FDA, applicable national and local health authorities, and IRB requirements. The Principal Investigator is responsible for keeping the IRB apprised of the progress of the study and of any changes made to the protocol as deemed appropriate, but in any case the IRB must be updated at least once a year. The Principal Investigator must also keep the IRB informed of any significant adverse events. Investigators are required to promptly notify their respective IRB of all adverse drug reactions that are both serious and unexpected. This generally refers to serious adverse events that are not already identified in the Investigator Brochure and that are considered possibly or probably related to the molecule or study drug by the investigator. Some IRBs may have other specific adverse event requirements that investigators are expected to adhere. Investigators must immediately forward to their IRB any written safety report or update provided by Galena Biopharma (e.g., IND safety report, Investigator Brochure, safety amendments and updates, etc.). Ethics and Regulatory Considerations The protocol will be reviewed and approved by the IRB or Independent Ethics Committee (IEC) of each participating center prior to study initiation. A list of IRB/IEC members should be obtained by the investigator and provided to the sponsor and sponsor representative. Any documents that the IRB/IEC may need to fulfill its responsibilities, such as protocol amendments and/or information from the sponsor will be submitted to the IRB/IEC. The IRB/IEC’s written unconditional approval of the study protocol and the informed consent form will be in the possession of the investigator and the sponsor before the study is initiated. The IRB/IEC’s unconditional approval statement will be transmitted by the investigator or designee to the sponsor/sponsor representative prior to shipment of study 42 Protocol: 2014-0443 Version 2.1 Version Date: 11 April 2016 drug supplies to the site. This approval document must refer to the study by exact protocol title and protocol version number/date and must identify the documents reviewed and the date of review. Protocol modifications or changes may not be initiated without prior written IRB/IEC approval except when necessary to eliminate immediate hazard to the patients. Such modifications will be submitted to the IRB/IEC and written verification that the modification was submitted and IRB/IEC acknowledgement/approval should be obtained and transmitted to the Sponsor/Investigator or Sponsor/Investigator’s representative. The IRB/IEC must be informed by the principal investigator of any changes or revisions of informed consent form or other documents originally submitted for review; serious and/or unexpected adverse experiences occurring during the study; any new information that may affect adversely the safety of the patients or the conduct of the study; annual updates and/or request for re-approval; and when the study has been completed. 6.5 Study monitoring requirements Site visits may be conducted by authorized Sponsor representative or Galena Biopharma representatives to inspect study data, patient’s medical records, and CRFs in accordance with current U.S. GCPs and the respective local and national government regulations and guidelines (if applicable). The Principal Investigator will permit authorized representatives of Sponsor/Investigator, Galena Biopharma, the U.S.