions by this employee were isolated to the one site and that they occurred after the completion of the study and the study report. There was no impact on the integrity of the study results or conclusion of the study.”
B-MS originally contracted with PPD to provide temporary site monitor staff to supplement B-MS-China monitor employees at two sites, according to the FDA report. PPD was also contracted to perform clinical monitoring, project management, data management, pharmacovigilance, and medical monitoring for the trial, according to BMS procedures.
Presence in China
The FDA documents also note that at the time of the study, PPD did not have a presence in China and therefore paid local contractors that were managed by BMS. These local contractors were cited in monitoring reports for not completing documents in a timely manner.
In 18 of 25 monitoring visits, the field investigators found that the monitors also failed to complete sections of the monitoring forms, while for four of 18 visits, the field investigators reported that the Source Data Verification Documentation section which verified if source data corroborated “was not completed,” according to the FDA.