Effective Date: October 2015

University of Maryland Greenebaum Cancer Center UMGCC Standard Operating Procedure Title: Data & Safety Monitoring Plan Effective Date: October 2015 Procedure No: DSM001 University of Maryland Greenebaum Cancer Center (UMGCC) governs clinical research through a parent Clinical Research Oversight Committee (CROC), which oversees the function of the Clinical Research Management Office (CRMO), and two under committees: the Data & Safety Monitoring/Quality Assurance Committee (DSM/QAC) and the Clinical Research Committee (CRC) that serves as the NCIrequired Protocol Review and Monitoring System (PRMS). These committees oversee the conduct of clinical research at UMGCC. This SOP describes the actions and procedures of the Data and Safety Monitoring/Quality Assurance Committee (DSM/QAC). I. DSM/QAC Scope and Function The DSM/QAC ensures patient and research subject safety and integrity of research in clinical trials conducted by UMGCC. It is the responsibility of the DSM/QAC to review all clinical studies for patient safety and quality control. The DSM/QAC has the authority to request modifications to incorporate safety information, to suspend trials pending investigation of toxicity and corrective action of protocol conduct which has led to deviations from the intended protocol, and to require additional patients be treated at a current or previous cohort for Phase I studies. The DSM/QAC may refer recommendations to the CRC to permanently close trials in which it is felt that the demonstrated risks outweigh the potential benefits of the study or where the expected trial outcomes cannot be achieved with further patient enrollment. The DSM/QAC can refer protocols for re-review by the CRC in the event that there is a question about the continuing scientific value or methodology that may warrant revisions of the protocol or warrant closure of the protocol for loss of scientific progress or priority. The DSM/QAC has the following functional tasks: A. Annual and semi-annual review of research The DSM/QAC provides ongoing safety review for UMGCC protocols which lack their own existing DSMB. These protocols include: Investigator-initiated protocols, except those for which the IRB has granted a waiver of consent (e.g., retrospective chart reviews) p1

NCI-sponsored Phase I and Phase II trials not conducted within the purview of an NCI-sponsored cooperative group, or where the relevant NCI-sponsored cooperative group does not have an appropriate external DSM. Industry-sponsored studies for which an external DSM group is not active. Other protocols may be considered for ongoing review at the request of the CRC or the IRB. Review may be conducted more frequently than semiannually if there is a specific reason or request from the CRC or IRB. B. Track Adverse Events Review Internal and External Serious Adverse Event (SAE) and Adverse Event (AE) experiences on the above designated protocol categories either semi-annually (high-risk studies) or annually (routine or low risk studies) to ensure that potential benefits of continuing research projects exceed potential harm from SAE and AE. Review on an ongoing basis external SAE (Outside Safety Reports) and DSM reports submitted to UMGCC investigators by trial sponsors, including reports from independent Data Safety Monitoring Boards for external randomized Phase III trials. For those external SAEs which do not meet IRB reporting criteria for immediate submission, the DSM/QAC will serve as the secondary reviewing entity of record, after the Principle Investigator review of information received from the sponsoring organization. A table of such external SAEs for each protocol is available for submission to the IRB with the protocol annual renewal. Assess Phase I studies for dose limiting toxicities after each cohort prior to dose escalation C. Review of significant findings generated during Internal Monitoring of Investigator Initiated Therapeutic Trials D. Review of significant findings generated during auditing (internal or external) of UMGCC clinical trials. II. Definitions A. Adverse Event Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for p2

example), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. B. Serious Adverse Event Any untoward medical occurrence that at any dose: results in death, is life threatening, requires hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity or, is a congenital anomaly or birth defect. Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be life threatening or result in death or hospitalization but may jeopardize the patient or require intervention to prevent one of the other outcomes listed in this definition. C. Clinical Trial The DSM/QAC follows the IRB s definitions for activities constituting human subjects research (i.e., clinical trial) as provided in the University of Maryland, Baltimore Human Research Protections Plan and Human Research Protections Investigators Manual This manual may be accessed at http://www.umaryland.edu/hrp D. Investigator-Initiated Clinical Trial An investigator-initiated (sometime referred to as institutional) clinical trial is defined for the purposes of these guidelines as a clinical research study authored or co-authored by a member of the UMGCC faculty or staff. An investigator-initiated trial is therapeutic if a drug substance is administered or the intent of the protocol activity is to affect therapeutic decision making. E. Quality Assurance Monitoring/Auditing UMGCC monitoring and auditing involves the Quality Assurance Manager (QAM) or non-crmo staff designee scrutinizing the actions of UMGCC investigators, with a requirement that the monitor/auditor be independent of the CRMO management structure and sponsor. F. External Audits p3

UMGCC trials may be audited by various external agencies including the IRB, NCI or its contractors, or the FDA. Audit activities typically involve a detailed review of the conduct of the clinical trial, including, but not limited to, subject enrollment, verification of source documentation of eligibility and data collection, review of serious adverse events, review of protocol exceptions and deviations, regulatory documents, drug accountability. G. Principal Investigator (PI) The PI is responsible for collecting and reporting adverse events on his/her clinical trials in a timely fashion to the applicable IRB, UMGCC DSM/QAC, FDA, trial sponsors, as well as all other relevant committees and agencies. H. Clinical Research Management Office(CRMO) The Clinical Research Management Office is the office that supports clinical research conducted by UMGCC faculty and has a staff of more than 30 individuals consisting of regulatory coordinators, study coordinators and data managers. The CRMO maintains a clinical research database of all protocols open at UMGCC. This database allows for the collection of AEs and SAEs, both internal and external, providing a framework for DSM/QAC review. I. Quality Assurance Manager (QAM) The QAM is the individual responsible for coordinating the DSM/QAC meetings, arranging internal monitoring of UMGCC trials as needed, auditing trials according to this DSM plan, assisting CRMO staff with external audits as needed, and providing education and training to UMGCC employees as needed, on preparing trials for audit and other related topics. To provide a degree of independence, this individual has no reporting ties to the CRMO management structure J. Clinical Research Committee (CRC) The CRC is responsible for the scientific review of new protocols. Their review is conducted prior to IRB review to assess CRMO resources to support study conduct. CRC review includes a consideration of the adequacy of the DSM plan proposed by the PI. The CRC may impose a stricter level of monitoring for higher-risk studies. The CRC is also responsible for reviewing accrual to all UMGCC trials on at least an annual basis to assure timely recruitment of subjects to trials. The CRC may be asked by the DSM/QAC or the IRB to provide continuing review of protocols about which questions have arisen in relation to new information received and the continuing scientific value of the research question. K. Clinical Research Oversight Committee (CROC) p4

The CROC is responsible for setting policies, processes and Standard Operating Procedures for clinical research at UMGCC and for considering the physical and personnel resource requirements for the CRMO. The CROC also has the authority to consider disciplinary sanctions against clinical investigators. L. Data and Safety Monitoring / Quality Assurance Committee (DSM/QAC) The DSM/QAC consists of a chair and UMGCC staff representing various disciplines and disease groups, including representation from Medical Oncology/ Hematology, Surgical Oncology, Radiation Oncology, and Clinical Pathology Disease Groups, Nursing, Pharmacy, and Supporting Services (Infectious Diseases, Biostatistics, Palliative Care). DSM/QAC activities are coordinated by the QAM. The DSM/QAC meets monthly and requires a quorum of three members. Members may designate a proxy of comparable expertise to attend in their place. See attachment 1 for membership. See figure 1 for overview of research oversight structure (including DSM/QAC) in place at UMGCC. M. University of Maryland Institutional Review Board (UMB IRB) The IRB is a federally required administrative body, accredited by the Association for the Accreditation of Human Research Protection Programs, established to protect the rights and welfare of human research subjects recruited to participate in research activities conducted under the auspices of University of Maryland, Baltimore, which includes UMGCC. The IRB has the authority to approve, require modifications to, suspend, terminate or disapprove all research activities that fall within its jurisdiction as specified by both the federal regulations and local institutional policy. The IRB also may observe or have a third party observe the consent process. N. Human Research Protections Office (HRPO) The HRPO is the coordinating office for the UMB IRB. The HRPO is responsible for providing periodic audits of designated trials. p5

Figure 1: Overview of Research Oversight at UMGCC III. DSM/QAC Procedures A. Review of Research 1. - Types of Reviews and Assignment of Risk a. Annual Review (High Risk) Phase II and III therapeutic studies designated as high risk by the Clinical Research Committee (CRC) are reviewed annually by the DSM/QAC for subject accrual, conduct of the trial and safety (internal and external SAE reports). b. Semi-Annual Review (Highest Risk) p6

All Phase I therapeutic trials and investigator-initiated Phase II/III therapeutic studies are designated by the CRC as highest risk. Studies designated as highest risk will be reviewed annually for subject accrual and conduct of trial; semi-annually for safety. The DSM/QAC has the discretion to review annually studies classified as highest risk, where the sponsor monitors and conducts cohort reviews, but lacks an independent DSM. c. Phase 1/Cohort Review For Phase 1 trials without an independent DSM, a member of the UMGCC DSM/QAC reviews the toxicity experience in all treated patients prior to escalating into the next cohort The cohort review is done by a single member of the DSM/QAC prior to the scheduled meeting, with results reported to the full DSM/QAC at the next meeting. Documentation of this cohort review is kept in the study file and forwarded to the IRB with the annual report. The PI of a Phase I study must receive explicit approval from the DSM/QAC member before proceeding to the next dose escalation cohort. 2. Annual and Semi-Annual Review Procedures To assure that DSM/QAC and IRB oversight of protocols is optimally coordinated, DSM/QAC annual review is timed for completion prior to the IRB anniversary date. As shown in figure 2 below, for those studies requiring DSM/QAC review, UMGCC clinical investigators compiles the IRB annual renewal submissions 90 days before IRB annual review. The DSM/QAC assigns a committee reviewer who will present their evaluation at the DSM/QAC meeting no later than 60 days prior to the IRB annual review. The DSM/QAC provides feedback and requests for clarification to the PI no later than 45 days prior to IRB annual review. The PI submits response to DSM/QAC inquiries no later than 30 days prior to IRB annual review, and the DSM/QAC reviews the responses at the next meeting, approximately 30 days prior to the IRB anniversary date. 90 days prior 60 days prior 45 days prior 30 days prior PI prepares annual submission DSM/QAC reviews DSM/QAC comments received by PI Fig. 2 Timeline for DSM/QAC annual review process DSM/QAC reviews revised PI submission IRB annual review p7

Semi-annual reviews are conducted on the same timeline to coincide with the IRB annual review date and also six months from same. PIs are expected to be available by pager or cell phone for DSM/QAC meetings where their protocols will be discussed. The below items are considered in DSM/QAC annual review. The semi-annual review will include only those items below related to safety. A cover form (Annual Renewal DSM/QAC) completed by the study team summarizing the activities of the prior reporting period. All SAEs and protocol-designated expeditiously reportable AEs, internal and external, including those that have previously been reported to the DSM/QAC. The DSM/QAC will have a full report on all internal SAEs concerning that clinical trial, including the nature of the SAE, grade, therapeutic agents involved, whether they were reported to all appropriate agencies within the mandated timeframes, and the investigator s assessment of whether the toxicity was study related. The DSM/QAC may recommend to the CRC to close studies with adverse event profiles that deviate in a substantial way from expected patterns of events. The consent form to determine if modifications are needed based on the accumulated AEs and SAE information. A summary of protocol deviations that have not yet been reviewed by the DSM/QAC. If available, interim outcomes and other results are assessed to see if response rates conform to estimates used to develop the statistical analysis. The DSM/QAC may recommend study closure to the CRC for studies with poorer than expected response rates that cannot meet stated outcomes targets even if the trial accrued fully. Conversely, response rates significantly greater than expected may lead to early termination of trials to prevent further assignment of patients to the inferior treatment arms in comparative trials. Periodic audit results, if available. The DSM/QAC may recommend study closure to the CRC for studies when the PI or research team show a pattern of persistent non-compliance with Good Clinical Practices policies. Upon conclusion of review, the DSM/QAC decides one of the following: Award final DSM/QAC approval to the protocol Find that minor revisions are needed for final DSMB approval Find that major corrections are needed to the protocol Suspend immediately to prevent harm to subjects or others Recommend closure of the protocol to the CRC due to GCP non-compliance or low accrual. p8

Refer the protocol back to the CRC for scientific re-review if new information has called into question the original study hypothesis. DSM/QAC actions are approved by majority committee member vote. Members with conflicts of interest will not serve as reviewers for protocols for which they are conflicted and will recuse themselves from discussions and voting on such studies The record of DSM/QAC actions for a protocol consist of: Chair notes, consisting of findings of the DSM/QAC reviewer, discussions and decisions by the DSM/QAC and specific issues requiring remediation DSM/QAC correspondence with the PI, specifying the actions to be taken (if applicable) and the acceptable turnaround time for response PI responses to DSM/QAC inquiries are reviewed at the next DSM/QAC meeting Final DSM/QAC review outcome provided to the PI Records of these reviews are made available to the IRB for consideration in their deliberations. B. Adverse Event Reporting The requirements for adverse event reporting for clinical trials are complex. In general, the DSM concentrates only on SAEs as defined by the FDA. In the event that the protocol uses other SAE definitions or designates certain AEs as having special reporting requirements even if they do not meet the acceptable definition of SAE, the DSM will consider those as well. The DSM may at any time consider patterns of AEs that warrant protocol or consent changes. DSM/QAC review of protocols includes checking whether AE and SAE reports have been properly reported to the sponsor, the IRB (if applicable), the FDA if applicable, co-investigators at participating institutions, and any applicable government agencies. The PI is ultimately responsible for ensuring that reporting of SAEs and AEs to all applicable bodies occurs within the designated timeframes. If the trial involves federal or other grant funding, the PI is responsible for summarizing adverse events in grant progress reports as per the requirements of the funding agency. 1. Reporting Bodies IRB Reporting: The UMB IRB currently requires expeditious reporting of events that convey information indicating a new or increased risk or a safety issue which may affect research subjects. Similarly, any harm experienced by a subject or other individual, which in the opinion of the investigator is unexpected and probably related to the research procedures must be reported. The UMB IRB also requires reporting of unanticipated adverse device effects. p9

All of these reporting requirements can be found at http://www.umaryland.edu/hrp/for-researchers/investigator-manual/. NCI Reporting: The NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs provides instructions for reporting adverse events to NCI for all of its trials. NCI Investigator Handbook (available at http://ctep.cancer.gov/investigatorresources/docs/investigatorhandbook.pdf) outlines specific expedited AE reporting requirements. Investigators and study staff are responsible for being aware of and complying with all requirements of both the IRB and NCI. FDA Reporting: In those cases where the PI or another UMB employee is the IND holder, current FDA reporting requirements (Suspected adverse reaction, Serious and Unexpected) must be met. Sponsor Reporting: Sponsor reporting guidelines are typically established to allow the sponsor to comply with its reporting requirements to the FDA and any applicable international regulatory authorities. 2. SAE Tracking The CRMO research database (OnCore ) has specific capacity to record the reporting dates of serious adverse events for tracking purposes. As it is likely that many events requiring expeditious reporting to the NCI or other sponsors will only be reported to the IRB with the annual renewal, CRMO staff must enter all SAEs in Oncore. The DSM will review summary reports of these events to ensure that proper reporting and assessment occurred. Internal SAEs must be assessed by the PI. The PI will make the determination as to whether the event requires expeditious IRB reporting or not. See figure 3 below for SAE management processes. p10

SAE received and logged into Oncore 5 business days Event, attribution, grade, other relevant info assigned by PI and entered into Oncore by data manager Yes PI determines if IRB reportable No PI reports to IRB Expeditiously DSM/QAC reviews to ensure not IRB reportable SAE incl. in IRB annual renewal Figure 3: SAE Management process Upon receipt of the external SAE (Outside Safety Report), the PI is presented with a summary report to allow PI acknowledgement of: Related or unrelated to the study therapy Seriousness Expected or unexpected Required IRB submission immediately or with annual report If requested by the PI, the comprehensive Outside Safety Report is sent to the PI for review. For those external SAEs which do not meet criteria for immediate submission to the IRB, the DSM/QAC serves as the second reviewing entity of record. Summaries of SAE reviews are presented as part of the protocols DSM review as described below. a. DSM/QAC Review of SAE p11

Designated DSM/QAC members review SAEs as appropriate for the type of trial and review the following determinations: Related or unrelated to the study therapy Seriousness Expected or unexpected Requires IRB submission immediately or with annual report The DSM/QAC has the authority to temporarily suspend or make a recommendation to the CRC to permanently close trials if review indicates that investigators or research staff have failed to follow adverse event reporting guidelines for the trial. Investigators or research staff who have a history of problems with meeting reporting guidelines will be referred to the CROC for potential disciplinary action. i. Phase I and Investigator Initiated Trials UMGCC regards Phase I trials and Investigator Initiated trials as the highest risk studies, so in addition to NCI- or sponsormandated reporting and review, UMGCC also requires local continuous monitoring of patient safety. The PI or study team provides the DSM with a report of all SAEs at every cohort, 6- month safety and annual review. ii. Phase II and Phase III Trials without external DSM UMGCC regards phase II and III trials without external DSM as high risk studies. As such the DSM/QAC reviews summary reports of all external SAEs on an annual basis. iii. Phase II and Phase III Trials with an external DSM These sponsored studies must have an independent DSM plan in place. Because of this, they are not reviewed by UMGCC DSM/QAC. iv. NCI-Sponsored Cooperative Group Studies The UMGCC has been a member of the Alliance, NRG (National Surgical Adjuvant Breast and Bowel Project - NSABP, Radiation Therapy Oncology Group - RTOG and Gynecology Oncology Group - GOG) and Children s p12

Oncology Group (COG). It may participate in occasional studies from other cooperative groups. Each of these groups develops peer-reviewed trials, which include detailed DSM plans. Adverse event reporting to the groups and the NCI is handled as per the specific instructions from the cooperative group. v. Gene Transfer Trials Adverse event reporting for studies involving recombinant DNA-containing products will follow NIH Guidelines for Research Involving Recombinant DNA Molecules in addition to any other applicable federal, state, institutional or sponsor guidelines for adverse event reporting for the trial. Briefly, any serious adverse event that is both unexpected and associated with the use of the gene transfer product (i.e., there is reasonable possibility that the event may have been caused by the use of the product; investigators will not await definitive proof of association before reporting such events) are clearly labeled as a Safety Report and submitted to the NIH Office of Biotechnology Activities (NIH OBA) and to the local Institutional Biosafety Committee. Any serious adverse event that is fatal or life-threatening, that is unexpected, and associated with the use of the gene transfer product are reported to the NIH OBA as soon as possible, but not later than 7 calendar days after the initial receipt of the information (i.e., at the same time the event must be reported to the FDA). Serious adverse events that are unexpected and associated with the use of the gene transfer product, but are not fatal or lifethreatening, are reported to the NIH OBA as soon as possible, but not later than 15 calendar days after the initial receipt of the information (i.e., at the same time the event must be reported to the FDA). vi. Multi-Institutional Investigator Initiated Trials Multi-institutional Investigator Initiated Trials where UMGCC serves as the coordinating center may or may not have industry sponsors. These trials receive the level of oversight appropriate to the risk involved in the trial (i.e., high or highest.). UMGCC follows the NCI guidelines for multi-institutional trials. The Lead Principle Investigator is responsible for the reporting requirements associated with subject safety. p13

Participating institutions report all reportable Adverse Events and SAEs to UMGCC who in turn reports to the applicable regulatory bodies. The CRMO research database will be used to collect all reportable AEs and SAEs for the protocol. The Lead Principle Investigator makes the determination if the reportable AE or SAE warrants revision to the protocol and informed consent. UMGCC disseminates this information to all participating centers in the form of a modified protocol and/or consent. To convey safety information in a more timely fashion, the Lead PI may also elect to send a safety letter to all co-investigators notifying them of the event and forthcoming changes to the protocol, if applicable. vii. Ad Hoc Reviews of SAEs The DSM/QAC reviews SAE (internal/external) reports as requested by the principle investigator. This ad hoc review occurs when the PI feels the SAE increases the risk to subject significantly or deems a second opinion on the matter is needed. C. Monitoring and Auditing of UMGCC Clinical Trials 1. Internal Monitoring/Auditing of UMGCC Clinical Trials Industry sponsored clinical trials which have their own independent monitoring service that performs monitoring on a routinely scheduled basis will not be subject to additional internal monitoring without cause. Likewise, NCI-sponsored trials that have periodic computerized data submission and independent auditing groups (e.g., Cooperative Groups) will also not be routinely monitored without cause. However, all therapeutic investigator-initiated trials will be subject to monitoring by the UMGCC at intervals as defined by the protocol monitoring plan. a. Procedures The QAM will be responsible for coordinating the monitoring and auditing of these trials. Designated non-crmo staff members (as identified and trained by the QAM) and/or the QAM will function as monitors and auditors for these trials. Therapeutic Investigator Initiated trials that do not have external monitoring will be monitored on an at least an annual basis. p14

b. Notification The Principal Investigator and Study Coordinators are notified in advance of a scheduled monitoring or auditing session in which subjects have been randomly selected for review by the QAM. The QAM, in conjunction with the lead CRA contacts the study team to arrange for a mutually agreed upon time for the session. The investigator and the research staff are responsible for gathering all of the materials germane to the review including medical records, case reports forms, and any other research records requested. If affiliate centers are enrolling subjects, the monitoring plan will outline affiliate site obligations. c. Implementation i. Monitoring: The lead CRA performs quality assurance review on the requested records to ensure compliance. A monitoring report is generated, and any significant findings will be presented at the next DSM/QAC monthly meeting. The monitoring report is sent to the Principal Investigator summarizing the findings and any recommendations. Any queries to the PI will need to be addressed by the next monitoring visit. Accrual findings will be presented to the CRC. Specific information requested includes: Regulatory Folder, to include copy of most current protocol, amendments, Investigator Brochure, availability of form 1572 Accrual listings for selected trails(s) Hospital medical record/access to emr Patient-specific research source binder Access to the Investigational Drug Pharmacy to ensure the presence of drug accountability forms specific to the clinical trial ii. Auditing: In order to assure the proper conduct of the clinical trials under the purview of the DSM/QAC, the QAM or adequately trained designee will perform internal audits of data collected. Specifically, 100% of patients accrued during the preceding calendar year on investigatorinitiated therapeutic trials and approximately 50% of the charts from the preceding calendar year for open and accruing therapeutic trials in the following categories: Phase 2 studies without external data safety monitoring, NCI Phase 1 studies and corporate/industry trials without external data safety monitoring. Standard auditing tools will be used. Specific issues to be examined include: p15

The proper maintenance of the regulatory file and database record with all necessary documents on hand, including the original IRB protocol approval, IRB approval of modifications, SAE reports and other regulatory documents Informed Consent Review (e.g. adequate consent form process, proper consent version used, properly executed consent form signed and dated) Documentation that the subject met the protocol required eligibility criteria to be enrolled. Documentation that the protocol-specific therapy was delivered in the specified manner, including doses, schedules and infusion times Documentation that appropriate study-related investigations, i.e., laboratory, radiology and study visits, were accomplished Verification of responses in those studies where clinical responses are to be noted Verification of toxicities where toxicities are an endpoint Verification that all SAE s were reported in a timely fashion. Verification of efficacy and /or endpoint data required per protocol. In the case of an internal audit, the auditor will prepare an audit report that will be presented to the DSM/QAC at the next available meeting if there are significant findings. A copy of this report will also be shared with the PI and CRMO management for consideration. 2. External Auditing of UMGCC Clinical Trials The UMGCC has many trials that are audited by external reviewers, including NCI contractors and industry representatives for data that is to be submitted to the FDA. Any audit report received from a Federal Agency or audit reports meeting IRB specified reporting requirements must be submitted to the IRB and reported to the DSM/QAC. The DSM/QAC has the authority to suspend and ultimately close trials in which adherence to good clinical research practices are lacking. The HRPO/IRB and/or the DSM/QAC may request audit of a trial or an audit of additional charts/trials depending on result or issues that may arise in relation to a particular trial or investigator. IV. DSM/QAC Meetings DSM/QAC agendas for the monthly meetings are maintained by the QAM. This individual maintains, with the assistance of the research database, lists of all protocols that are subject to semi-annual and annual review, all protocols for which the DSM/QAC serves as the DSMB, and all Phase I trials which will require dose escalation approval. All protocols from each of the above categories are added to DSM/QAC agendas at the appropriate time points. The QAM also schedules p16

consideration of audit reports and follow-up discussion of PI responses to protocols reviewed at prior meetings. The summary reports of the SAEs that have been assessed in the intervals between meetings is prepared and provided to the DSM by the QAM. Minutes of the DSM/QAC meetings consists of a record of attendance, the chair notes for each of the protocols reviewed, DSM/QAC reviewer summaries of protocol reviews, letters to the PIs, and PI responses received for studies reviewed at earlier meetings, and chair documentation of any other issues discussed. Decision to Suspend or Make Recommendation to Close Should the DSM/QAC exercise its authority to suspend or make a recommendation to the CRC to close a trial under any of the above review mechanisms, the DSM/QAC promptly notifies the IRB of this decision. The DSM/QAC requires the PI notify the sponsor, collaborators, grant program director if applicable, any and all appropriate governmental agencies (i.e. FDA, NCI), and any other appropriate party. The PI provides the DSM/QAC with copies of all such notifications. If the trial is suspended or closed by any other party, the PI is expected to promptly provide the DSM/QAC with copies of the suspension or closure, and documentation that appropriate parties have been notified. The CRMO research database is configured such that a trial that is suspended or closed by the DSM/QAC is unavailable for further patient registration. While the PI is responsible for primary notification to appropriate treating physicians and nurses about protocol closure, the research database provides a secondary notification system. V. Conflict of Interest Policies The DSM/QAC will follow the conflict of interest policies set out by the UMB IRB, which has the responsibility for monitoring conflict of interest. These policies are completely described at http://www.umaryland.edu/hrp. All investigators, including those operating or employed outside of UMB, and their study personnel must disclose in advance all outside activities and economic interests that might be or have the appearance of being conflicts of interest as described above to the UMB IRB. If a conflict of interest occurs after the research study has commenced, the investigator must promptly update the COI information in CICERO. A disclosure shall be sufficiently detailed and timely as to allow accurate and objective evaluation prior to making commitments or initiating activities that represent potential conflict situations. The information must be accurate and not known by the Investigator to be false, erroneous, misleading, or incomplete. Each individual has an obligation to cooperate fully with the IRB and the appointed Conflict of Interest (COI) Officer in the review of the pertinent facts and circumstances regarding any conflict of interest disclosed. p17

The IRB or designated UMB official will determine whether the disclosed economic interest is likely to compromise or appear to compromise the design, conduct or reporting of the study. The DSM/QAC follows any recommendations from the IRB with respect to conflict of interest and reserves the right to impose even more stringent conflict management. It assures that no reviews or audits are conducted by individuals with conflicts. The DSM/QAC further assures that, even where no economic conflict exists, studies will not be monitored or reviewed by individuals who may have significant scientific interest in the outcome. p18