System Info - 110721 MCWATTERS, BERNARD 13-Nov-2009 08:37:05 MCWATTERS
RECORD OF TELEPHONE CONVERSATION
Submission Type: Original Application Submission ID: 125297/0 Office: OVRR
Novartis Vaccines and Diagnostics, Inc.
Telecon Date/Time: 17-OCT-2008 12:00 AM Initiated by FDA? No
Author: BERNARD MCWATTERS
Requested from telecon on 9-23-08 reporting results of investigation at clinical study sites in the Dominican Republic.
FDA Participants: Bernard McWatters
Non-FDA Participants: Hillel Cohen
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
Overview of the Monitoring of the Clinical Sites
for Agrippal® Study V71P6
October 17, 2008
Agrippal® Study V71P6 was conducted by Novartis Vaccines and Diagnostics (NV&D) at two sites in Santo Domingo under the supervision of the Principal Investigator (PI) Dr. Luis Rivera. The study sites were Center No./Site: 10 at the Hospital Maternidad Nuestra Señora de la Altagracia, Santo Domingo, and Center No./ Site: 11 at the Centro Sanitario de S Domingo, Calle galvan 24, Gazcue, Santo Domingo. These sites were initially assessed by NV&D via pre-study visits on 27-Jun-2007 (site 10) and between 18-21 Sep-2007 (both sites 10 and 11). Both sites were determined eligible to participate in the trial based on the information provided during these visits. Subsequently, site initiation visits for both sites 10 and 11 were conducted by NV&D and --b(4)-- on 25-Oct-2007 and 6-Nov-2007, respectively. These visits were in order to provide detailed training on study procedures to the site staff and verify that each site was ready to conduct the study. The Clinical Research Associates (CRAs) from NV&D and --b(4)-- returned to the sites at the time of first subject enrollment on 12-Nov- 2007. Thereafter, one or more CRAs were at the site every week until mid February-2008. Frequency of monitoring after this period was at least monthly and will continue until close-out (see attached list of monitoring visits and participants).
As indicated by the above summary of the monitoring schedule, the study sites were continuously monitored by NV&D and the CRO from the start of the trial. In addition, a routine GCP audit of the study sites was also conducted as part of the internal audit program at both sites on February 28-29, 2008. During monitoring visits, any issues identified were addressed with the PI and/or his staff through monitoring follow-up letters. Once the PI had awareness of these issues, the PI and his staff would generally address them as appropriate. Any unresolved issues were addressed during subsequent visits until resolution.
The issues identified during monitoring visits mainly included:
- Compliance with protocol (e.g., visits performed out of window, use of inappropriate birth control)
- Documentation and verification of informed consent by subjects (e.g., dates on IC forms not written by subjects themselves, copy of signed consent form not provided to subjects at time of signature)
- Completion of records and reports (e.g., subjects’ diary cards were either lost or partially completed due to loss of follow-up or withdrawn consent)
A total of 337 out of 1493 exposed subjects (22.6%) experienced any protocol deviation. Most of the deviations concerned incorrect use of thermometers resulting in low body temperature [<35 ºC] (9.6%), visit outside the pre-defined time window (5.4%), loss to follow-up (3.3%), withdrawal of consent (2.4%), refusal of blood draw (1.8%) and positive pregnancy test (0.6%). Protocol deviations concerning entry criteria and vaccine allocation were rare: 12 (0.8%) exposed subjects did not meet inclusion/exclusion criteria, of which 7 (0.5%) used inappropriate birth control; 10 (0.7% exposed subjects were assigned the wrong vaccine. From a review of monitoring reports it appears that any inaccuracy in the completion of the Informed Consent form was documented in less than 10% of exposed subjects.
As part of resolution, the PI and his staff were re-trained on the protocol, informed consent requirements, and clinical trial procedures. Issues in relation to source data and CRF entries were addressed as part of the monitoring processes. The PI was requested to review diary data information with subjects as necessary and clarify as many issues as possible for accurate CRF entry. The PI and his staff were re-trained on the use of the diary card and specifically on proper documentation and review of such information with the study subjects. When appropriate, the local Ethics Committee and the national Ethics Committee (CONABIOS) were notified of any deviations.
At this time, the study sites are still active and routine monitoring is ongoing. The close out of these study sites will be determined when all pending clinical issues are addressed and resolved. An interim clinical study report, for the first three weeks on study (core period), has been submitted by NV&D as part of the BLA. The final clinical study report will be prepared thereafter with any updates to the data listings included.