Common use of ICON Clause in Contracts

ICON. Write Protocol (Covered under a previous consulting agreement.) [***] [***] Design CRF (Covered under a previous consulting agreement) [***] [***] Conduct Site Qualification Visits [***] [***] Select Investigators [***] [***] Negotiate Investigator Agreements [***] [***] Administer Investigator Payments [***] [***] Collect Site Regulatory Documents [***] [***] Provide Randomization Schedule [***] [***] Study Drug Storage and Shipment to Sites [***] [***] Participate in Investigators’ Meeting [***] [***] Conduct Site Initiation Visits [***] [***] Conduct Interim Monitoring Visits [***] [***] Conduct In-House Site Management [***] [***] Provide Medical Monitoring [***] [***] Process SEAs [***] [***] Conduct Site Audits [***] [***] Conduct Site Closeout Visits [***] [***] Conduct Data Management Activities [***] [***] Prepare Statistical Analysis Plan (SAP) [***] [***] Provide Tables, Listings, and Graphs [***] [***] Prepare Final Clinical Study Report [***] [***] • This study will be processed using DataFax, version 3.5 or higher. For costing purposes, it was assumed that the study site will fax all study CRF pages into DataFax. Electronic images of CRF pages will be delivered to NTI at the end of the study • ICON will assign a clinical data reviewer (CDR) to provide data review and CRF page sign-off within DataFax. • Some costs for protocol and CRF development were included in a previous consulting agreement. Additional costs for these tasks have been included in the budget for this study. • ICON assumes that NTI will prepare a mockup of the CRF binders that will be sent to an outside printer for production and shipment. ICON will review the mockup and provide comments. • ICON assumes that there will be a maximum of 27 unique CRF templates and up to 60 CRF pages per patient that will be completed by the investigational sites and entered into the study database. • ICON estimates that a maximum of 9,270 CRF pages will be processed. This total consists of an average of 60 pages for each of 120 patients, or 7,200 original CRFs, along with the assumption that up to 35% of the CRF pages, or 2,520, will generate queries that will require additional data processing. • The study nurse/coordinator at each study site will complete the CRF pages for all patient visits. • For costing purposes, ICON estimates that up to 15 sites may be used for this study. • ICON will program a series of logic checks in DataFax and in SAS to ensure that CRF data are consistent and within the appropriate ranges for this study. These checks will be run up to 12 times during the study. • Following resolution of all queries at the end of the study, the database will be audited. ICON proposes a data audit scheme whereby the study database will be inspected by independent sampling of up to 50% of the CRF templates (i.e., a total of 13 CRF templates). Supplemental audit/correction efforts will be undertaken should discrepancies in excess of those allowed by audit specifications be detected. • The database will not be audited prior to the interim analysis. • CRF templates will be selected for audit based upon the following criteria: (a) file contains safety data (e.g., adverse event, laboratory, study termination, serious adverse event, or death information); (b) file contains efficacy or other important outcome data; (c) file contains data that have been identified as potentially problematic (e.g., site had problems filling out the form, or the form had fields that may have had a higher than usual rate of data entry errors). NTI will approve the selection of files to be subjected to audit. • Approximately one week prior to anticipated data lock for each part of the study, ICON will randomly select records from each data file. The number of data records per data file that will be selected is shown below. 15 [***] [***] [***] 16–20 [***] [***] [***] 21–25 [***] [***] [***] 26–35 [***] [***] [***] 36–50 [***] [***] [***] 51–70 [***] [***] [***] 71–110 [***] [***] [***] 110–140 [***] [***] [***] 141–215 [***] [***] [***] 216–850 [***] [***] [***] >850 [***] [***] [***] • A data specialist will audit each data file by comparing the randomly selected data records to the raw data (CRF images from DataFax). The results of the audit for each data file will fall into one of three categories: (a) the number of defective records is less than or equal to the acceptance number, and the data file is accepted; (b) the number of defective records is greater than the rejection number due to a systematic error that, when corrected, renders the data file acceptable (i.e., the number of defective records is less than or equal to the acceptance number); or (c) the number of defective records is greater than the rejection number, and the data file is rejected. • ICON will resolve the errors uncovered by the audit and make the necessary corrections to each data file. For data files that were rejected, ICON will randomly select records from the corrected data files and perform a second audit. For any data file that is rejected during the second audit, ICON will conduct a 100% quality control review. ICON will report the audit results to NTI. • Data files for the study will be considered “locked” after all selected data files have passed audit inspection and corrections identified during the audit have been made. • ICON assumes that it will provide up to 24 monthly DataFax reports to NTI for this study. These reports will include information on visits completed and CRFs faxed, by site and patient number. • ICON assumes that the study sites will complete serious adverse event forms for each SAE and fax them directly to the designated Medical Monitor. The Medical Monitor designated by NTI will review the completed forms, resolve any outstanding questions, and prepare any documentation necessary for the FDA. • NTI will be responsible for periodically reconciling the clinical study database with the SAE data on file at NTI.

ICON. Write Protocol (Covered under a previous consulting agreement.) [***] [***] Design CRF (Covered under a previous consulting agreement) [***] [***] Conduct Site Qualification Visits [***] [***] Select Investigators [***] [***] Negotiate Investigator Agreements [***] [***] Administer Investigator Payments [***] [***] Collect Site Regulatory Documents [***] [***] Provide Randomization Schedule [***] [***] Study Drug Storage and Shipment to Sites [***] [***] Participate in Investigators’ Meeting [***] [***] Conduct Site Initiation Visits [***] [***] Conduct Interim Monitoring Visits [***] [***] Conduct In-House Site Management [***] [***] Provide Medical Monitoring [***] [***] Process SEAs [***] [***] Conduct Site Audits [***] [***] Conduct Site Closeout Visits [***] [***] Conduct Data Management Activities [***] [***] Prepare Statistical Analysis Plan (SAP) [***] [***] Provide Tables, Listings, and Graphs [***] [***] Prepare Final Clinical Study Report [***] [***] • This study will be processed using DataFax, version 3.5 or higher. For costing purposes, it was assumed that the study site will fax all study CRF pages into DataFax. Electronic images of CRF pages will be delivered to NTI at the end of the study • ICON will assign a clinical data reviewer (CDR) to provide data review and CRF page sign-off within DataFax. • Some costs for protocol and CRF development were included in a previous consulting agreement. Additional costs for these tasks have been included in the budget for this study. • ICON assumes that NTI will prepare a mockup of the CRF binders that will be sent to an outside printer for production and shipment. ICON will review the mockup and provide comments. • ICON assumes that there will be a maximum of 27 unique CRF templates and up to 60 [***] CRF pages per patient that will be completed by the investigational sites and entered into the study database. • ICON estimates that a maximum of 9,270 [***] CRF pages will be processed. This total consists of an average of 60 [***] pages for each of 120 patients, or 7,200 [***] original CRFs, along with the assumption that up to 35% of the CRF pages, or 2,520[***], will generate queries that will require additional data processing. • The study nurse/coordinator at each study site will complete the CRF pages for all patient visits. • For costing purposes, ICON estimates that up to 15 [***] sites may be used for this study. • ICON will program a series of logic checks in DataFax and in SAS to ensure that CRF data are consistent and within the appropriate ranges for this study. These checks will be run up to 12 times during the study. • Following resolution of all queries at the end of the study, the database will be audited. ICON proposes a data audit scheme whereby the study database will be inspected by independent sampling of up to 50% of the CRF templates (i.e., a total of 13 CRF templates). Supplemental audit/correction efforts will be undertaken should discrepancies in excess of those allowed by audit specifications be detected. • The database will not be audited prior to the interim analysis. • CRF templates will be selected for audit based upon the following criteria: (a) file contains safety data (e.g., adverse event, laboratory, study termination, serious adverse event, or death information); (b) file contains efficacy or other important outcome data; (c) file contains data that have been identified as potentially problematic (e.g., site had problems filling out the form, or the form had fields that may have had a higher than usual rate of data entry errors). NTI will approve the selection of files to be subjected to audit. • Approximately one week prior to anticipated data lock for each part of the study, ICON will randomly select records from each data file. The number of data records per data file that will be selected is shown below. 15 [***] [***] [***] 16–20 16-20 [***] [***] [***] 21–25 21-25 [***] [***] [***] 26–35 26-35 [***] [***] [***] 36–50 36-50 [***] [***] [***] 51–70 51-70 [***] [***] [***] 71–110 71-110 [***] [***] [***] 110–140 110-140 [***] [***] [***] 141–215 141-215 [***] [***] [***] 216–850 216-850 [***] [***] [***] >850 [***] [***] [***] • A data specialist will audit each data file by comparing the randomly selected data records to the raw data (CRF images from DataFax). The results of the audit for each data file will fall into one of three categories: (a) the number of defective records is less than or equal to the acceptance number, and the data file is accepted; (b) the number of defective records is greater than the rejection number due to a systematic error that, when corrected, renders the data file acceptable (i.e., the number of defective records is less than or equal to the acceptance number); or (c) the number of defective records is greater than the rejection number, and the data file is rejected. • ICON will resolve the errors uncovered by the audit and make the necessary corrections to each data file. For data files that were rejected, ICON will randomly select records from the corrected data files and perform a second audit. For any data file that is rejected during the second audit, ICON will conduct a 100% quality control review. ICON will report the audit results to NTI. • Data files for the study will be considered “locked” after all selected data files have passed audit inspection and corrections identified during the audit have been made. • ICON assumes that it will provide up to 24 monthly DataFax reports to NTI for this study. These reports will include information on visits completed and CRFs faxed, by site and patient number. • ICON assumes that the study sites will complete serious adverse event forms for each SAE and fax them directly to the designated Medical Monitor. The Medical Monitor designated by NTI will review the completed forms, resolve any outstanding questions, and prepare any documentation necessary for the FDA. • NTI will be responsible for periodically reconciling the clinical study database with the SAE data on file at NTI.