Clinical Investigator Handbook

Clinical Investigator Handbook Version: July 2010 (Note that individual components requiring institutional approvals may have been approved separately and prior to release of complete handbook. Those sections will reflect date of institutional approval.)

UNIVERSITY OF MARYLAND MARLENE AND STEWART GREENEBAUM CANCER CENTER 22 S. Greene Street, Baltimore, MD 21201 http://www.umgcc.org

Table of Contents Introduction......................................................................3 Protocol initiation flowcharts...........................................5 Committee structure.........................................................8 CICERO and the IRB.....................................................11 Clinical Research Committee (CRC).............................36 Data and Safety Monitoring (DSM) ..............................64 General Clinical Research Center (GCRC) ...................90 Ongoing Protocol Management .....................................97 Annual Renewals ...................................................98 Monitoring and Audits.........................................110 Reportable Events ................................................141 Adverse Events ......................................................141 Exceptions/Deviations/Unanticipated Problems ..............144 Amendments ........................................................147 Clinical Research Shared Service ................................149 Current Committee Membership .................................155 Glossary .......................................................................159

Introduction Clinical Research is an integral part of the mission of the University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCC). Funding to support Clinical Research is only partially recouped by funds from study sponsors or grants. Additional support for Clinical Research functions comes in part from the University of Maryland Medical System and from funds available to the Director, UMGCC. Therefore, UMGCC has adopted a series of policies and processes to make certain that adequate resources are available to support clinical trials and that limited resources are prioritized appropriately based on patient safety and scientific merit.

The Clinical Research Shared Service (CRSS) is organized to support clinical research.

Comprising over 30 FTEs, it is charged with managing data and regulatory actions related to clinical trials. The manager of the CRSS reports to the Associate Director for Administration with professional guidance for the allocation of resources from the Associate Director for Clinical Research.

Initiation Clinical research may not be initiated without complying with both regulatory and budgetary policies and procedures. The flow of these regulatory and budgetary processes is depicted in the charts following this introduction.

NCI-funded Cancer Centers are required to assure the quality of protocols and timely accrual to such protocols via a Protocol Review and Monitoring System (PRMS). The UMGCC PRMS is the Clinical Research Committee (CRC). Protocols emerge from groups of physicians dedicated to a disease type (Disease Groups; e.g., Hematologic Malignancies, Thoracic). The protocolspecific regulatory process commences with review by the CRC for scientific merit and prioritization of CRSS resources. To submit a protocol related to cancer treatment, diagnosis, imaging or prevention to the CRC, the prospective investigator must obtain: 1) Concurrence and sign-off from their Disease Group Head AND the Associate Director for Clinical Research 2) Concurrence from the Head of the CRSS that appropriate data management and research nurse support exists.

Review by the CRC requires the submission of a packet of information. This includes entry of the protocol into the CICERO electronic submission mechanism for the University of Maryland School of Medicine IRB (IRB) so that the CRC may review the intended IRB submission.

Following successful address of any CRC issues, the CICERO protocol and supporting documents can be submitted to the IRB. Since the CRC ratifies to the IRB the scientific value of the study and UMGCC’s commitment to the study, the IRB will not review a protocol without evidence of CRC approval attached to the submission. The IRB submission system also requires electronic concurrence by the Associate Director for Clinical Research, as well as the Radiation Oncology Chair for those protocols originating in the Radiation Oncology program.

Response to any IRB issues must then be made.

Those protocols originating from the Radiation Oncology program which deal solely with technology-related matters are analogously reviewed by the Technology Research Review Committee (TRRC), a subcommittee of the CRC, prior to IRB submission.

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Concurrent with and/or subsequent to scientific and regulatory review, budgetary issues including investigational agent supply, administration of agent, correlative study funding, research nurse and regulatory support for the protocol must be settled. The General Clinical Research Center (GCRC) is the intended locus of studies not supported by corporate or grant funding where the study involves the administration of investigational agents. On a case-by-case basis, “complex� corporate trials may be undertaken in the GCRC. Application to the GCRC is made after IRB approval.

The protocol may be initiated after all scientific, regulatory and budgetary concerns have been addressed.

Management Ongoing protocol management includes annual renewals, routine monitoring and auditing, adverse event reporting, reporting of deviations, and submission of amendments. The governing and reviewing processes for ongoing protocol management are depicted in the flowchart following this introduction.

Protocols must be renewed annually with the IRB. Protocol renewal requests must be submitted to the IRB no later than 45 days prior to the protocol renewal date. For those protocols which are monitored by the UMGCC Data and Safety Monitoring/Quality Assurance Committee (DSMQAC), the renewal package must first be reviewed by the DSMQAC within 90 days of protocol renewal to allow timely response to DSMQAC concerns prior to IRB submission.

The DSMQAC reviews PI initiated trials, NCI sponsored Phase I and Phase II trials, and certain industry-sponsored trials that do not have adequate external DSM plans. The renewal submission to the IRB including accrual and adverse event information must be submitted to the DSMQAC for these trials.

For trials reviewed by the DSMQAC which lack outside safety monitoring, CRSS personnel are employed. The Human Research Protections Office (HRPO) of the University of Maryland School of Medicine conducts auditing of those trials reviewed by the DSMQAC and provide the DSMQAC with the audit results. The DSMQAC may recommend that the CRC close protocols which are not accruing successfully, have exceeded accrual goals, or which have a type and frequency of adverse events that do not seem appropriate in view of the potential benefit to the patient and/or society.

The IRB will automatically close any protocol for which a timely renewal is not submitted.

Closure of the protocol requires resubmission of the entire package to the IRB for re-review.

Adverse event (AE) reporting is a requirement for all trials and must comply with IRB, DSM and sponsor policies.

Changes to the protocol must be submitted as amendments to the IRB, as well as complying with sponsor policies. Exceptions requests and deviation reports should also submitted to the IRB through CICERO. The figures below provide an overview of the protocol initiation process, illustrate the steps in the regulatory process, and offer a detailed look at the budget process for various trial types.

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Protocol Initiation Process PI must secure consensus of Disease Group Head AND Assoc Dir Clin Res re: resource allocation

For all new trials (GCC, Industry, NCI, Coop Group) PI submits electronic documents to CRSS manager (sign-off by Disease Group Head AND Assoc Dir Clin Res, sponsor info, scope of trial, draft budget and contract, protocol)

Contract / Budget Process PI work with Admin and CRSS staff

Regulatory Process (CRC, IRB, GCRC) PI work with CRSS staff

Approval to Initiate Trial Only Once Contract, Budget and Regulatory Complete Clinical Investigator Handbook July 2010 Version - Page 5

Protocol Initiation – Overview of Regulatory

Disease Group or AD Clin Res

PI

Manager CRSS

CRC CRSS

IRB

GCRC** ** - NCI sponsored investigational drug studies see appropriate sections for full discussion of requirements Clinical Investigator Handbook July 2010 Version - Page 6

CLINICAL RESEARCH SHARED SERVICE GREENEBAUM CANCER CENTER DETAILED BUDGET & PROTOCOL SUBMISSION PROCESS FOR NEW TRIALS All new trials: GCC, Industry, NCI, Co-op groupPI presents protocol to disease group

Statement by Disease Group Head and AD, Clinical Research approving trial at GCC. (Regulatory Coordinator completes Disease Group Form & obtains signature of disease group head CRSS Manager to verify Protocol within the capacity of CRSS. Obtains signature of Dr Sausville; assigns GCC( local) protocol Number

PI submits all protocol and budget documents in ELECTRONIC FORMAT, to the manager of CRSS. Required: Protocol, Model Consent, Investigator Brochure, IND Safety Reports, FDA/ Sponsor Documents (See Regulatory document checklist),

NCI, Co-op Group, PI Initiated

Industry Trials

Manager of CRSS will electronically submit: Service request form to the SOM Center for Clinical Trials (CCT): http://www.medschool.umaryland.edu/cct

REGULATORY PROCESS

CRSS will contact GCC Grants Office and work with Grants Administrator to Formulate Budget:

CRSS Regulatory Contact designated by Disease Specialty Manager emails or faxes draft budget (internal and sponsor), contract, protocol, study calendar, & Medicare Analysis (signed) to CCT & Office of Research & Development (legal) Fax: 410-706-4853 Email: cct@som.umaryland.edu

CCT will produce first budget draft. ORD will prepare contact.

CRSS/ Manager will review for accuracy and communicate with PI and Study Coordinator

CRC Submission (Clinical Research Committee Submission)

by Disease Group Reg. Coordinator Includes entering info into BRAAN: web based IRB

Schedule of Events or Sponsor’s Draft Budget required for budget negotiations**

Grants Administrator confirms budget and other grant items with PI.

↓ CCT and ORD, upon completion of budget & CTA negotiations, emails the CRSS Manager Grants / Contacts Administrator of GCC. CRSS manager obtains required signatures on CTA, Internal budget, billing analysis and sends back to CCT and ORD.

ORD will sign and execute the agreement provided that: • Principal Investigator has signed the agreement • A copy of the protocol has been received for permanent record.

• IRB approval / Pending letter has been received • Routing Form has been submitted to the Office of Research and Graduate Studies and approval has been returned to the CCT.

CRC Review ↓

CRC Approval ↓ Essential Documents Coordinator (Terri Joneckis) completes pre reg. Documents and routes to sponsor) ↓

IRB Submission ORD forwards the executed agreement and protocol to the Office of Research and Development for activation of FAS/ Raven account.

A copy of the executed agreement will be sent to the Department business contact and the Principal Investigator.

(Institutional Review Board) **Materials should be submitted to the IRB as soon as possible. Do not wait for completion of clinical trial agreement negotiations

Grants Office routes proposal through SOM’s Office of Research & Development.

10.31.09

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Grants Office routes proposal through SOM’s Office of Research & Development.

Committee Structure Governing Clinical Research at UMGCC

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Clinical Research Oversight Committee (CROC) The Clinical Research Oversight Committee (CROC) is the committee that oversees the Clinical Research Shared Service. The CROC defines and adjusts physical and personnel resources, is responsible for setting policies and processes for clinical research, and has the authority to consider disciplinary sanctions against clinical investigators. The CROC does NOT participate in the review of protocols.

Current CROC members are listed in the appendix.

Clinical Research Committee (CRC) The CRC functions as the Protocol Review and Monitoring System for the UMGCC NCI Cancer Center Support Grant. It reviews protocols for scientific merit and approves them for submission to the IRB. The CRC also closes protocols for poor accrual following annual review or at the recommendation of the Data and Safety Monitoring / Quality Assurance Committee (DSM/QAC) based on lapses in protocol adherence, poor audit outcome or adverse event profiles.

Data and Safety Monitoring / Quality Assurance Committee (DSM/QAC) The DSM/QAC functions as the monitoring committee of record for institutional/PI-initiated clinical trials; NCI sponsored Phase I and II trials; and corporate trials that do not have a fully independent DSM. The DSM/QAC considers the number and nature of adverse events both internal and external; the quality of protocol conduct; and the likelihood of meeting the trial goals. When necessary, the DSM/QAC recommends that the CRC consider closing protocols for deficiencies in these areas.

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Clinical Trial (Proposed)

Role of UMGCC Committees in Review of Clinical Trials and of Clinical Research Shared Service

CRC Review ‐scientific merit ‐priority IRB Review ‐human protections Clinical Research SS ‐conduct study

CRSS Oversight Committee ‐SS operational oversight ‐ensure equal access ‐identify resources for SS DSM ‐monitoring ‐qa

Clinical Trial (Completed/Closed)

CRC ‐accrual monitoring Clinical Investigator Handbook July 2010 Version - Page 10

CICERO The IRB’s Electronic Submission System Example Submission with Comments

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CRC Clinical Research Committee

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University of Maryland Marlene and Stewart

Subject: Clinical Research Committee (CRC)

Effective: July 2010

Procedure No: CRC001

Function: Protocol Review and Monitoring System

UMGCC governs clinical research through a parent Clinical Research Oversight Committee (CROC), which oversees the function of the Clinical Research Shared Service, and two independent committees: the Data & Safety Monitoring/Quality Assurance Committee (DSM/QAC) and the Clinical Research Committee (CRC).

These committees coordinate to oversee the conduct of clinical research at UMGCC. The relationships between and the flow of protocols through these committees are shown in the attached Figures.

This SOP describes the Clinical Research Committee which serves as the Protocol Review and Monitoring System at UMGCC. Definitions 1. Principal Investigator (PI) The PI is responsible for the completion of the CRC packet, which contains the information necessary for the CRC to properly review the protocol, and submitting the completed packet to the CRC by the CRC deadline. The PI is also responsible for proposing a DSM plan as part of the scientific review by the CRC.

2. Clinical Research Management Office (CRMO) The CRMO is the physical space housing staff of the Clinical Research Shared Service (CRSS). It maintains a clinical research database of all protocols open at UMGCC. CRMO staff may be called upon by the PI to assist in preparation of materials for CRC review. Should the PI require such assistance the PI must provide the manager of the CRSS with a copy of the signed approval from the disease group head. However, the PI is ultimately responsible for the accuracy of the information and should review the entire packet prior to submission to the CRC Coordinator.

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3. Clinical Research Oversight Committee (CROC) The CROC defines and adjusts physical and personnel resources of the CRSS. It also is responsible for setting policies and processes for clinical research at UMGCC. The CROC also has the authority to consider disciplinary sanctions against clinical investigators.

4. Data and Safety Monitoring / Quality Assurance Committee (DSM/QAC) The DSM/QAC is responsible for ongoing safety and quality assurance review of protocols at UMGCC. 5. University of Maryland School of Medicine Institutional Review Board (UMB or IRB) The IRB is an 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 in, or disapprove all research activities that fall within its jurisdiction as specified by both the federal regulations and local institutional policy. The IRB makes use of an electronic database system to receive communications regarding protocols under their jurisdiction.

6. Human Research Protections Office (HRPO) The HRPO is the coordinating office for the UMB IRB. CICERO is the electronic database utilized by the HRPO and IRB.

Purpose The Clinical Research Committee (CRC) will provide scientific review and evaluation of all cancer clinical protocols throughout the institution involving clinical subjects.

The CRC will provide initial review of these protocols for scientific merit, methodology, validity of statistical analysis, potential for successful completion based upon anticipated accrual and scientific priority, availability of resources and funding including P30 Protocol Specific Research Support funding. CRC will require the submitted new protocols to be prioritized by the Disease Group Head or the investigator in the event of competing protocols prior to submission to insure appropriate accrual strategy, and in the event of an excessive queue of protocols, the CRC may review the queue with the Disease Group Head and require withdrawal of protocols. The CRC will also review the adequacy of accrual during the course of the study. The CRC will provide continuing scientific review of ongoing protocols if an issue arises during the annual accrual review or if the DSM/QAC or University of Maryland IRB so requests.

Such continuing review may be occasioned by receipt of new information concerning a

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treatment in the protocol or questions concerning the continuing scientific importance or methodology.

Approval by the CRC will be required in order to gain access to the Clinical Research Shared Service and Investigational Pharmacy of the Greenebaum Cancer Center.

The CRC is composed of a chair and representatives from all the relevant areas of the Cancer Center (e.g. biostatistics, hematology/oncology, surgical oncology, radiation oncology, and pharmacy). Members either volunteer or are assigned based on need and availability from the relevant areas. There is no fixed term length to committee service.

Current membership, including voting and non-voting members, is shown in the Appendix. Ad hoc voting CRC members appointed by the Chair for a particular meeting and indicated in their review as “ad hoc� may be used when necessary to address specific areas of expertise not covered by standing committee members or to assure independent review if the required expertise resides in a member with a conflict of interest. In addition, an observer from the IRB is invited to allow IRB awareness of issues that arise in protocol review. A quorum consists of three voting members plus a chair or acting chair.

Objectives of the CRC: 1. To review all new cancer-related protocols for scientific merit, methodology, human resources, security of funding source, ethical appropriateness, and reasonableness of accrual goals prior to submission to the IRB. 2. To ensure that expert biostatistical planning regarding clinical trial design, calculation of sample size and monitoring for early closure will be part of each institutional protocol.

3. To provide review as needed of Medicare coverage and PI determinations of research v. standard of care procedures.

4. To work with the Disease Group Heads to assure proper prioritization of new and existing protocols.

5. To review on a continuing basis accrual to all studies supported by the Clinical Research Shared Service, including underserved minority demographics and to oversee the development of corrective action plans or require closure of poorly accruing trials.

6. To provide scientific review of issues that may arise in continuing review by the CRC, the DSM/QAC or the University of Maryland IRB. The committee will judge the acceptability of the proposed research, based upon scientific merit, which includes the scientific question being posed, from which the study derives. The committee will also review the scientific design, statistical endpoints, study calendar, rules for monitoring as well as the likelihood of completing accrual in a defined time period (usually 3-4 years for institutional sponsored protocols). The review criteria are described below. The committee will have the authority to decline activation for protocols which do not meet scientific criteria or for which priority is not high compared to other protocols in the same disease area.

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The CRC will additionally consider the adequacy of the suggested Data Safety Monitoring plan for each individual protocol. The CRC may impose a stricter level of monitoring for “high or highest risk” studies.

The CRC has the authority to close protocols due to poor accrual. On an annual basis the CRC will review accrual to all UMGCC trials to assure timely recruitment of subjects to trials. Typically timely accrual will entail accrual averaging at least 20%33% of total target accrual per year, but consideration will be given to prevalence of the indication and other factors outside the PI’s control. This will also entail the assessment of progress in reaching protocol-defined clinical response endpoints

Subcommittees and Delegation In December 2005, the Department of Radiation Oncology, in conjunction with UMGCC and the Clinical Research Committee, formed the Technology Research Review Committee (TRRC) as a sub-committee of the CRC. The TRRC was formed as a subcommittee under the CRC to supplement the review capacity of technology protocols. This sub-committee reviews research proposals that do not affect patients' treatment modalities, but instead study technology to help advance treatment planning or improve the use of technology assessment tools.

The subcommittee meets on the first Monday of every month, and members include representatives from the Department of Radiation Oncology, the Department of Radiobiology, the Department of Biostatistics, the Greenebaum Cancer Center, and CRC. Faculty of the University of Maryland School of Medicine Department of Pediatrics are members of the Children’s Oncology Group, which is the source of most of their clinical research protocols. The CRC delegates to the Department of Pediatrics the review of pediatric cooperative group studies. Pediatric protocols are reviewed by the Department of Pediatrics according to departmental guidelines and receive second level review by the Associate Director for Clinical Research, UMGCC per IRB guidelines.

The CRC will review investigator-initiated and industry-sponsored pediatric protocols with usual review process, after signoff by the pediatric departmental reviewer, and at its discretion, the CRC can elect to review any specific cooperative group protocol.

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Procedure 1.

Initial Review of Protocols CRC Packets The CRC packet includes the information necessary for the CRC to properly review the protocol. The CRC packet includes (samples of each form and a checklist provided in the Appendix): •

• • • •

• • • •

•

•

Investigator & Disease Group Worksheet – this form allows the protocol to be properly categorized and prioritized. The PI in particular should make sure that sponsorship of the protocol is clear (e.g., “Industry-sponsored” studies imply provision of drug if not standard practice plus a per patient fee; “PI-initiated” studies may utilize drug provided by a sponsor and have partial financial support but not a full per patient reimbursement). The PI must also indicate the expected duration of the accrual period across all sites and provide justification for UMGCC participation for protocols for which the study is unlikely to be open to accrual for at least 18 months. The disease group head and Associate Director for Clinical Research must sign this form.

A printout of the CICERO protocol – this allows the CRC to view the protocol in the form in which it will appear before the IRB Consent Form adapted to local IRB requirements, including 7th grade reading level (Industry studies need to have consent form approved by sponsor before IRB submission.)

Data and Safety Monitoring Level Designation (see DSM/QAC materials) Website Form – any proposed advertisement will be reviewed by the IRB and must be available to the CRC for review. For industry sponsored trials, the proposed advertisement should be reviewed by the sponsor. In addition, the PI should ensure that the protocol is registered with clinicaltrials.gov Copy of the Sponsor’s Protocol. For PI-initiated studies, all co-investigators including the statistician should initial the face page of the submitted protocol.

PDF file of the Investigator Brochure (if applicable) HIPAA Authorization – the IRB will not review a protocol until this form is available Study Schedule marked with R (research procedure) and C (standard of care procedure). The study calendar should be generated in Oncore®, the CRSS research database. The PI must sign this calendar, which will become the basis for a billing plan to be used by UMMC to ensure that research subjects are not charged for research procedures, or to review the consent to define that such charges are explicitly outlined.

Plans for funding (part of the Disease Group Head or AD Clinical Research approval). If the PI is requesting use of P30 Protocol Specific Research Support (PSRS) funding, the PI will need to address the additional information described below under Criteria for Review.

Model chemotherapy order set if required by the Pharmacy to allow generation of pre-printed orders p5 Clinical Investigator Handbook July 2010 Version - Page 41

•

A preliminary Medicare coverage analysis showing whether the trial is “deemed” according to Centers for Medicare & Medicaid Services criteria for coverage by Medicare

Chart reviews and other minimal risk studies not involving therapy can be submitted with documents pertaining only to therapy (e.g., chemotherapy orders) omitted.

The CRC submission packet can be accessed on the G drive at g:\protocol\reports\irb\packet or on the S drive s:\CRC Submission. Copies of the template documents follow this plan.

The packet should be submitted via hard copy. An electronic version or disk version should be submitted to the CRC Coordinator.

The CRC meets on the second Tuesday of the month. The deadline for submitting a packet for consideration at the CRC is the last Monday of the prior month but in no case less than 2 weeks prior to the meeting. In rare cases where time is of the essence and there is a valid reason why the protocol cannot be reviewed at a regularly scheduled committee meeting, the CRC chair may convene an ad hoc meeting to review a specific therapeutic protocol.

In the event of a queue of protocols in excess of the capacity of the CRC or the CRSS, the Disease Group Head may be requested to prioritize and eliminate trials from the queue pertinent to their area of responsibility. If this measure is inadequate to reduce the queue of protocols to a manageable number, a Disease Group Head may be invited to a CRC meeting to present a streamlining plan for the Disease Group. If the Disease Group Head is unable to reduce the queue of protocols to a manageable number, the CRC will review the queue at a meeting and require the Disease Group Head to withdraw certain protocols summarily.

Reviewer Assignments Reviewers are assigned based on scientific expertise. For NIH Cooperative Group trials (e.g. CALGB, RTOG, NMDP) and trials sponsored by major pharmaceutical companies of at least 500 employees and/or with a prior track record of having submitted at least one well-constructed statistically sound trial to UMGCC, one primary reviewer is assigned as these studies have already received extensive review. For all other Industry and PI-initiated protocols two reviewers are assigned; one primary reviewer and one secondary reviewer. For chart reviews and other minimal risk protocols not involving therapy, a single reviewer is assigned and the chair decides whether the protocol may be reviewed ad hoc with a report of review at the meeting or whether the entire committee should discuss the results of the review. Reviewers are generally committee members, although additional reviewers may be recruited to provide specific expertise. Only non-cooperative group trials will require statistical review. The pharmacy representative will review the model chemotherapy orders if necessary. The complete CRC packet, except for those documents only required for

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administrative processing, will be distributed to reviewers five days in advance of the meeting with other members receiving only the proposed CICERO submission.

Procedures at Meeting and Criteria for Review The meeting will be led by the CRC Chair or an Acting Chair appointed by the Chair.

The PI is expected to be available by pager at the time of review of the protocol by CRC. At the meeting, the assigned primary reviewer will give a brief synopsis of the protocol followed by a critique. Secondary and statistical reviewers then add any additional comments. Reviewers provide written synopses of their comments to the CRC Coordinator. Minor editorial or typographical comments do not require discussion at the meeting.

The criteria for review include appropriate prioritization within the disease group, biostatistical input and review, scientific justification, if the study design is appropriate, if the risks are appropriate for the nature of disease, if the standard of care is maintained, potential for accruing at acceptable pace, adequacy of the consent form, consideration of the Medicare coverage analysis and designation of research procedures in the study calendar, and if the data and safety monitoring plan described is appropriate. The study is rated adequate or not adequate for each of these criteria as shown in the template documents following this plan.

Additional Criteria for Protocols Requesting PSRS Funding To gain access to P30 Protocol Specific Research Support (PSRS) resources, investigators will have provided the following, in addition to the usual information currently required for a CRC submission: • Describe how the protocol is significant and innovative in achieving the goal of attaining a novel cancer diagnosis, treatment, imaging, or prevention strategy • Describe the correlative science to be enabled as a result of PSRS funding and indicate whether translational collaborators and assays are in place • Describe the independent funding applications that will be developed for the activity and indicate the anticipated total cost of conducting the trial The CRC weighs each of these criteria using a 1–10, NIH-like priority scale. Protocols that achieve an aggregate ranking (equally weighted) of 40 or better are considered for PSRS resources.

Following discussion of the review criteria and DSM plan, a member will make a motion to approve, approve with minor or major modifications, scientifically disapprove, or defer.

The CRC Coordinator will take notes at the meeting and ultimately compile the comments of the reviewers. The review letters distributed to the PIs constitute the minutes of the meeting.

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Post-Meeting Activities After the CRC meeting an e-mail will be forwarded to the PI from the CRC Coordinato including a detailed memo from the Chair regarding the protocol including reviewer comments and disposition. The CRC Chair will designate the appropriate level of DSM plan in the letter to the PI with copies to the DSM/QAC and the CRMO. The DSM plan will remain in effect until all enrolled patients are beyond the time period when study-related adverse events would likely be seen. Copies of this letter are sent to the Associate Director of Clinical Research and the DSM/QAC Coordinator. A copy is also included in the regulatory binder kept with the CRMO. The PI is ultimately responsible for addressing the comments of the CRC and insuring that the appropriate changes are made before IRB submission. CRMO staff can be enlisted to assist in this process, but the PI remains responsible for the content of the submission. A response to the CRC’s recommendations should be addressed within a month of the date of the memo unless more extensive communication with the sponsor dictates a longer turnaround time.

1) When a protocol is approved as written, no further review by CRC is needed.

2) When a protocol is approved with minor revisions, the changes are returned to the CRC chair. If in the opinion of the chair, who may consult the original reviewers at chair’s discretion, approval can be granted by the chair.

3) When a protocol is approved with major revisions, a revised submission should be resubmitted for review at a CRC meeting. In most cases, the original reviewers should receive the revised package. PI may be invited to the meeting to discuss the points raised by the reviewers.

4) When a protocol is deferred, the CRC will provide the PI with written recommendations. Protocol can be re-submitted to a future CRC meeting with no prejudice.

5) When a protocol is scientifically disapproved, the CRC chair will be available to meet with the PI to discuss re-design of the study. If the PI chooses to resubmit, the CRC chair may designate independent ad hoc reviewers to assure impartial re-review.

The independent reviewers should be made aware of the prior issues in review by the CRC. The PI response memo to the CRC chair should be forwarded to the CRC coordinator.

The CRC coordinator reviews for technical compliance with the CRC review and then forwards to the CRC chair for final review. Once the chair, the full committee or the delegated ad hoc/CROC members have reviewed the changes, the PI and PI’s regulatory staff will be notified via e-mail that the PI may submit the protocol to IRB via CICERO. This notification may originate from the CRC Chair or CRC Coordinator.

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Cancer Center Signatories will be informed of the submission as a reminder to sign off on the IRB submission once notified via CICERO e-mail.

The CRC letter to the PI, the PI’s response to the CRC, and the CRC’s final approval should be attached to the CICERO submission in Section S so that the IRB can see the record of scientific review.

2. Accrual Monitoring All trials, regardless of whether an independent DSMB exists or not, will be subject to at least annual review of accrual by the CRC. The CRC may close studies with persistently poor enrollment, typically accrual averaging less than 20% - 33% of total target accrual per year, but consideration will be given to prevalence of the indication and other factors outside the PI’s control.

The CRC will consider the following items in its review.

• Accrual of research subjects to the study will be reviewed for adequacy by the CRC. The CRC will determine if early closure is justified if anticipated accruals cannot meet stated study goals.

Following review of the accrual information, the CRC will make one of the following recommendations: • • •

Allow protocol to remain open.

Request corrective action plan to improve accrual from PI Close the protocol

The CRC will not issue a determination letter for those protocols that may remain open without corrective action. The CRC will send the PI a letter either requesting a corrective action plan or informing the PI that the protocol will be closed. In the event of a closure recommendation, the IRB, any appropriate granting agency, the sponsor, and any other appropriate body will be sent a copy of the letter.

3.

Continuing Review of Protocols

Upon referral from the DSM/QAC or the University of Maryland IRB, or if the CRC’s own accrual monitoring indicates, the CRC will provide continuing scientific review of protocols in which questions have arisen as to the continuing scientific importance or appropriateness of the research question; which require proper consideration of significant new information; or for which questions have been raised by investigator or participant experiences since the last review. The CRC will not as a matter of routine re-review protocols without cause.

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The process of the continuing review will be identical to the initial review with the following exceptions: • The review packet will contain a summary from the IRB, the DSM/QAC, the CRC chair or designee as to why re-review is necessary.

The PI will be expected to include a written response to the issue raised. • The outcome of the review will have the following categories: o Continue protocol as previously o Modify protocol as specified by the CRC with or without suspension of accrual until amendment completed o Close protocol In each case, the determination of the CRC will be final.

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CRC Packet Sample documents Download from cancer center server drive G to ensure most current version

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REGULATORY DOCUMENT CHECKLIST FOR CRC AND IRB SUBMISSION Regulatory Coordinator __________________ Regulatory Preparation By_________________

Protocol #__________________________

CRC SUBMISSION Study will not be reviewed unless all documents are completed and submitted

Please provide CRC Committee with the following: CICERO Protocol Completed CICERO Consent Completed Copy of Sponsors Protocol Copy of Sponsors Model Consent Investigator Brochure ONCORE Study Schedule Complete and print the following (may be found in CRC folder of G Drive 1. Disease Group Review Form - signed by chair; should be provided by PI with protocol documents 2. Completed Regulatory documents checklist

Initial when complete

IRB SUBMISSION Ensure completion of the following prior to submitting to IRB: CICERO Protocol CICERO Consent Attach the following in section “Final – Additional Documents” of CICERO: 1. Copy of Sponsors Protocol 2. Copy of Sponsors model consent 3. Sponsor approval of UM draft consent) 4. Investigator Brochure IB 5. ONCORE Study Schedule 6. Disease Group Review Form - signed by chair; should be provided by PI with protocol documents 7. CRC review letter 8. PI’s response letter to CRC review 9. CRC approval letter 10. Drug information sheet / Package insert 11. Questionnaires:Surveys/Quality of Life 12. Consent Evaluation Tools (if required) 13. Recruitment material (if any) 14. Patient education (if any) 15. Grant Application, if applicable (Federal ) 16. NCI approval letter (if applicable) 17. External safety reports Complete and upload the following (may be found in IRB folder of G Drive 18. HIPAA Consent (IRB amended version 10/2007)

Version date: 10/18/08

19. DSMP - Data Safety Monitoring Plan 20. Web Posting 21. Eligibility Checklist 22. Signed scanned1572

Clinical Investigator Handbook July 2010 Version - Page 48

Initial when complete

GCC Clinical Research Shared Service Budget and Regulatory Process for New Trials

PROTOCOL DOCUMENTS CHECKLIST THE FOLLOWING DOCUMENTS ARE TO BE SENT ELECTRONICALLY TO THE MANAGER OF THE CRSS

BY THE PI OR STUDY TEAM UPON RECIEPT FROM THE SPONSOR

Protocol Model consent Investigator brochure, IND safety reports Draft Budget Draft Contract IN ADDITION THE FOLLOWING REQUIRED / ESSENTIAL FORMS AND DOCUMENTS for FDA ARE TO BE SENT ELECTRONICALLY TO THE MANAGER OF THE CRSS

BY THE PI OR STUDY TEAM UPON RECIEPT FROM THE SPONSOR

Signed Protocol page FDA Form 1572 Delegation of Authority / Site Signature Log Financial Disclosure Form Signed Confidentiality Agreement Acknowledgment of Receipt signature pages (if required)

↓ THESE DOCUMENTS ARE then PREPARED BY: Terri Joneckis, Regulatory Document Specialist and routed to disease group members for signature .

↓ Upon IRB approval of protocol, the above essential documents and the following are sent to the study sponsor: Curriculum Vitae for Investigator Sub-investigator’s Curriculum Vitaes List of IRB/EC Members and Affiliations Laboratory Normal Values Laboratory Certification/Accreditation (CLIA & CAPS) IRB/EC Approval Letter IRB/EC Approved Informed Consent All regulatory documentation is sent via DHL or sponsor prepaid Fed Ex packet

Clinical Investigator Handbook July 2010 Version - Page 49

Greenebaum Cancer Center Clinical Research Committee Disease Group / CRO Director Review & Approval Date of Meeting: Disease Group:

Thoracic

Head & Neck, GI Hematology

BMT

Breast/GYN

Prostate, GU

Phase I

Protocol # / Title:

0936GCC: A Phase 1/2 Study of SCH727965 in Patients with

Malignant Melanoma Principal Investigator: Edward Sausville Co Investigators (as per FDA 1572): Petr Hausner, Susan Kesmodel, Martin Edelman Research Coordinator(s): Vera Kuffour-Manu Data Manager: Juliet Nacario Bio Statistician (if applicable):

Funding Source: NCI/U01

Worldwide Accrual goal:

90

Local Accrual goal: 15 Estimated # of eligible patients at GCC: 15 Estimated # of eligible patients at VAMC:

/N.A.

Sponsor’s Accrual/Enrollment period (date sponsor plans to close to accrual):

If study is already open at other sites, how many openings remain available? n/a (Please provide name of contact to verify)

1 Version date 05.29.2008 Clinical Investigator Handbook July 2010 Version - Page 50

Sponsor/Category

*X NCI

* Cooperative Group

Industry Company name Institutional, PI Initiated *if box is checked, complete GCRC application or provide justification as to why GCRC cannot be used Single Center Study

X Multi Center study

Is GCC Coordinating Center Yes

X No

VAMC

First Author Status: Yes

X No

Type of Treatment: X Interventional (Treatment or other interventions) Non-Interventional (Blood drawing, QOL, Survey, etc.)

X PK s required Phase: X I /II

II

III

If yes, how many? 12 Other

Does this study have competing studies for patients? No overlap DSI MEL/MEL 2005-01; H0636GCC 28562; HP00042681

0794GCC H-29873;

X Yes – partial

A Random-Assignment Study Of Hepatic Arterial Infusion Of Melphalan With Venous Filtration Via Peripheral Hepatic Perfusion Alexander, OPEN TO 04/25/2008 (PHP) (Delcath System) Versus Best H Richard ACCRUAL Alternative Care For Ocular And Cutaneous Melanoma Metastatic To The Liver Treatment Of Melanoma With Wild-Type P53 And Detectable S100B Using Pentamidine: A Phase II Trial With Correlative Biomarker Endpoints

0794 requires patients to have wild type p53.

0636 has eligibility criteria related to ability to tolerate surgical procedure and is open only to ocular or cutaneous melanoma metastatic to liver

Protocol:

Approved to be submitted to CRC

Disapproved

Chair

Date

Approval for issuance of GCC protocol number: Approved

Dr. Edward Sausville Version date 05.29.2008 Clinical Investigator Handbook July 2010 Version - Page 51

Disapproved

Date

2

Cancer Center Data and Safety Monitoring Plan Title of Study: IRB#:

Level (check one): ___

Routine

All SAE’s reported to the IRB, FDA (if appropriate affiliated research sites) in a timely fashion. Summary of SAE’s submitted with annual report for review

by DSMC and IRB.

___

High

(Prospective review) All SAE’s reported to the IRB, FDA (if appropriate affiliated research sites) and DSMC in a timely fashion. Summary of SAE’s is submitted with annual report for review by DSMQAC and IRB. Requires annual review by DSMQAC. Includes high-dose treatments or those expected to cause significant risk of complications whether due to study drug or not, e.g. BMT, acute leukemia.

___

Highest

Dose escalation studies – Phase I All SAE’s reported to the IRB, FDA (if appropriate affiliated research sites) and DSMC in a timely fashion. Summary of SAE’s submitted with annual report for review by the DSMC and IRB. Expedited review by member of DSMC before each new cohort. (This includes single- patient cohort, accelerated trial design.) Requires review of patient outcome every 6 months.

Requires review of original patient records or case report forms.

___

Special

Institutionally developed, single-site or multi-site Phase III trials require a Data and Safety Monitoring Board (DSMB). See GCC DSM planning document for details.

___

External

External DSMB in place. All SAE’s submitted to the IRB, FDA and sponsor.

Summary of SAE’s submitted with annual report.

Copy of this form must go to Mary Quinn as well as to CRC. Oncore Data Monitoring field must match this form. If anything but external is checked, this study will be monitored by UMGCC DSMQAC. Protocol must be assigned to DSMQAC monitoring group in Oncore.

Signature of Principal Investigator: (copy with signature on file in CRMO offices)

Clinical Investigator Handbook July 2010 Version - Page 52

Home|Submit A Trial|Edit A Trial|Help|logout

Please click Help to fill the fields in their right format Study Number:

Help

Official Title:

Help

Brief Summary:

Investigator:

Help

Disease Site:

Help

Disease Stage:

Help

Condition:

Help

Intervention:

Help

Phase:

Help

Inclusion Criteria:

Help Exclusion Criteria:

Help Contact Person

Help preview

submit

Clinical Investigator Handbook July 2010 Version - Page 53

TO CREATE A WEB PAGE FOR A CLINICAL TRIAL: 1. Enter this URL in your web browser:

http://209.251.35.110/scripts/trials/back-end-2/login.cfm Bookmark this page so you can find it easily the next time you need it.

2. Login to our account Username: Everyone Password: 338b 3. Click “Manage the UMMS CT Database” 4. Click “Submit a Trial” 5. Complete the Trial Submission Form (see “helpful hints” next page).

6. Click the “Preview” button to see the page as it will appear on the GCC Clinical Trials web site.

7. If you need to make corrections, click the “Close Window” button on the bottom of preview page to go back to the form.

8. If the page is okay and you do not need to make corrections, save it using the “Save” button on “File” menu bar then print a copy using the “Print” button on “File” menu bar. Then click the “Close Window”.

9. Then click the “Submit” button at the bottom of the preview page. (The information submitted to the database will be held in the database until the IRB/sponsor company has approved the trial. Then the trial will be posted on the web site.)

10. Then print and attach to your IRB protocol submission for approval.

(In addition, this web page should be approved by the sponsor (if industry-sponsored trial)

G:/protocol/CRC submission packet/07-webpageform/8/01/04

Clinical Investigator Handbook July 2010 Version - Page 54

Helpful hints for completing the clinical trials submission form:

Please make sure to follow these editorial guidelines when posting new trials and making edits to existing trials: •

Study Number – Always begin with the trial letters designation followed by one space and the study number. i.e. “GCC 0098”, “CALGB 10102”, “RTOG P-0126”, “ECOG 2100”.

Doing this keeps the trial listings in their correct alpha-numeric order on the public website.

•

Official Title – Use title case but no all-caps. Do not include the trial number in the title.

•

Investigator – Choose the primary investigator from the drop down list. If the investigator is not present in the drop down list, contact the protocol office to request inclusion of that investigator into the database.

•

Summary – Paragraph format. No line-breaks.

•

Disease Site – Choose the disease site from the drop-down list.

•

Disease Stage – Phrase Format.

•

Condition – Sentence Format.

•

Intervention – Phrase Format.

•

Phase – Roman numerals Format, i. e. “IV”

•

Inclusion Criteria – List format. The “HTML” tag <li> must be placed before each criterion. Refer to the existing trials for reference.

•

Exclusion Criteria – Same as “Inclusion Criteria”.

PLEASE TAKE NOTE:

ALL INFORMATIONS IN THIS WEB PAGE SHOULD BE IN LAY TERMS

G:/protocol/CRC submission packet/07-webpageform/8/01/04

Clinical Investigator Handbook July 2010 Version - Page 55

Health Insurance Portability and Accountability Act (HIPAA) AUTHORIZATION TO OBTAIN, USE AND DISCLOSE PROTECTED HEALTH INFORMATION FOR RESEARCH Name of Study Volunteer: _________________________________________________________ Date of Birth: ______________

Medical Record Number: ___________________

NAME OF THIS RESEARCH STUDY:

<Title>

UMB IRB APPROVAL NUMBER:

<IRB number>

RESEARCHER’S NAME:

<PI name>

RESEARCHER’S CONTACT INFORMATION: University of Maryland Marlene and Stewart Greenebaum Cancer Center 22 South Greene Street Baltimore, Maryland 21201 This research study will use health information that identifies you. If you agree to participate, this researcher will use just the health information listed below.

THE SPECIFIC HEALTH INFORMATION TO BE USED OR SHARED: • Health-related information you have been asked to provide for the study during interviews, via questionnaires, from diaries • Lab test results, reports of x-rays (and/or films), diagnostic tests, consultations, surgical and pathology reports, clinic notes, office notes, hospital admission/discharge summaries, reports of research related procedures, and pharmacy records that are pertinent to your illness and for research purposes.

• Billing and payment information and the medical information required to justify it.

Federal laws require this researcher to protect the privacy of this health information. He/she will share it only with the people and groups described here.

PEOPLE AND ORGANIZATIONS WHO WILL USE OR SHARE THIS INFORMATION: • Dr. < PI name > and his/her research team.

• The sponsor of the study, or its agents, such as data repositories or contract research organizations • <_________>, manufacturer of the drug <drug name> • Representatives of University of Maryland Baltimore IRB-Institutional Review Board, ORS-Office of Research Subjects, OHRP-Office of Human Research Protections, University of Maryland Baltimore/VAMHCS Research Compliance Offices, UMMS/UPI/VAMHCS Legal Counsel, FDA-Food and Drug Administration, NIH, National Institute of Health (NCI-National Cancer Institute), DHHSDepartment of Health and Human Services, DSS-Department of Social Services, and other state and federal agencies as required by law.

• The Data Safety Monitoring Committee that will monitor the study for safety. This is the committee that makes sure the study is being done properly and makes sure it is safe to keep doing the study.

• Organizations that will coordinate health care billing or compliance such as offices within UMSOM; the University of Maryland, Baltimore (UMB); University Physicians, Inc. (UPI) and the faculty practices of the UMB; University of Maryland Medical System (UMMS) and the Veterans Affairs Maryland Health Care System (VAMHCS).

• You health insurer or payor to pay for covered treatments THIS AUTHORIZATION WILL NOT EXPIRE. BUT YOU CAN REVOKE IT AT ANY TIME. One copy of this document, signed and dated, must be given to the research subject Clinical Investigator Handbook July 2010 Version - Page 56

Revised: October 19, 2007 Page 1 of 2

To revoke this Authorization, send a letter to this researcher stating your decision. He/she will stop collecting health information about you. This researcher might not allow you to continue in this study. He/she can use or share health information already gathered. The data will be destroyed at the time indicated below: • •

The data will be destroyed at the end of the time period required by the FDA for storing clinical trials records.

NOTE THAT THE VA REQUIRES A STATEMENT THAT RECORDS MAY BE STORED INDEFINITELY

[SPECIFY A DIFFERENT TIME AS NEEDED] ADDITIONAL INFORMATION: •

• • •

You can refuse to sign this form. If you do not sign it, you cannot participate in this study. This will not affect the care you receive at: o University Physicians, Inc. (UPI) o University of Maryland Medical System (UMMS) o Veteran Affairs Maryland Health Care System (VAMHCS) It will not cause any loss of benefits to which you are otherwise entitled.

Sometimes, government agencies such as the Food and Drug Administration or the Department of Social Services request copies of health information. The law may require this researcher, the UMSOM, UPI, UMMS or VAMHCS to give it to them.

This researcher will take reasonable steps to protect your health information. However, federal protection laws may not apply to people or groups outside the UMSOM, UPI, UMMS or VAMHCS. Except for certain special cases, you have the right to a copy of your health information created during this research study. You may have to wait until the study ends. Ask this researcher how to get a copy of this information from him/her.

My signature indicates that I authorize the use and sharing of my protected health information for the purposes described above. I also permit my doctors and other health care providers to share my protected health information with this researcher for the purposes described above.

Signature: ___________________________________________ Date: _______________________ Name (printed) ______________________________________ Privacy Questions? Call the UMSOM Privacy Official (410-706-0337) with questions about your rights and protections under privacy rules.

Other Questions? Call the researcher named on this form with any other questions.

One copy of this document, signed and dated, must be given to the research subject Clinical Investigator Handbook July 2010 Version - Page 57

Revised: October 19, 2007 Page 2 of 2

Short Title: Ph 2 of SCH 727965 in Relapsed and Refractory AMLStatus: New

Study No.: 0844GCC

Treatment (ALL pts)

Adverse Events Blood Chemistries CBC w/diff and platelets, Comprehensive chemistry panel Bone Marrow [3; 4] Concomitant Medications Correlative studies (non PK, PD) [6] EKG Medical History PKs [5] Performance status [1] Physical Exam Pregnancy Test [1] Questionnaires Treatment Administration SCH 727965 Treatment Administration Mylotarg Urinalysis Vital Signs BSA calculation, Diastolic BP (mmHG), Pulse (/min), Respiration Rate (/min), Systolic BP (mmHG), Temperature (C) [2]

Pre TTreatment 6 Cycles @21Days C1D1 C1D2 C1D8 C1D15 C1D21 C2D1 C2D2 R R R R R R R

C C

C

C

C

C

C

C

C

C

C2D8 C2D15 C2D21 R R R

C

C

C C

C

C

C

C3D1 C4D1 R R

C

C

C C

C

C

C

C

C4D21 C5D1 R R

C

C6D1 R

C

C C

C

C

C

C6D21 End ofOff Study R

C

C

C C

C R

C

C

C

R C C

C C R

C R

R

R

R

R

R

C C

C C

C C

C C

C C

C C

R

R

R

R

R

R

R

R

R

R

R

R

C

C C

C

R

R

C C R

R

R

R

R

R

R

R

Calendar Foot Notes 1. Also at progression before crossover if applicable.

2. Height and weight for BSA only needed at certain visits. View protocol for details.

3. Pts have bone marrow q6wks from c3 on. For GO pts, q3mo is std of care interval so every other bone marrow is research for those pts.

4. A portion of bone marrow samples collected at screening, c1d21, and c2d21 are sent for pharmacogenomics if pt signs optional consent.

5. SCH 727965 patients only 6. See protocol for timepoints. Certain timepoints only if patient has consented to pharmacogenomic substudy. If no consent for PG, then only SCH 727965 patients.

Clinical Investigator Handbook July 2010 Version - Page 58

R

R

UM/SOM/CCT PRELIMINARY MEDICARE COVERAGE ANALYSIS/QUALIFYING CLINICAL TRIAL (Only for use with non-phase I trials) CCT#: 0292-08 Principal Investigator Name: Edelman, Martin Sponsor: Bristol Myers Squibb Study Title: A Randomized Phase 2 Study of Ixabepilone Plus Carboplatin and Paclitaxel Plus Carboplatin in Subjects With Advanced Non-Small Cell Lung Cancer

Medicare NCD 310.1 defines a qualifying trial as one that meets all 3 criteria in PART I and at least one of the criteria outlined in PART II. If a study does not meet the criteria for a qualifying trial, then none of the routine costs (conventional care) can be billed to Medicare.

If the trial is a qualifying trial the investigator must be able to provide objective sources such as peer-reviewed literature or medical practice guidelines that support the designation of all conventional care performed in the study that is to be billed to Medicare.

However, Medicare in this region currently will not reimburse for phase I studies.

Please complete the questions below to determine if this study is a qualifying trial as defined by Medicare.

PART I---REQUIREMENTS FOR MEDICARE COVERAGE OF ROUTINE COSTS Question Yes No Must List Supporting Information 1.Does the investigational item/service fall within a Medicare benefit category?

2. Does the trial have therapeutic intent? Specify and cite supporting page(s) in protocol

3. Does the trial enroll patients with diagnosed disease? If yes, specify

PART IIâ&#x20AC;&#x201D;DETERMINATION OF DEEMED TRIAL Question 1. Is the study funded by NIH, DCD, AHRQ, CMS, DOD, or VA? 2. Is the study funded by a cooperative group that receives funding by NIH, DCD, AHRQ, CMS, DOD, or VA? 3. Is the study conducted under an investigational new drug application (IND)? If yes, list IND# 4. Is the study exempt from an IND under 21 CFR 312.2(b)(1)?

Yes

No

If Yes, Specify

Part IIIâ&#x20AC;&#x201D;Medicare Certification by Principal Investigator (for non phase I studies) I certify that this clinical trial meets the above Medicare criteria for qualifying trials.

I certify that this clinical trial does not meet the above Medicare criteria for qualifying trials.

Principal Investigator Signature Version #6 10/29/08

Principal Investigator Printed Name Page 1 of 1

Clinical Investigator Handbook July 2010 Version - Page 59

Date

DATE:

September 8, 2009

TO:

Edward A. Sausville, M.D., Ph.D. Principal Investigator

FROM:

H. Richard Alexander, M.D. Chair, Clinical Research Committee

SUBJECT:

0936GCC: A Phase 1/2 Study of SCH 727965 in Patients with Malignant Melanoma

The Clinical Research Committee is charged with the task of reviewing all cancer-related protocols for scientific merit, ethical appropriateness, statistical feasibility as well as financial impact on the Cancer Center. The above-mentioned protocol, of which you are the principal investigator, was discussed at the most recent meeting of the CRC. This protocol was approved with minor modifications.

Please submit all relevant documents (those not included in CICERO) on a disk or in an electronic form to cvillena@umm.edu.

The following issues need to be addressed: 1. Please comment on who will determine that a patient with stage III disease is unresectable.

2. Please comment on prioritization if patients are eligible for both 0794GCC and this study.

3. In the risk section of the consent, please better explain inadequate blood supply to the intestines and redness. Please also change decreased weight to weight loss. Please determine whether the risks of secondary cancers and infertility should be added.

CRC CHAIRâ&#x20AC;&#x2122;S SUMMARY OF PROTOCOL Adequate (may need minor revisions) Appropriate prioritization within research group Biostatistical input & review Scientific justification Study design appropriate Risks appropriate for nature of disease Standard of care maintained Potential of accruing at acceptable pace Consent form CICERO protocol information Data and safety monitoring plan described

X X X X X X X X X X

Clinical Investigator Handbook July 2010 Version - Page 60

Not Adequate

DSM level recommended by the CRC: Routine

___ High

____ Highest

____ Special

H. Richard Alexander, M.D. Chair, Clinical Research Committee cc:

Edward A. Sausville, M.D., Ph.D. Mary Quinn, R.N. Charit Villena

Clinical Investigator Handbook July 2010 Version - Page 61

_X_ External

Date

DATE:

September 8, 2009

TO:

Anil Dhople, M.D. Principal Investigator

FROM:

H. Richard Alexander, M.D. Chair, Clinical Research Committee

SUBJECT:

0618RTOG: A Phase II Trial of Stereotactic Body Radiation Therapy (SBRT) in the Treatment of Patients with Operable Stage I/II Non-Small Cell Lung Cancer

By NCI guidelines, the Clinical Research Committee is charged with the task of reviewing all cancer-related protocols for adequacy of accrual. The above-mentioned protocol, of which you are the principal investigator, was discussed at the most recent meeting of the CRC. This protocol has accrued no patients since its inception and it was renewed by the IRB in August 2009. If no patients are accrued by the time of the next renewal, the CRC will require closure of this protocol absent exceptionally compelling circumstances.

H. Richard Alexander, M.D. Chair, Clinical Research Committee cc:

Edward A. Sausville, M.D., Ph.D. Mary Quinn, R.N. Charit Villena

Clinical Investigator Handbook July 2010 Version - Page 62

Date

UNIVERSITY OF MARYLAND

CLINICAL RESEARCH COMMITTEE Protocol Review Worksheet Reviewer's Name:

Date:

Protocol Title & Number:

PI: Co-PI:

Co-PI: Statistician for In-House Studies: Phase:

I

Anticipated Accrual:

II

HI

Other

Rate of Accrual:

Rationale: Has sufficient scientific rationale been provided?

Yes

No

Has the hypothesis been clearly stated and justified?

Yes

No

Is the protocol clear with respect to study group and treatment protocol?

Yes

No

Are the objectives stated clearly?

Yes

No

Is the treatment plan feasible?

Yes

No

Given the study background and proposed plan, is the study ethical for conduct?

Yes

No

Is there "prioritization" among competing trials?

Yes

No

Are the eligibility criterion clear and objective?

Yes

No

Have appropriate measures been applied to answer the protocol objective?

Yes

No

Is there evidence of biostatistical input into the study design?

Yes

No

Is there a data and safety monitoring plan described?

Yes

No

Yes

No

Study Design:

Biostatistics:

Scientific Basis: Has relative importance and value of trial been presented taking into consideration "standard" therapy and competing trials?

Financial impact/additional tests/procedures

Other Comments:

Action:

___ Approve ___ Request major modifications Investigator Handbook July 2010 Version - Page Disapprove 63 ___ Approve with Clinical minor modifications ___

N/A

N/A

DSM/QAC Data and Safety Monitoring/Quality Assurance

Clinical Investigator Handbook July 2010 Version - Page 64

University of Maryland Greenebaum Cancer Center

Subject: Data & Safety Monitoring Plan

Effective: July 2010

Procedure No: DSM001

Function: Data & Safety Monitoring

UMGCC governs clinical research through a parent Clinical Research Oversight Committee (CROC), which oversees the function of the Clinical Research Shared Service, and two independent committees: the Data & Safety Monitoring/Quality Assurance Committee (DSM/QAC) and the Clinical Research Committee (CRC).

These committees coordinate to 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 will ensure patient and research subject safety and integrity of research in clinical trials conducted by the University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCC). It is the responsibility of the DSM/QAC to review ongoing clinical studies for patient safety and quality control.

The DSM/QAC has the authority to request modifications of the protocol and consent forms to incorporate safety information, to suspend trials pending investigation of toxicity and corrective action of protocol conduct which has led to deviations and exceptions 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 Clinical Research Committee 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 The DSM/QAC will provide ongoing safety review for UMGCC protocols which lack their own existing DSMB. These protocols include: â&#x20AC;˘ Investigator-initiated protocols except those for which the IRB has granted a waiver of consent (e.g., retrospective chart reviews)

p1 Clinical Investigator Handbook July 2010 Version - Page 65

•

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 semi-annually if there is a specific reason and 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 a monthly basis external SAE 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 UMB IRB criteria for immediate submission, the DSM/QAC will serve as the reviewing entity of record after receipt 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 the results of internal Monitoring of Investigator Initiated Therapeutic Trials D. Review the results of University of Maryland HRPO audits of UMGCC clinical trials.

DSM/QAC functions are in addition to, not in place of, the IRB, FDA or other sponsor reporting/monitoring that may be required within certain timetables.

II. Definitions and Scope of Responsibilities A. 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 Program and Institutional Review Board Policies and Procedures Manual. This manual may be accessed at https://medschool.umaryland.edu/hrpo

p2 Clinical Investigator Handbook July 2010 Version - Page 66

B. Definition of an Investigator-Initiated Clinical Trial An investigator-initiated (sometimes referred to as institutional) clinical trial is defined for the purposes of these guidelines as a clinical research study authored by a member of the UMGCC faculty or staff. Such studies are not primarily sponsored or subject to scientific review or monitoring by an outside agency (e.g., industry, cooperative group, NCI, NIH, FDA, or other institution). 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. Although an investigator may obtain investigational drugs and/or funding from an outside agency or industry in support of the research, if the clinical trial is not subject to monitoring by that agency it is categorized as an investigator-initiated clinical trial and internally monitored by the DSM/QAC. Those investigator-initiated clinical trials that are peer-reviewed by the NCI, but are not subject to on-site monitoring by the NCI via contract organizations (clinical trials that obtain investigational drugs from NCI) are also internally monitored through this mechanism.

C. Monitoring Monitoring involves UMGCC Clinical Research Management Office staff or external sponsors scrutinizing the actions of UMGCC investigators without a requirement that the monitor be independent of the study team or sponsor. Monitoring activities at minimum include verifying that research documents (e.g. informed consent, eligibility checklist, case report forms), and the regulatory binder are complete and current, in order that a detailed audit may be conducted. The scope of monitoring activities may be expanded to include examination by Clinical Research Shared Service staff of case report forms and comparison of case report forms with source documentation for Investigator Initiated therapeutic clinical trials at the request of the DSM/QAC or IRB; as indicated by a prior or current record of deficiencies; as a precautionary measure in the case of exceptionally complex studies.

D. Audit Audit activities by definition involve staff external to UMGCC. UMGCC trials may be audited by various external agencies including the UMB IRB, NCI or its contractors, or the FDA. Audit activities will 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.

E. Principal Investigator (PI)

p3 Clinical Investigator Handbook July 2010 Version - Page 67

The PI is responsible for collecting and reporting adverse events on his/her clinical trials in a timely fashion to the UMB IRB, UMGCC DSM/QAC, FDA, trial sponsors, external IRBs for multi-institutional trials, as well as all other relevant committees and agencies. The PI is also responsible for proposing a DSM plan (Attachment 1) as part of the scientific review by the Clinical Research Committee and IRB submission packages for new trials.

F. Clinical Research Management Office (CRMO) The CRMO is the physical space housing staff of the Clinical Research Shared Service. It 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. Further, a senior CRMO staff member coordinates DSM/QAC activities and CRMO staff may be called upon by the DSM/QAC to assist in data collection and auditing.

G. Clinical Research Committee (CRC) The CRC is responsible for the scientific review of new protocols. Their review is conducted prior to IRB review and includes a consideration of the adequacy of the DSM plan proposed by the PI. The CRC may impose a stricter level of monitoring for â&#x20AC;&#x153;higher-riskâ&#x20AC;? studies (see Attachment 2). The Chair of the CRC will designate the appropriate level in the approval letter to the PI and CRC minutes, and will forward a copy of this designation to the coordinator of the DSM/QAC. 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 the continuing scientific value or importance of the research question of the protocol. The CRC may also be asked by the DSM/QAC or the IRB to review whether, in light of new information received during the prior review period, the protocol in question is still scientifically of high priority.

H. Clinical Research Oversight Committee (CROC) The CROC defines and adjusts physical and personnel resources of the CRSS. It also is responsible for setting policies and processes for clinical research at UMGCC. The CROC also has the authority to consider disciplinary sanctions against clinical investigators.

I. Data and Safety Monitoring / Quality Assurance Committee (DSM/QAC) The DSM/QAC will consist 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, Administration). DSM/QAC activities will be

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coordinated by a senior member of the UMGCC Clinical Research Management Office. The DSM/QAC will meet monthly and requires a quorum of three members.

Members may designate a proxy of comparable expertise to attend in their place. See appendices for membership.

J. University of Maryland School of Medicine Institutional Review Board (UMB or IRB) The IRB is an 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 in, or disapprove all research activities that fall within its jurisdiction as specified by both the federal regulations and local institutional policy. The IRB makes use of an electronic database system (CICERO) to receive communications regarding protocols under their jurisdiction. The DSM/QAC accepts the IRB definitions of what constitutes SAEs and AEs, currently located in the IRB policies found at http://medschool.umaryland.edu/orags/hrpo/policies.asp.

K. Human Research Protections Office (HRPO) The HRPO is the coordinating office for the UMB IRB. The HRPO will be responsible for providing periodic audits of designated trials.

II.

Monitoring and Auditing of UMGCC Clinical Trials A. Monitoring of UMGCC Clinical Trials Industry sponsored clinical trials that have their own independent monitoring services, and perform monitoring on a routinely scheduled basis, will not be subject to additional monitoring by the CRMO. Likewise, NCI-sponsored trials that have periodic computerized data submission and independent auditing groups (e.g., Cooperative Groups) will also not be routinely monitored. However, all therapeutic investigator-initiated trials will be subject to monitoring by the UMGCC. 1. Monitoring Procedures The manager of the CRSS and a designated senior member of the research team together will act as the Monitoring Team Coordinators and will be responsible for coordinating the monitoring of these trials. Designated members of the CRSS will function as monitors for these trials. The Coordinator of the DSM/QAC will be provided with the dates the trials will be monitored. Therapeutic Investigator Initiated trials which do not have external monitoring will be monitored on an at least an annual basis.

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2. Notification The Principal Investigator and Study Coordinators are notified in advance of a scheduled monitoring session in which subjects have been randomly selected for review by the Monitoring Team Coordinators. The Monitoring Team Coordinator contacts the study team to arrange for a mutually agreed upon time for the monitoring 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, materials needed for the review from the outside centers must be provided to the Monitoring Team.

Specific information requested for the monitoring session includes: • • • • •

Regulatory Folder, to include copy of most current protocol, amendments, Investigator Brochure, availability of form 1572 Accrual listings from Oncore/Research Database Hospital medical record Patient-specific research record, which would include at a minimum the eligibility checklist, data collection forms, copies of serious adverse event reports Access to the Investigational Drug Pharmacy to ensure the presence of drug accountability forms specific to the clinical trial

3. Monitoring Session Implementation The monitoring team will perform quality assurance review on the requested records to ensure compliance for an audit by the HRPO. The monitoring team will complete the checklist (Form Attachment 5), and the findings will be presented at the next DSM/QAC monthly meeting. A letter will be sent from the DSM/QAC to the Principal Investigator summarizing the findings and any recommendations. Any queries to the PI will need to be addressed by the next meeting of the DSM/QAC. Accrual findings will be presented to the CRC. B.

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. However, a significant number of in-house trials, e.g. Investigator-Initiated, Phase I, or Phase II, do not have external auditors. In order to assure the proper conduct of the clinical trials under the purview of the DSM/QAC, the UMGCC will submit to periodic audits by the IRB/HRPO. In any given year, the HRPO/IRB will audit the patients accrued during the preceding calendar year on 100% of investigator-initiated 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 p6 Clinical Investigator Handbook July 2010 Version - Page 70

studies without external data safety monitoring, NCI Phase 1 studies and corporate/industry trials without external data safety monitoring. Members of the DSM/QAC will review the results of the audits.

Standard auditing tools will be used. Specific issues to be examined include: • • • • • • • • • • •

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 Demonstration of an adequate consent form process Properly dated consent form Properly executed consent form, with the appropriate signatures No protocol related treatment starting before the date of consent PI’s attestation document stating that the informed consent has been properly delivered 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.

To ensure independence of review, the HRPO/IRB will typically select the trials and charts to be audited, but the DSM/QAC may select up to 10% of the auditing capacity based on the results of its annual and semi-annual reviews. HRPO audit reports will be sent to the DSM/QAC and the HRPO Director of Quality Improvement. If required, audit results will be reported to a fully convened UMB IRB panel. The DSM/QAC has the authority to suspend and recommend to the CRC closure of trials in which adherence to good clinical research practices are lacking. The IRB, if not already so informed, and affiliated sites will be notified of all audit results. PI’s at affiliated sites will be notified of audit results as well. The HRPO/IRB will have the discretion to adjust the selection percentages based on accrual or return to studies that have closed to accrual. The HRPO/IRB and/or the DSM/QAC may also audit additional charts/trials pending results of these audits or issues that may arise in relation to a particular trial or investigator.

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III. Procedures A. Types of Reviews and Assignment of Risk Annual Review (Routine and High Risk) Phase II and III therapeutic studies shall be designated as at least high risk by the Clinical Research Committee (CRC) (Form Attachments 1 and 2). Chart reviews and other non-therapeutic studies are typically designated by the CRC as routine risk, but may be assigned a higher risk category based on the complexity of the study. Studies designated by the CRC as routine and high risk will be reviewed annually. The DSM/QAC will also have the discretion to review on only an annual basis highest risk studies where the sponsor monitors appropriately and conducts cohort reviews but lacks an independent DSM. More detail on the process is provided in III.B. below.

Semi-Annual Review (Highest Risk) All Phase I therapeutic trials and at the determination of the CRC investigatorinitiated Phase II/III therapeutic studies are designated as highest risk. Studies designated by the Clinical Research Committee (CRC) as highest risk will be reviewed annually for subject accrual by the CRC and by the DSM/QAC for conduct of trial and semi-annually for safety. More detail on the process is provided in III.B. below.

Phase 1/Cohort Review A member of the DSM/QAC will act as a protocol monitor to review the toxicity experience in all treated patients prior to escalating into the next cohort. It is understood that in some cases with accelerated dose escalation designs, the cohort may be composed of a single patient. Since the DSM/QAC meets monthly, to avoid delay in the study the review of the previous cohort can be done by a member of the DSM/QAC prior to the scheduled meeting with reporting to the full DSM/QAC on these activities. Documentation of this cohort review will be 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. This cohort escalation review is in addition to the review process described in detail below.

Ad Hoc Review of SAEs and DSM reports The DSM/QAC will review in real time external SAE and DSM reports submitted to UMGCC investigators by trial sponsors for all protocols, including reports from independent Data and Safety Monitoring Boards for external randomized Phase III trials. More detail is provided in Section III.C. below.

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B. Annual and Semi-Annual Review Procedures To insure that DSM/QAC and IRB oversight of protocols is optimally coordinated, DSM/QAC annual review will be timed for completion prior to the IRB anniversary date. For those studies requiring DSM/QAC review, UMGCC clinical investigators will compile the IRB annual renewal submissions 90 days before IRB annual review in the IRB’s software system. The DSM/QAC will assign 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 will provide feedback and requests for clarification to the PI no later than 45 days prior to IRB annual review. The PI will complete response to DSM/QAC inquiries no later than 30 days prior to IRB annual review, and the DSM/QAC will review at the meeting approximately 30 days prior to the IRB anniversary date.

90 days

60 days

45 days

30 days

PI prepares annual submission

DSM/QAC reviews

DSM/QAC comments received by PI

DSM/QAC reviews revised PI submission

IRB annual review

Fig. DSM1 Timeline for DSM/QAC annual review process

Semi-annual reviews will be conducted on the same timeline to coincide with the IRB annual review date and also six months from same. PIs are expected to attend DSM/QAC meetings where their protocols will be discussed.

The below items will be considered in DSM/QAC annual review and appropriate recommendations made. The semi-annual review will include only those items below related to safety.

•

• •

All adverse events, internal and external, including those that have previously been reported to the DSM/QAC. The DSM/QAC will have a full report on all SAE’s 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 whether it needs modification based on the accumulated AEs and SAEs. The DSM/QAC may require amendment of consent forms to reflect new or continuing information.

The protocol regulatory binder maintained by the CRMO for any relevant items that may not be available electronically. The DSM/QAC may

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•

•

recommend to the CRC to close studies when the PI or research team show a pattern of persistent non-compliance with Good Clinical Practices policies.

If available, interim outcomes and other results will be assessed to see if response rates conform to estimates used to develop the statistical analysis.

The DSM/QAC may close studies early 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 to the CRC to close 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 will make one of four possible final decisions regarding the disposition of the protocol: • • • •

Award final DSM/QAC approval to the protocol Find that minor revisions are still needed for final DSMB approval Find that major corrections are still needed to the protocol Recommend to the CRC to close the protocol for uncorrectable deficiencies

Additionally, the DSM/QAC may refer for scientific re-review by the CRC those protocols in which new information may have called into question the original hypothesis underlying a particular study.

DSM/QAC actions will be 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 voting on such studies. DSM/QAC review information will be added to the IRB’s electronic database record, and the IRB will only conduct annual review for those protocols that have completed or are undergoing DSM/QAC review.

The record of DSM/QAC actions for a particular UMGCC protocol will consist of: • Chair notes documenting initial DSM/QAC review, discussions, decision of the DSM/QAC, and specific corrective actions requested from the PI • DSM/QAC correspondence with the PI • PI responses to DSM/QAC inquiries • Subsequent DSM/QAC review including final decision by the DSM/QAC Chair notes will consist of findings of the DSM/QAC reviewer, decisions by the DSM/QAC and specific issues requiring remediation. The PI will be sent a letter specifying the actions to be taken and the acceptable turnaround time for response. PI responses will be reviewed at the next DSM/QAC meeting. The PI will then be provided with a final DSM/QAC review. Records of these reviews will be made available to the IRB. (See Form Attachments 3-4) p10 Clinical Investigator Handbook July 2010 Version - Page 74

C. Ad Hoc Reviews of SAEs and DSM reports The DSM/QAC will review in real time external SAE and DSM reports submitted to UMGCC investigators by trial sponsors, including reports from independent Data Safety Monitoring Boards for external randomized Phase III trials. This does not supplant the PIs responsibility to report directly to the IRB in established timelines all internal SAEs and those external SAEs that present serious risk of harm to patients.

External SAEs will be captured in the Oncore® database maintained by the CRMO as per Figure DSM2. Designated DSM/QAC members will review these reports no less than every four weeks and review the following determinations: • • • •

Related or unrelated to the study therapy Seriousness Expected or unexpected Requires IRB submission immediately or with annual report External SAE received

5

3

business days

business days

Event, attribution, grade, other relevant info entered into Oncore by coordinator/data manager Event # assigned

PI determines if IRB reportable

PI reports to IRB expeditiously

DSM reviews to insure not IRB reportable

SAE incl. in IRB annual renewal Fig DSM2. Flowchart for review of external SAEs

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All of these decisions will be captured in the database record for the protocol, along with relevant reporting dates. For those external SAEs which do not meet UMB IRB criteria for immediate submission, the DSM/QAC will serve as the reviewing entity of record after receipt from the sponsoring organization. Summaries of these SAE reviews will be presented at the next DSM/QAC meeting.

The CRMO research database has the capability to send out email alerts if the number/severity/expectedness of SAEs in a certain time period reaches a specified level which may be indicative of a troubling pattern of SAEs. When the DSM/QAC members receive such an alert, they will review the protocol on an ad hoc basis to determine if further action is needed.

IV. DSM/QAC Meetings DSM/QAC agendas for the monthly meetings will be maintained by the DSM/QAC coordinator. This individual will maintain, 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. Protocols will remain subject to their DSM plan until all enrolled patients are beyond the time period when study-related adverse events would likely be seen. Under some circumstances, the DSM/QAC may still review protocols for certain IRB, GCP, and data integrity issues. The coordinator will make sure that all protocols from each of the above categories are added to DSM/QAC agendas at the appropriate time points. The coordinator will also schedule follow-up discussion of PI responses to protocols reviewed at prior meetings. The coordinator will also print for review at each meeting the summary reports of the external SAEs that have been assessed in the intervals between meetings.

Minutes of the DSM/QAC meetings will consist 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 (see Attachments 3 and 4).

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 will promptly notify the IRB of this decision. The DSM/QAC will require that 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 will provide 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

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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. Types of Trials and Adverse Event Reporting The requirements for adverse event reporting for clinical trials are complex.

DSM/QAC review of protocols will include checking whether AE and SAE reports have been properly reported to the sponsor, the IRB, the FDA if applicable, coinvestigators at participating institutions, and any applicable government agencies.

The CRMO research database has specific capacity to record the reporting dates of adverse events for tracking purposes (Fig. DSM3). Research staff for protocols will be expected to avail themselves of this capacity unless they can provide alternate adequate documentation of adverse event reporting, as perhaps in the case of multiinstitutional studies that may have other established systems. If the trial involves federal or other grant funding, the PI will be responsible for summarizing adverse events in grant progress reports as per the requirements of the funding agency. More specific guidelines for the various types of trials expected to be undertaken at UMGCC are described below.

Fig DSM3. CRMO research database has the ability to record notification dates of SAEs to appropriate agencies.

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 are failing to follow adverse event reporting guidelines for the trial.

Investigators or research staff who have a consistent history of problems with meeting reporting guidelines will be referred to the CROC for potential disciplinary action.

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A. Phase I Trials (Highest Risk) UMGCC conducts Phase I trials both with NCI-sponsored and industry-sponsored agents.

As described above, UMGCC regards these Phase I trials as highest risk studies, so in addition to NCI- or sponsor-mandated reporting and review, UMGCC also requires local continuous monitoring of patient safety.

All NCI Phase I studies go through detailed audits by NCIâ&#x20AC;&#x2122;s clinical trials monitoring system using private contractors. Data are submitted to the appropriate NCI clinical trials monitoring system using standardized forms. It is an NCI requirement that any serious, unexpected adverse event possibly related to the study drug be reported immediately via an adverse event expedited reporting system. Details of this process are available at http://ctep.info.nih.gov.

Industry-sponsored studies in most cases have external safety monitoring boards.

Where this is not the case, the investigator can request that the DSM/QAC serve as the safety monitoring committee of record provided that the sponsor agrees to make the group aware of external site SAEs. Irrespective of sponsor, for all agents UMGCC adopts NCIâ&#x20AC;&#x2122;s guidelines for determining reporting requirements to the IRB (see table below). UMGCC will also report to NCI or other sponsor as per their specific requirements.

Phase 1 Trials Grade 1

Grade 2

Grade 2

Grade 3 Grade 3 Unexpected Expected Unexpected Unexwith without with without and pected Expected Hospitali- Hospitali- Hospitali- HospitaliExpected zation zation zation zation 10 10 Unrelated Not Not Not Not Not Calendar Calendar Unlikely Required Required Required Required Required Days Days Possible 10 24-Hour; 24-Hour; 10 Not Not Not Probable 5 Calendar 5 Calendar Calendar Calendar Required Required Required Definite Days Days Days Days

Grades 2 4&5 Unexpected and Expected 24-Hour; 5 Calendar Days 24-Hour; 5 Calendar Days

All deaths on study require both routine and expedited reporting regardless of causality.

Attribution to treatment or other cause must be provided.

Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or prolongation of existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with the exception of any events identified as protocol-specific expedited adverse event reporting exclusions.

Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects must be reported Adverse events of Grade 3 with hospitalization or prolongation of hospitalization, Grade 4 unexpected or any Grade 5 with attribution of possible, probable or definite that occur greater than 30 days after the last dose of treatment must also be reported.

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B. Phase II Trials â&#x20AC;&#x201C; UMGCC Phase II trials constitute the most common investigator-initiated trials at the UMGCC. In addition, UMGCC investigators participate in industry or NCI sponsored Phase II studies, in some cases as a lead Institution, and in other cases as a partner with Institutions holding a NCI-funded Phase II contract. Both investigator initiated and NCI-sponsored Phase II trials will be subject to at least annual review by the DSM/QAC. Industry-sponsored Phase II trials lacking an independent DSM will also be reviewed by the DSM/QAC. In-house Phase II trials will receive the level of oversight appropriate to the risk involved in the trial (i.e., high, highest, etc.) as assigned by the CRC. Irrespective of sponsor, for all agents UMGCC adopts NCIâ&#x20AC;&#x2122;s guidelines for determining reporting requirements to the IRB (see table below). UMGCC will also report to NCI or other sponsor as per their specific requirements.

Phase 2 and 3 Trials Grade 1

Grade 2

Grade 2

Grade 3 Grade 3 Unexpected Expected Unexpected Unexwith without with without and pected Expected Hospitali- Hospitali- Hospitali- HospitaliExpected zation zation zation zation 10 10 Unrelated Not Not Not Not Not Calendar Calendar Unlikely Required Required Required Required Required Days Days Possible 10 10 10 10 Not Not Not Calendar Calendar Calendar Calendar Probable Required Required Required Definite Days Days Days Days

Grades 2 4&5

Grades 2 4&5

Unexpected

Expected

10 Calendar Days 24-Hour; 5 Calendar Days

10 Calendar Days 10 Calendar Days

All deaths on study require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause must be provided.

Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or prolongation of existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with the exception of any events identified as protocol-specific expedited adverse event reporting exclusions.

Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects must be reported Adverse events of Grade 3 with hospitalization or prolongation of hospitalization, Grade 4 unexpected or any Grade 5 with attribution of possible, probable or definite that occur greater than 30 days after the last dose of treatment must also be reported.

C. Phase III Trials Large randomized Phase III trials are the least common clinical trials at the UMGCC. Most of our Phase III efforts involve participation in multi-center trials, either pharmaceutical-sponsored or cooperative group-sponsored. These sponsored studies must have an independent DSM plan in place before the CRC will approve it. Should

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UMGCC investigators participate in multi-site, non-sponsored trials coordinated by an outside institution, it will be the responsibility of the outside institution to provide a DSM plan and monitoring board, if appropriate. If the UMGCC is the coordinating center of a Phase III study, the DSM plan will require a Data and Safety Monitoring Board (DSMB) with appropriate qualifications. In accordance with published guidelines, the DSMB will be composed of at least three clinicians and a clinical biostatistician with relevant expertise. The DSMB will be appointed by the DSM/QAC. No member of the DSMB will be associated with the trial.

All blinded trials will require a randomization schema and specific criteria for unmasking any blinding. The individual protocol must specify the frequency of the DSMB meeting, list the data elements to be provided to the DSMB and list prospective members of the independent DSMB, along with their affiliations with any commercial interests which might constitute a conflict of interest.

Irrespective of sponsor, adverse event reporting to the IRB will follow the guidelines above for Phase II and III trials. UMGCC will also report to NCI or other sponsor as per their specific requirements. The DSM/QAC will review external SAE reports forwarded by the central IRB, NCI, other participating institutions, and study sponsor (if any) to the UMGCC PI. SAE’s impacting UMGCC participation will be forwarded to the UMB IRB. D. NCI-Sponsored Cooperative Group Studies (External) The UMGCC is a member of the Cancer and Leukemia Group B (CALGB), Gynecologic Oncology Group (GOG), Radiation Therapy Oncology Group (RTOG), Children’s Oncology Group (COG) and American College of Surgeons Oncology Group (ACOSOG). It may participate in occasional studies from other cooperative groups. Each of these groups develops peer-reviewed Phase I, II, or III trials, which include detailed DSM plans. Data management is handled through the standardized reporting forms and reported centrally. Adverse event reporting is handled as per the specific instructions from the cooperative group.

E. Multi-Institutional Cooperative Trials Multi-institutional trials may or may not have industry sponsors. These trials, whether coordinated at UMGCC or at another affiliated research sites, will receive the level of oversight appropriate to the risk involved in the trial (i.e., routine, high, highest, etc.).

NCI has specific guidelines for the conduct of multi-institutional trials using NCIsponsored agents. UMGCC will follow these guidelines for multi-institutional trials sponsored by NCI or sponsored by any other entity which does not provide acceptable alternate coordination guidelines.

•

The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and for monitoring its progress. All reporting requirements are the responsibility of the Protocol Chair.

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• •

•

•

The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety of the patients.

Where UMGCC is the Coordinating Center, it will maintain documentation of AE reports. There are two options for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the Coordinating Center (this option only available for NCI-sponsored trials), or (2) participating institutions report to UMGCC who in turn reports to the sponsor.

The CRMO research database will be used to collect all AEs for the protocol.

Audits may be accomplished in one of two ways: (1) source documents and research records for selected patients are brought from participating sites to the Coordinating Center for audit, or (2) selected patient records may be audited on-site at participating sites. If the NCI or another sponsor chooses to have an audit at the Coordinating Center, then the Coordinating Center is responsible for having all source documents, research records, all IRB approval documents, NCI Drug Accountability Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the audit.

The protocol will include the following minimum information: ¾ The title page must include the name and address of each participating institution and the name, telephone number and e-mail address of the responsible investigator at each participating institution. ¾ UMGCC as the Coordinating Center must be designated on the title page. ¾ Central registration of patients is required. The CRMO research database is equipped to maintain these records. The procedures for registration will be stated in the protocol. ¾ Data collection forms will be of a common format. Sample forms should be submitted with the protocol. The frequency and timing of data submission forms to the Coordinating Center will be specified. ¾ Describe how AEs will be reported from the participating institutions ¾ Describe how Safety Reports and Action Letters from NCI CTEP or any other sponsor will be distributed to participating institutions.

F. 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) will be 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 will be reported to the NIH OBA as soon as possible, but not later than 7 calendar days after the initial

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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 life-threatening, will be 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).

VII. Conflict of Interest Policies The DSM/QAC will follow the conflict of interest policies set out by the UMSOM IRB, which has the responsibility for monitoring conflict of interest. These policies are completely described at http://medschool.umaryland.edu/orags/hrpo/policies.asp.

Briefly however, 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. An economic disclosure form is provided by the IRB for easy reporting. If a conflict of interest occurs after the research study has commenced, the investigator must promptly notify the IRB in writing. 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.

The IRB will determine whether the disclosed economic interest is likely to compromise or appear to compromise the design, conduct or reporting of the study.

Specifically, the IRB will consider the impact of the economic interest on: 1. Study design; 2. Protocol; 3. Informed consent form (particularly representations of risks and benefits); 4. Data collection and reporting; 5. Eligibility determinations and application of inclusion and exclusion criteria; 6. Continuing consent; 7. Protecting the privacy interests of participants and maintaining the confidentiality of identifiable data; 8. Clinical determinations (e.g., dose modifications, removing patients from study, related care); 9. Determination and reporting of adverse events and their relationship with study mechanism for data and safety monitoring; 10. Data made available on continuing review (integrity and sufficiency); 11. Consequences from conflict affecting clinician researcherâ&#x20AC;&#x2122;s clinical duties to participant as patient.

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After a thorough review has been conducted by the IRB and input has been provided by the COI Officer as applicable, the IRB may disapprove research that involves a conflict of interest or it may require changes at the Investigatorâ&#x20AC;&#x2122;s or sponsorâ&#x20AC;&#x2122;s expense to eliminate or manage the conflict. Required actions include, but are not limited to: 1. Requiring divestiture or termination of relevant economic interest; 2. Requiring Investigator recusal from a study; 3. Modification in participation in all, or a portion, of the research funded; 4. In case of equity, imposing a bar on insider trading, or requiring the transfer of securities to an independent financial manager or blind trust, or limiting the timing of sales or distributions; 5. Monitoring of research (i.e., independent review of data and other retrospective reviews for bias, objectivity, comprehensiveness of reporting versus withholding data); 6. Requiring independent clinical review of appropriateness of clinical care given to research participants; 7. Monitoring the consent process; 8. Requiring disclosure to institutional committees, research participants, journals, and data safety monitoring boards.

The DSM/QAC will follow any recommendations from the IRB with respect to conflict of interest and will reserve the right to impose even more stringent conflict management. It will assure that no reviews or audits are conducted by individuals with conflicts. The DSM/QAC will further assure 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.

p19 Clinical Investigator Handbook July 2010 Version - Page 83

Attachment 1

Form Attachment 1

CANCER CENTER DATA AND SAFETY MONITORING PLANS (This form completed by PI at time of submission to CRC. CRC will review and either accept PI designation or assign a different level of risk. Form then included in initial IRB submission.)

Title of Study: IRB#:

Level (check one): ___

Routine

All SAEs reported to the IRB, FDA (if appropriate affiliated research sites) in a timely fashion. Summary of SAEs submitted with annual report for review by DSM/QAC and IRB.

___

High

(Prospective review) All SAEs reported to the IRB, FDA (if appropriate affiliated research sites) and DSM/QAC in a timely fashion. Summary of SAEs is submitted with annual report for review by CRC and IRB. Requires annual review by DSM. Includes high-dose treatments or those expected to cause significant risk of complications whether due to study drug or not, e.g. BMT, acute leukemia.

___

Highest

Dose escalation studies â&#x20AC;&#x201C; Phase I All SAEs reported to the IRB, FDA (if appropriate affiliated research sites) and DSM/QAC in a timely fashion. Summary of SAEs submitted with annual report for review by the DSM/QAC and IRB. Expedited review by member of DSM/QAC before each new cohort. (This includes single- patient cohort, accelerated trial design.) Requires review of original patient records or case report forms.

___

Special

Institutionally developed, single-site or multi-site Phase III trials require a Data and Safety Monitoring Board (DSMB). See GCC DSM planning document for details.

___

External

External DSMB in place. All SAEs submitted to the IRB, FDA and sponsor.

Summary of SAEs submitted with annual report.

Signature of Principal Investigator:

p20 Forms subject to minor revision without need for re-review of DSM plan.

Clinical Investigator Handbook July 2010 Version - Page 84

Form Attachment 2

CRC CHAIRâ&#x20AC;&#x2122;S SUMMARY OF PROTOCOL (This form included in CRCâ&#x20AC;&#x2122;s initial review of protocol and communicates the designation of risk to the PI and the DSM/QAC).

Adequate (may need minor revisions)

Not Adequate

Special

External

Appropriate prioritization within research group

Biostatistical input & review

Scientific justification

Study design appropriate

Risks appropriate for nature of disease

Standard of care maintained

Potential of accruing at acceptable pace

Consent form

Data and safety monitoring plan described

DSM level recommended by the CRC: Routine

High

Highest

Chair, Clinical Research Committee

Date

p21 Forms subject to minor revision without need for re-review of DSM plan.

Clinical Investigator Handbook July 2010 Version - Page 85

Form Attachment 3 Annual Renewal

University of Maryland Greenebaum Cancer Center DSM/QAC

Date Form Completed:

Protocol:

Phase of Study: Principal Investigator: IRB #: Designated CRA or Research Coordinator: Statistican: Annual Reviewer: IRB: Initial IRB approval date: Date of last IRB renewal: Lapse in IRB renewal: Comments:

Ο YES

Ο NO

ACCRUAL: In Oncore Ο YES

Current accrual: as of: Targeted accrual: Projected duration of study: Date first subject enrolled: Date most recent subject enrolled: Number of subjects enrolled since last review: Total number still receiving therapy: Total in follow-up: Total withdrawn: Subject request: Comments:

Toxicity:

Ο NO

PI withdrawal:

For Treatment Studies: Record Best Response Complete Response:

Partial Response:

Stable Disease:

Progressive Disease: p22

Forms subject to minor revision without need for re-review of DSM plan.

Clinical Investigator Handbook July 2010 Version - Page 86

Serious Adverse Events Number of external SAEs reported since last annual review: Number of internal SAEs reported since last annual review: Number of SAEs reported expeditiously to the IRB: List Events Reported:

Was consent form modified due to reported SAE: Adverse Event (s) Added to Consent:

Deviations and Exceptions

Trends in Safety Data

Î&#x; YES

Î&#x; NO

Comments:

Comments:

p23 Forms subject to minor revision without need for re-review of DSM plan.

Clinical Investigator Handbook July 2010 Version - Page 87

Form Attachment 4

DSM/QAC CHAIRâ&#x20AC;&#x2122;S SUMMARY OF PROTOCOL (This form provided to PI and IRB following each DSM/QAC review of protocol) Recommendation: Allow protocol to remain open Close protocol

Reason(s): Response rates Accrual not met SAE rates too high SAEs not reported to IRB Consent form issues Other:

Recommendation(s) for improvement:

Chair, Data and Safety Monitoring Committee

Date

p24 Forms subject to minor revision without need for re-review of DSM plan.

Clinical Investigator Handbook July 2010 Version - Page 88

Form Attachment 5

p25 Forms subject to minor revision without need for re-review of DSM plan.

Clinical Investigator Handbook July 2010 Version - Page 89

GCRC General Clinical Research Center Example Submission for Protocols Requesting GCRC Resources

Clinical Investigator Handbook July 2010 Version - Page 90

Print: GCRC00000140 - GCRC: 0507GCC (HP-00042937_1)

View: SF_Protocol Information Date: Tuesday, November 03, 2009 8:51:53 AM

Print

Protocol Information 1 2

Name of this GCRC Submission: GCRC: 0507GCC (HP-00042937_1) Enter Study Acronym: 0507GCC

3

ID Number of Parent Protocol: HP-00042937_1 Short Title of Parent Protocol: 0507GCC Ivana Gojo PI of Parent Protocol:

4

Point of Contact for Protocol: Decker

5

Shannon

Other Members of the Research Team: Name Patricia Lesho Maureen Klein Charit Villena Maria Baer Kathleen Tiefenwerth Angela Scardina Julieta Nacario Curt Milnes

6

Edit Submission yes yes yes no yes yes yes yes

CC on Email yes yes yes no yes yes yes yes

Research Role Study Coordinator Other Other Sub-Investigator Study Coordinator Study Coordinator Other Other

Lay Abstract:

This is a two arm, dose escalating Phase 1 study to determine the effects of UCN-01 and perifosine in combination in relapsed and refractory acute leukemias. UCN-01 will be dose escalated to a maximum tolerated dose/recommended phase 2 dose in the presence of the recommended phase 2 dose of perifosine. The sequence of administration of the two drugs will also be studied. The current proposed protocol will examine in a focused way whether in patients with circulating or marrow-accessible tumor cells each agent alone and in combination will affect akt phosphorylation status, the possible target of perifosine. Owing to the tight binding of UCN-01 to alpha1-acid glycoprotein, a Phase I escalation of UCN01 is proposed initially in the presence of the recommended Phase 2 concentrations of perifosine to confirm the absence of unexpected toxicities of the combination. Neither agent was myelotoxic in initial Phase I studies conducted by a co-investigator (Sausville) of this proposed protocol. UCN-01 caused dose limiting hyperglycemia and nausea, while gastrointestinal side effects dominated in the case of perifosine. Note that the perifosine schedule proposed for use here utilizes a style of loading and maintenance perifosine doses that achieves similar perifosine concentrations with potentially continuous rather than interrupted dosing with manageable gastrointestinal toxicity, as compared to the interrupted schedule in the NCI phase 1 experience. Antiemetic prophylaxis will be routinely used prior to perifosine loading, and with UCN-01 as needed. In prior perifosine and UCN-01 phase 1 investigations, drug concentrations as single agents expected to modulate akt were achieved. UCN-01 will be administered as a three hour infusion, a schedule with which University of Maryland has experience and has already developed supportive care algorithms owing to a previous combined UCN-01 and carboplatin phase I experience.

7

Type of Study (from IRB Protocol form): Multi-Site

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Close

Print: GCRC00000140 - GCRC: 0507GCC (HP-00042937_1)

8

* Is

this a Clinical Trial:

Yes

No

If Yes, the appropriate phase is: Drug, Phase I/II

Drug, Phase II

Drug, Phase III

Device

Drug, Phase IV

Drug, Phase I

Drug, Approved

9

List of Drugs used in this Study, with IND information (if appropriate): FDA Approved

Experimental/Investigational

Intended Indication

IND Number

PI IND Holder

[View] UCN-01

Drug Name

no

yes

yes

49,169

no

[View] Perifosine

no

yes

yes

58,156

no ID: VIEW4401DE422A800 Name: SF_Protocol Information

View: SF_Services and Resources Needed

Services and Resources Needed 1

Indicate which of the following GCRC services and/or resources will be needed. Select all appropriate items:

Nursing Resources: Ancillary Resources:

✔

✔

(clinical lab or Investigational Drug Service costs)

Genomics Core: Biomedical Infomatics: Biostatistics: Clinic Space: ID: VIEW45411904B2800 Name: SF_Services and Resources Needed

View: SF_Nursing 1

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Print: GCRC00000140 - GCRC: 0507GCC (HP-00042937_1)

GCRC Nursing Resources The GCRC supports nursing resources at the following locations: * Outpatient visits on the GCRC unit (10 South) * Inpatient admissions to the GCRC unit * Other UMMC locations (Scatter visits) * Maryland Psychiatric Research Center visits

1

Outpatient visits on the GCRC Unit (10 South) *

Is Service Needed?:

Yes

No

10

If Yes - Number of Subjects anticipated in next 12 months: 13 Number of visits for each subject in 12 months: 7 Hours per visit (average): 2

Inpatient admissions to the GCRC Unit *

Is Service Needed?:

Yes

No

If Yes - Number of Subjects who will stay as Inpatients in 12 months: Number of Inpatient days for each subject: 3

Visits to collect data at other UMMC locations (Scatter visits) *

Is Service Needed?:

Yes

No

If Yes - Number of Subjects anticipated in next 12 months: If Yes - Visits per Subject in next 12 months: If Yes - Hours per visit (average): 4

Maryland Psychiatric Research Center Visits (MPRC) *

Is Service Needed?:

Yes

No

If Yes - Number of Subjects anticipated in next 12 monts: If Yes - Visits per Subject in next 12 months: If Yes - Hours per visit (average): Please select MPRC services that apply

Rater: Tester: Nurse: ID: VIEW45739225D1000 Name: SF_Nursing 1

View: SF_Nursing 2

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Print: GCRC00000140 - GCRC: 0507GCC (HP-00042937_1)

Specific Nursing Procedures Needed Please check all that apply 1

Specimen Collection ✔

✔

Blood, simple phlebotomy

✔

✔

Blood, serial collection Urine Specimen Processing

Other specimen (specify): 2

Point of Care Testing (CLIA certified) Urine Pregancy Test Urine Dipstick (glucose, blood, protein, nitrite, leukocytes, specific gravity) ✔

✔

Blood Glucose Hemoglobin Hemocult

3

Procedures Vital Signs, routine ✔

✔

Complex Vital Signs/Monitoring

✔

✔

Study Drug Administration Glucose Tolerance Testing, Oral IV Dexa Scan Questionnaire Administration

✔

✔

12-Lead EKG Subject Teaching Assist with Bedside Procedures (e.g biopsies, Lumbar Puncture)

Other (specify): ID: VIEW457392AA6A000 Name: SF_Nursing 2

View: SF _Data Safety Monitoring 1

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Print: GCRC00000140 - GCRC: 0507GCC (HP-00042937_1)

Data and Safety Monitoring Plan A Data and Safety Monitoring Plan is required for all studies supported by the GCRC including minimal risk studies. Please provide the following supplemental information to complete the GCRC DSMP. You may refer to protocol section, if applicable.

1

Please describe the plan for adverse event monitoring including a) grading and attribution scale; and b) plan for reporting adverse events:

Common Scales Help

The PI will use an alternative attribution scale.Unrelated The AE is clearly NOT related to the intervention Unlikely The AE is doubtfully related to the intervention Possible The AE may be related to the intervention Probable The AE is likely related to the intervention Definite The AE is clearly related to the intervention Expedited reports are submitted to CTEP via the secure AdEERS application accessed via the CTEP web site (https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$. startup). Those AEs that do not require expedited reporting must be reported in routine (CDUS) study data submissions. AEs reported through AdEERS must also be reported in routine study data submissions. The Investigational Drug Branch, CTEP, NCI (interim head, Dr. Anthony Murgo) is responsible for the monitoring of AE reports submitted through AdEERS. The complete table of reporting requirements for this protocol is found in section 12 of the sponsor's protocol. In addition to the responsibilities to the sponsor, we will also follow the guideline "Unanticipated Problems Involving Risk to Subjects: Reporting Adverse Experiences to the IRB" dated April 2004. The Division of Cancer Treatment and Diagnosis (DCTD) of the National Cancer Institute (NCI), has the scientific mission, the organizational scope, and the obligation to oversee the research directions of clinical cancer treatment.

Among its responsibilities, the DCTD is the sponsor of Investigational New Drug Applications (IND) for new anticancer agents and Biological Response Modifiers. The DCTD has the obligation to closely monitor all investigational drug trials conducted under DCTD sponsored INDs. Therefore all investigators conducting such studies are periodically monitored on site. Since Phase II and III trials are inherently safer for the patient, these studies are monitored ON SITE less frequently than Phase I studies. The current contractor for the DCTD Clinical Trials Monitoring Service is Theradex. TheradexÂŽ is an international contract research organization providing complete professional services for the clinical research and development of pharmaceutical compounds, medical devices and diagnostic tests in the areas of oncology and life-threatening diseases. In addition to the monitoring of the studies provided by the sponsor, the UMGCC DSM/QAC provides additional monitoring of all NCI-sponsored studies to make sure that these studies receive the frequency of monitoring required by the UM IRB. UMGCC monitoring follows the plan on file with the IRB.

2

* Will the results of specimens collected be communicated to physicians, counselors, the patient or patientâ&#x20AC;&#x2122;s family, or be used to make a diagnosis or determine patient therapy?

Yes

No

If yes, where will those laboratory tests be performed?: 3

* Are

any study drugs or devices synthesized in a research laboratory or facility?

Yes

No

If Yes - please describe the facility, process, ongoing quality assurance and safety measures. You may refer to a specific protocol section or upload a document explaining the details (click Continue to go to the Document Upload page): ID: VIEW466AACEC25800 Name: SF _Data Safety Monitoring 1

View: SF_Documents

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Print: GCRC00000140 - GCRC: 0507GCC (HP-00042937_1)

Document Uploads These funding documents are required for administrative and NCRR reporting purposes.

Please upload the documents appropriate for the funding source for this protocol

1

Notice of Grant Award (NIH funded):

2

Contract or Award Letter (other funded):

3

Budget Pages from Grant or Contract:

No document available

4

Other Documents: Name There are no items to display

Created ID: VIEW45DA9D534A400 Name: SF_Documents

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Ongoing Protocol Management

Clinical Investigator Handbook July 2010 Version - Page 97

Annual Renewals

Clinical Investigator Handbook July 2010 Version - Page 98

It is the responsibility of the PI to submit annual renewals to the IRB for every active protocol. The CRSS will assist with this process, however, the PI should provide any information he/she has learned from investigator meetings, relevant conferences, etc that may not be available to the CRSS, such as updates on new relevant lab studies, other clinical studies of the agent, etc.

An example follows.

Clinical Investigator Handbook July 2010 Version - Page 99

Print: HCR-HP-00040060-1 - CR 1 for IRB Protocol #HP-00040060

View: CR Introduction Page Date: Thursday, November 05, 2009 9:02:31 AM

Print

Continuing Review Introduction REGULATORY REQUIREMENTS

The federal regulations require an IRB conducts continuing review of research at intervals appropriate to the degree of risk, but not less often than once a year (45 CFR 46.109(e).

WHAT CONSTITUTES SUBSTANTIVE AND MEANINGFUL CONTINUING REVIEW?

The federal regulations require that the IRB review and satisfy the criteria for IRB approval of research, 21 CFR 56.111 and 45 CFR 46.111, at the initial review and during each continuing review. Continuing review of research must be substantive and meaningful. In conducting continuing review of research IRB members should review a protocol summary and a status report on the progress of the research, including: ● ●

●

● ● ●

The number of participants accrued; A summary of adverse events and any unanticipated problems involving risks to participants or others and any withdrawal of participants from the research or complaints about the research since the last IRB review; A summary of any relevant recent literature, interim findings, and amendments or modifications to the research since the last review; Any relevant multi-center trial reports; Any other relevant information, especially information about risks associated with the research; and A copy of the current informed consent document and any newly proposed consent document.

When reviewing the current informed consent document(s), the IRB should ensure the following: ● ●

The currently approved or proposed consent document is still accurate and complete;

Any significant new findings that may relate to the participant's willingness to continue participation are provided to the participant in accordance with federal regulations (45 CFR 46.116(b)(5) and 21 CFR 50.25(b)(5)).

IS MY STUDY ELIGIBLE FOR CLOSURE?

To be eligible for closure the IRB study must meet all of the following criteria: A. Data collection is complete; B. There is no more participant contact (i.e. phone calls, long term follow up, data collection visits, surveys are completed); and Clinical Investigator Handbook July 2010 Version - Page 100

https://cicero.umaryland.edu/CICERO/ResourceAdministration/Project/PrintSmar...intHeaderView=False&PrintHeaderInfo=True&PrintPageBreak=False&PrintLogo=True (1 of 10)11/5/2009 9:03:02 AM

Close

Print: HCR-HP-00040060-1 - CR 1 for IRB Protocol #HP-00040060

C.

The only research activity being conducted is data analysis of de-identified data.

ID: VIEW45B2C80EAFC00 Name: CR Introduction Page

View: Protocol Summary

Protocol Summary This submission is a Continuing Review for the following Protocol: 0643GCC Protocol Name: 1/8/2009 Date last approval: Date approval expires: 1/7/2010 Edward Sausville Listed PI: Greater Than Minimal Risk Risk Level: ID: VIEW449EF2E1FC800 Name: Protocol Summary

View: Funding / Industry > $10,000 Sponsor

Funding / Industry > $10,000 Sponsor Current sponsor information: Vickey Buskirk Endocyte, Inc. 3000 Kent Avenue â&#x20AC;&#x201C; Suite A1-100 West Lafayette, IN 47906-1075 Vickey Buskirk 765/807-0617 vbuskirk@Endocyte.com

Sponsor's Study Number:

EC-0225-01

Study Site Number: Sponsors PO Number: * Has

there been a change in financial support since the last IRB review?

Yes

No ID: VIEW457D9C18AD000 Name: Funding / Industry > $10,000 Sponsor

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Print: HCR-HP-00040060-1 - CR 1 for IRB Protocol #HP-00040060

View: Conflict of Interest

Conflict of Interest 1

* Has the research team's Conflict of Interest information provided to the IRB since the last review changed?

Yes

No ID: VIEW457D93B16E000 Name: Conflict of Interest

View: Drugs / Substances

Drugs / Substances Current drugs associated with this study: 99mTc-EC20 EC-0225

The study is placebo controlled? no

The justification for placebo use: 1

Has any of the information regarding the drugs used in this study changed sinced the last IRB review?

Yes

No ID: VIEW457DAC478CC00 Name: Drugs / Substances

View: IBC Information

IBC Information The approved study involves human gene transfer: no

The approved study involves the administration of pathogenic microorganisms: no

The approved study involves the sampling of materials for subsequent use in laboratory research:

yes

The approved study specifically applies to human in which induction or enhancement of an immune response to a vector-encoded microbial immunogen is the major goal, and such an immune response has been demonstrated in model systems, and the persistence of the vector-encoded immunogen is not expected: 1

* Has

any of the above information changed since the last IRB review?

Yes

No ID: VIEW457DC9AE40800 Name: IBC Information

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View: Protocol Lay Summary

Print: HCR-HP-00040060-1 - CR 1 for IRB Protocol #HP-00040060

Protocol Lay Summary The summary of the study in lay terms:

Folic acid is a water-soluble vitamin of the B-complex. The folate receptor (FR) (one of the ways in which cells take up folic acid) is only minimally distributed in normal tissues, but it is overexpressed (overly abundant) in a large fraction of human tumors, including cancers of the ovary, breast, lung, kidney and brain. This characteristic allows FR to act as a tumor- specific marker. EC0225 is a conjugate of folic acid coupled to mitomycin-C (MMC) and desacetylvinblastine hydrazide (DAVLBH); the latter two entities being potent antitumor agents. We are testing the hypothesis that attaching potent anticancer agents to folic acid will allow delivery of drug to tumor cells where the folate receptor is overexpressed. This study is a multi-center, nonrandomized, open-label, dose-escalating Phase 1 investigation of EC0225, given as anintravenous dose on Day 1, 3, 5, 8, 10 and 12 of a 4-week cycle, in patients with refractory or metastatic cancer who have exhausted standard therapeutic options.

ID: VIEW457DC11353800 Name: Protocol Lay Summary

View: Current Study Status

Current Study Status 1

* Is the study open to accrual?

Yes, and participants are currently receiving study intervention.

2

* Is

approval for this study expired?

Yes

No ID: VIEW457DDB741A400 Name: Current Study Status

View: Recruitment & Enrollment Activities 2

Recruitment & Enrollment Activities You were initially approved to enroll 40 locally and 80 worldwide.

1

Indicate the current number of participants that have been enrolled to date: * Locally 23

* Worldwide 58

2

* How 26

many individuals have signed a UMB IRB approved consent form?

3

* How 3

many individuals failed screening?

4

* How 23

many of these individuals were enrolled into active study participation?

5

* How 1

many participants were withdrawn from the study at this site?

5.1

Summarize the reasons for participant withdrawal:

One patient withdrew consent before starting treatment, wanting to re-consider other treatment options.

5.2

The approved ages of the subjects in this study are: 18 to 44 years (Adult) 45 to 64 years (Middle Age) 65 plus years (Elderly)

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6

The approved vulnerable populations for this study are: Women of Child-bearing Potential

Break down the vulnerable populations enrolled in this study: (To view totals, save this page before you continue.)

UMB Male

Vulnerable Populations

UMB Female

Children

UMB Total

VA Male

VA Female

VA Total

Grand Total

0

0

0

Cognitively Impaired

0

0

0

Critically Ill or Injured Patients

0

0

0

Educationally Disadvantaged

0

0

0

Emancipated Minors

0

0

0

Emergency Room Patients

0

0

0

Employees or Lab Personnel

0

0

0

Fetuses

0

0

0

Homeless or Economically Disadvantaged

0

0

0

Mentally Ill

0

0

0

Neonates

0

0

0

Post Traumatic Stress Disorder (PTSD) Participants

0

0

0

Pregnant Women

0

Prisoners

0

0

Students

0

0

0

Terminally Ill Patients

0

0

0

Wards of the State

0

0

0

Women of Child-bearing Potential

7

0

4

4

4

The approved populations by race/ethnicity for this study are: All Races Included

Break down the ethnicity of populations enrolled in this study: (To view totals, save this page before you continue.)

Race / Ethnicity

UMB Male

UMB Female

American Indian/Alaskan Native Asian

1

Asian Vietnamese Black or African American Hispanic or Latino

6

3

UMB Total

VA Male

VA Female

VA Total

Grand Total

0

0

0

1

0

1

0

0

0

9

0

9

0

0

0

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Mixed Race or Ethnicity Native Haiwaiian or Pacific Islander Caucasian

5

8

0

0

0

0

0

0

13

0

13 ID: VIEW46AD8C330E000 Name: Recruitment & Enrollment Activities 2

View: Monitoring & Audit Activities

Monitoring & Audit Activities 1

* Have you been inspected or investigated for any study by the Sponsor, the FDA, OHRP, the HRPO, or any other regulatory agency since your last report?

Yes

2

No

* Are

there any current inspections or investigations involving the Principal Investigator or any SubInvestigator(s)?

Yes

3

* Have

No

research privileges for the Principal or Sub-Investigator(s) been revolked since your last report?

Yes

No ID: VIEW457EF0D878400 Name: Monitoring & Audit Activities

View: Laws

Laws 1

* Is

the PI aware of any changes in the state local laws related to research?

Yes

2

No

If Yes, summarize these changes: ID: VIEW457EF60103000 Name: Laws

View: Continuing Review Progress Report

Continuing Review Progress Report 1

* Summarize

the results since the last review. For Cooperative and Multicenter studies, if overall study results have not been provided, indicate as much and summarize local experience: Twenty-three patients have been enrolled at this site. Two patients are currently on treatment. One patient expired while on study. One patient withdrew consent before starting treatment. The remaining patients experienced disease progression and therefore met off study criteria.

2

* Provide a summary of plans Continue treating new patients until MTD reached.

3

* Provide 12/31/2010

4

* Is no

for the coming year:

a projected date of study completion:

there any information you have not otherwise reported that you would like to convey at this time?

Clinical Investigator Handbook July 2010 Version - Page 105

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5

Attach any additional documents related to the Continuing Review application. (ex., DSM reports): There are no items to display

ID: VIEW456A8A0ADB000 Name: Continuing Review Progress Report

View: Risk/Benefit Analysis

Risk/Benefit Analysis 1

* Has

there been any new information regarding the risk that would affect this research and/or a participant's willingness to continue?

Yes

1.1 2

No

If Yes, provide a summary of this information: * Considering

your experience with this study's implementation to date and your review of the relevant recent literature, has the relationship between study risks and benefits changed since your last renewal of this project? In answering this question, analyze how adverse events, protocol violations/ incidence reports, monitoring/auditing activities, protocol modifications, and results from other studies might have affected the prior risk/benefit ratio.

Three external SAEs were received during this report period. All were within consent. The internal SAEs are shown below.

The study has been modified during this approval period to adjust the PK schedule, the dose schedule and the dose escalation plan in view of the data obtained in the earlier dose cohorts. These changes should assure that the risk/benefit ratio remains favorable.

3.

Reportable Events Adverse Events: RE Name

ID#

Date Submitted

Type

Description

Event Location

Event: Patient is a 56-year old male with prostate cancer, metastatic to mediastinal and retroperitoneal lymph nodes. He began cycle 1 of therapy on September 21, 2009 and received the first 3 doses without incident. On cycle 1 day 8 when the patient presented to clinic for blood counts, he was complaining of dizziness and was found to be orthostatic. He received hydration with resolution of symptoms. Of note, patient had history of dehydration requiring intravenous hydration prior to study entry; he also noted decreased appetite for which he had been prescribed low dose dexamethasone by his treating physician. He was also complaining of constipation on this date. On cycle 1 days 10 and 11, the patient also required hydration due to symptomatic orthostasis. On cycle 1 day 15 the patient came to clinic for week 3 of therapy. At that time, he was again dizzy and found to be orthostatic. He was also complaining of constipation and had an abdominal Xray which Clinical Investigator Handbook July 2010 Version - Page 106 demonstrated a moderate amount of stool https://cicero.umaryland.edu/CICERO/ResourceAdministration/Project/PrintSmar...intHeaderView=False&PrintHeaderInfo=True&PrintPageBreak=False&PrintLogo=True (7 of 10)11/5/2009 9:03:02 AM

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RE 3 for IRB Protocol #HPHRE-HP-00040060-3-AE 10/9/2009 6:57 PM 00040060

Initial Report

throughout the colon, but no bowel obstruction.

His performance status had declined due to fatigue. Hydration again was administered and a bowel regimen was outlined for the patient, and EC0225 was held. On cycle 1 day 17, the patient came to clinic stating the previous day, his appetite was improved and he was taking in approximately 2 liters of fluid per day. However, he was symptomatic of orthostasis and required hydration. He also had some diarrhea due to the laxatives. Upon completion of the hydration, the dizziness and orthostasis resolved. Therefore, a decision was made to treat the patient with study drug (EC0225). On cycle 1 day 19, the patient came to clinic and was found to have a blood pressure of 67/38 and heart rate of 120. He was complaining of severe dizziness, headache, and blurry vision; he did not have these symptoms the previous day. He was sent immediately to the emergency room and has subsequently been admitted to the hospital, with the intent of obtaining a neurology work-up. This report will be updated when information is available. Of note, because of the patientâ&#x20AC;&#x2122;s prior history of anorexia and prior episodes of orthostatic hypotension, the occurrences prior to cycle 1 day 19 were considered unlikely related to drug. However, the occurrence of hypotension clearly two days after a dose of the agent raises the possibility that the drug had exacerbated an underlying condition and therefore results in reclassification to possibly related to study drug.

Date: Fri Oct 9 00:00:00 EDT 2009 Description: Please see adverse event Event Type: Serious, Unexpected Activity: Possibly

Event: 59 y/o caucasian male with diagnosis of Small Cell Lung Cancer since April 2006 being treated under this study for his cancer. Admitted to a local hospital and transferred to JHH diagnosis of Deep Vein Thrombosis on Course 1 Day 28 of this study.

Date: Sun Oct 12 00:00:00 EDT 2008 Description: 59 y/o caucasian male with diagnosis of Small Cell Lung Cancer since April 2006 and having been treated with multiple first line therapies with continued progression of disease is being treated under this study for his cancer. His history is significant for Pulmonary Emboli in the past and is on coumadin to prevent RE 1 for IRB Protocol #HPclot development. Despite preventative coumadin HRE-HP-00040060-1-AE 1/15/2009 12:35 PM Initial Report 00040060 therapy patient was admitted to a local hospital and transferred to JHH under the care of his primary physician with diagnosis of Deep Vein Clinical Investigator Handbook July 2010 Version - Page 107

Internal Event (i.e an event involving a participant consented using a consent document approved by the UMB IRB)

Internal Event (i.e an event involving a participant consented using a consent document approved by the UMB IRB)

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Thrombosis on Course 1 Day 28 of this study.

Recurrent Pulmonary Emboli were also identified during his admission. Condition assessed by Dr. Edelman as unexpected, serious, life threatening and definitely not related to study medications but recurrence of existing condition. Patient discharged to home from JHH on 10/16/2008.

Radiology reports increasing metastatic disease and patient removed from study for progressive disease.

Event Type: Serious, Unexpected Activity: Not Related

RE 2 for IRB Protocol #HPHRE-HP-00040060-2-AE 10/19/2009 7:21 AM Initial Report 00040060

Event: The patient is a 65-year old female with pancreatic cancer, metastatic to liver; of note, the patient has a stent in the common bile duct. She underwent a folate scan on 9/21/09 per protocol GCC 0643. She presented to clinic today to begin treatment with EC0225. Upon presentation, the patient complained of increased abdominal pain, with increased weakness; the patient states she â&#x20AC;&#x153;fellâ&#x20AC;? on Saturday. She denied any fevers or chills at home. Vital signs in clinic were temperature 97.7, pulse 119, respirations 18, blood pressure 84/53 (on 9/21/09, blood pressure was 96/58).

Laboratory values revealed a bilirubin of 3.6, direct bili of 2.6, AST of 103, ALT of 93. Total white blood cell count was 20,400 with 91.5% segs. On 9/21/09 total white blood cell count was 17,700 with 81% segs. Baseline CT scan on 8/31/09 revealed interval increase in size and number of liver lesions. There was also mention of intrahepatic ductal dilatation in the right hepatic lobe. The patient will be admitted to the hospital for work-up and repeat scans. The CT scan revealed progression of disease as well as findings consistent with chronic pancreatitis. She had experienced hypotension during her hospital stay which was believed to be due to volume depletion secondary to very poor oral intake. She received 2.5 liters bolus of fluids upon her admission and was maintained on normal saline throughout her hospitalization. All of her blood pressure medications were removed. She also experienced anemia and was transfused two units of PRBCs and they did not know the reason for this since the CT showed no evidence of bleeding. She was discharged to her sister and hospice care. It is unclear at this time whether she will move in with her sister in New York, or be admitted to inpatient hospice in Maryland. Her case worker and social worker are following up on this.

Date: Mon Sep 28 00:00:00 EDT 2009 Description: See above . Subject never

Internal Event (i.e an event involving a participant consented using a consent document approved by the UMB IRB)

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received the EC0225. She had received the EC20 with the folate scan, however, this was not due at all to study per physician's attribution.

Event Type: Serious, Unexpected Activity: Not Related Event: Hypotension Date: Fri Oct 9 00:00:00 EDT 2009 Description: To update, the patient had Head MR, Chest X-Ray, Echocariogram during his hospital stay. The result of which were within normal range. It was concluded that the most likely cause of the patient's symptomatic orthostatic hypotension was to be autonomatic dysfunction. Cardiology evaluated the patient while admitted. They agreed with the diagnosis.

Ad first line treatment, they recommended thighRE 4 for IRB Protocol #HPHRE-HP-00040060-4-AE 10/19/2009 11:18 AM Follow-Up Report high compression stockings to be worn at all 00040060 times, as well as permissive excessive salt intake.

Both of these recommendations were passed on to the patient. Regarding medication management, cardiology expressed concern regarding the use of florinef due to its potential for hypokalemia. The patient will be followed very closely in clinic and has labs routinely checked.

They decided to start the patient on Florinef 0.1 mg daily.

Event Type: Serious, Unexpected Activity: Possibly

Internal Event (i.e an event involving a participant consented using a consent document approved by the UMB IRB)

Unanticipated Problems: RE Name ID# No Unanticipated Problems reported this review cycle

Date Submitted

Description

ID#

Date Submitted

Description

ID#

Date Submitted

Description

Deviation: RE Name No Deviations reported this review cycle Exception: RE Name No Exception reported this review cycle

ID: VIEW456914C9B8000 Name: Risk/Benefit Analysis

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Monitoring and Audits

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Investigators should expect that all of their trials will be monitored and/or audited at some point during the course of the trial. Routine monitoring and auditing is an assurance that the study is being conducted in accordance with all applicable laws, regulations and standards. The UMGCC has contracted with the University of Maryland IRB to perform routine auditing of all trials conducted at UMGCC that do not have an independent DSM. In addition to routine audits, protocols may be audited for cause if there is reason to believe the trial conduct is in some way deficient. Potential auditors include: • • • •

the FDA the NCI’s contract monitoring service Theradex CALGB or other cooperative groups as appropriate industry appointed medical monitors or contract organizations • UMGCC’s DSM/QAC • University of Maryland’s IRB

research

Although the CRSS staff will typically order charts from medical records and prepare the charts for the audits, PIs should be aware that this is a very time-consuming process. If a PI receives any information about the audit or receives a request for additional information from the CRSS staff, PIs should promptly communicate with CRSS staff to insure that the CRSS staff have sufficient time to complete preparations for the audit.

The CRSS has established procedures for preparing for Theradex audits.

Auditing bodies such as CALGB often provide guidance documents for preparing for audits. Examples of such documents follow. PIs are advised to consult with the auditing body for the most current guidance at the time an audit notice is received.

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University of Maryland Greenebaum Cancer Center

Subject: Audits Conducted by CTMS (Theradex)

I.

Function: Clinical Research and Protocol Management

Purpose

The Clinical Trials Monitoring Service was established by the Division of Cancer Treatment and Diagnosis (DCTD) of the National Cancer Institute (NCI) with one of its mandates to monitor studies being conducted by the DCTD. This is accomplished by on-site monitoring of Phase 1 trials every three months, and at least every 3 years for Phase 2 and 3 trials; however, there can be a spot-check audit of the Phase 2, 3 trials. The on-site monitoring provides assurance to DCTD that the investigators are in compliance with NCI policies and FDA regulations regarding the conduct of clinical trials, with regards to such elements as data quality, patient rights protection, investigational agent and storage, II.

Responsibility

The manager of the Clinical Research Shared Service (CRSS) and the Principal Investigators (PIs) will receive an initial notification from Theradex sixty days prior to the site visit. Thirty days prior to the visit, a list of the protocols and patients to be audited will be sent to the PIs and the CRMO manager. This information will be communicated to the appropriate teams and the manager of the Investigational Drug Pharmacy. The Research Coordinator will work with the data manager/CRA and regulatory personnel to ensure that the documents needed for the audit are in order.

III.

Preparing for the Audit

Three-Month Audit: •

Research Coordinator/Data Manager

1. Order the outpatient/hospital charts for the patients being audited. Put these charts with the research chart.

2. Print a copy of the protocol, eligibility checklist, and study calendar.

3. Using the “Monitoring Checklist” (Appendix A) provided by Theradex as a guideline for the data being audited, tag the charts using the color schema provided in Appendix B. 4. If data is missing, make every effort to obtain the missing information. If unable to locate needed data, or if in the course of review, errors are noted, inform Research Coordinator and PI immediately.

5. The data manager/CRA should print from the Oncore database a listing of the external Serious Adverse Events (SAEs) that have been received and assessed. The external SAE file with the hard copies of the reports should be made available at the time of audit.

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â&#x20AC;˘

Regulatory Coordinator

1. The team-specific regulatory coordinator, in collaboration with the Regulatory Document Protocol Coordinators, should ensure that the regulatory binder is updated and accurate. The binder should include the Institutional Review Board (IRB) documents for approvals, re-approvals, amendment approvals; annual reports submitted to the IRB; and the current version of the protocol and informed consent. â&#x20AC;˘

Pharmacy

1. Ensure that the records regarding the disposition of investigational drugs and the NCI DARFs are accurate. On the day of the audit, an onsite inspection will be conducted of the investigational agent storage and the records.

Triennial Audit: 1. In addition to the items listed above, obtain radiology exams on the patients being audited. Have a viewbox available for the monitors.

Exceptions to On-Site Audit There are occasions when there are no patients accrued to the open trials, or the number of unaudited patients currently accrued does not meet the monitoring requirements. The site will receive a letter from Theradex stating the data audit will be deferred. However, a request for up-to-date patient registration lists for the protocols and copies of the NCI Drug Accountability Record Forms (NCI DARFs) must be forwarded to Theradex in the timeframe requested in the letter. This task will be accomplished by the Data Safety Monitoring Coordinator.

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Adverse Event Reporting

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Adverse Event Reporting Adverse event collection and reporting is a routine part of every clinical trial, with the requirements for collection and reporting of data varying between the sponsors of the trial. Sponsors could include pharmaceutical companies, Cooperative Groups, or the NCI Cancer Therapy Evaluation Program (CTEP); there are also investigator-initiated trials. The requirements for collecting and reporting of adverse events are clearly defined within the protocol, and as such, should be the point of reference to guide practice.

The protocol Principal Investigator (PI) has the ultimate responsibility for identifying adverse events, and subsequently determining the seriousness of the event, the expectedness of the event, and the assignment of attribution of the study agent with relation to the event.

Seriousness is not the same as severity. Serious is based on patient/event outcome associated with events that pose a threat to a patientâ&#x20AC;&#x2122;s life or functioning. Severity is often used to describe the intensity of an event.

Expectedness of an event references whether the adverse event is included in the informed consent for the study. For commercial agents, it is based on the package insert and/or the Investigator Brochure.

Attribution refers to the investigatorâ&#x20AC;&#x2122;s clinical judgment about the drugâ&#x20AC;&#x2122;s relation to the event (unrelated, unlikely, possible, probable, definite).

There are descriptive tools available to investigators to assist in the definition and grading of adverse events. To ensure uniformity in the reporting and grading of adverse events, the Common Terminology Criteria for Adverse Events (CTCAE) is a tool that is frequently employed. This can be accessed at the following web address: ctep.cancer.gov An adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure. However, on a baseline assessment, there may be a pertinent positive finding that would not be considered an adverse event. For example, if a patient has a baseline hemoglobin of 9 g/dl, this would not be recorded as an adverse event. However, if the value were to decline to a certain level during the clinical trial, it could be recorded as an adverse event. Whether it is related to the drug therapy (attribution) is determined by clinical evaluation, e.g. was there a significant amount of blood drawn for research purposes (unlikely attribution); is the drug known to cause a decrease in hemoglobin (probable attribution).

A serious adverse event (SAE) is defined in the FDA CFR 312 as any adverse drug experience occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization, or prolongation of

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existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be lifethreatening, or require hospitalization may be considered a serious adverse drug experience when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Although all adverse events occurring on a clinical trial are submitted in an annual report to the FDA, there are some adverse events that will need to be reported expeditiously to the sponsor and/or the FDA. Expedited reporting is determined by the seriousness of the event, the expectedness of the event, and the attribution of the event to the study agent.

The mechanism for expedited adverse event reporting is also contained within the protocol.

The University of Maryland IRB has specific guidelines for expedited adverse event reporting; these are dependent on whether the event occurred internally (here at the University of Maryland) or externally (off-site). These policies can be found in the IRBâ&#x20AC;&#x2122;s policies and procedures manual which can be accessed using the following URL: If an event meets the http://medschool.umaryland.edu/orags/hrpo/policies.asp. requirements for expedited reporting to the IRB, an SAE report is filed in the CICERO system.

In addition to the IRB reporting requirements, ALL external SAEs must be reviewed by the Principal Investigator and subsequently be entered into the Oncore database by a member of the CRSS. For those events that require a change to the informed consent, the data entry staff who input these data will immediately notify the appropriate research coordinator and regulatory coordinator of this change.

Oncore Record of SAE

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Exceptions/Deviations/ Unanticipated Problems Involving Risks to Subjects

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A protocol exception is a prospective request to the IRB to not follow the protocol in a particular instance related to a particular patient. For example, if the patient had CT scans on November 1st, and the protocol requires scans within one month before enrollment, the PI could request an exception to enroll a patient on December 2nd to avoid exposing the patient to excess radiation or to prevent the patient from having to pay out of pocket for an extra scan. A protocol deviation is a post hoc notification to the IRB that the protocol was not followed, for instance, if a lab or vital sign was missed on a particular day. The PI is responsible for reporting all protocol exceptions and deviations to the IRB. This is in addition to any sponsor reporting requirements. CRSS staff can assist with this process, but as with all other reporting issues, the ultimate responsibility rests on the PI. Protocols deviations and exceptions are processed as Reportable Events through the IRBâ&#x20AC;&#x2122;s CICERO system.

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Unanticipated Problems Involving Risks to Subjects Federal regulations require PIs to report unanticipated problems involving risks to subjects. These include any incident, experience, or outcome that meets all of the following criteria: • unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied; • related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and • suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

While many of these unanticipated problems will also be deviations or adverse events, there are still unanticipated problems that are neither deviations nor adverse events but nevertheless require reporting to the IRB. Examples are the loss or theft of confidential patient information or the suspension of an investigator’s privileges.

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Amendments

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The PI is responsible for submitting any amendments to the IRB through CICERO as necessary. This is in addition to the requirement to submit amendments to the NCI, industry sponsors, and any other sponsors/coordinating centers. The CRSS will assist with this process, however, the PI should provide information on what sections of the protocol, consent and study schedule require changes. If the IRB requires any clarifications or modifications to the amendment, the PI and other designated staff will receive e-mail notification.

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Clinical Research Shared Service

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University of Maryland Greenebaum Cancer Center

Effective Date:

Subject: Clinical Research Shared Service

Function: Clinical Research and Protocol Management

I.

Procedure No:

Purpose

The Clinical Research Shared Service (CRSS) is organized to support clinical research. Comprising approximately 30 FTEs, it is charged with managing data and regulatory actions related to clinical trials.

The head of the CRSS reports to the Associate Director for Administration with professional guidance for the allocation of resources from the Associate Director for Clinical Research. CRSS staff do not report to individual principal investigators. While the CRSS manager will typically assign the same staff to a disease team for all of its protocols, the CRSS manager has the discretion to assign staff as needed to best accommodate the needs of all disease groups. The services and structure of the CRSS are dictated and approved by NCI as part of the UMGCC Cancer Center designation.

II.

Services

The CRSS provides the following services in support of clinical research at UMGCC. • • • •

• • • • •

Design Study with P.I. Negotiate with Sponsor Coordinate Local Review: o Clinical Research Committee: Science o Investigational Review Board: Safety Implement Study o Record Dosing o Score Adverse Events o Follow Milestones Complete Case Report Forms Submit to IRB o Severe Adverse Events o Annual Reports (Including Data Safety Monitoring Report) Prepare / Respond to Audits Investigator / Sponsor Info Requests Maintain Oncore Clinical Research Database o Accrual Statistics o Committee (CRC and DSM) Statistics

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III.

Structure

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IV. Database Capabilities and Responsibilities A key function of the CRSS is to maintain the Oncore database that is essential to UMGCCâ&#x20AC;&#x2122;s ability to comply with NCI reporting requirements. While PIs are not expected to enter data into Oncore, PIs are expected to comply with all requests from CRSS staff for information needed for entry into Oncore.

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CLINICAL RESEARCH & PROTOCOL MANAGEMENT PHONE LIST June 23, 2010 Name Phone Ext. Fax # Pager # Office Location ASSOCIATE DIRECTOR: Edward Sausville, MD, PhD, FACP 8-7394 8-6896 410-389-0650 CLINIC RES. QUALITY ASSURANCE: Maureen Klein, RN 8-7512 8-2578 2018 /410-389-2266 N9E36 Breast & GYN Katherine Tkaczuk, MD 8-2565 8-6896 8704 Sara Chumsri- MD 8-6373 8-6896 Ting Bao - MD 8-6842 8-2578 2509 Nancy Tait, RN – Study Coordinator 8-3546 8-1741 0943 S9B Jane Lewis, RN- Study Coordinator 8-7856 8-1741 8742 / 410-389-2228 S9B Michelle Medeiros, Regulatory Coordinator (Group Leader) 8-1160 8-8616 N9E02 Margaret Griffin, -Data Manager 8-7339 8-1741 S9B Bone Marrow & Stem Cell Transplant 8-1230 8-1975 410-389-1624 Saul Yanovich, MD 8-1230 8-1975 3685 Aaron Rapoport, MD 8-1230 8-1975 410-389-7879 Gorgan Akpek, MD 8-1230 8-1975 410-389-7880 Ashraf Badros, MD 8-8198 8-1180 S9A06 Carolynn Harris, CRA- Regulatory Coordinator 8-8199 8-1180 1834 S9A06 Philip, Sunita MS – Study Coordinator (Group Leader) 8-2577 8-1180 1831 S9A06 Pat Lesho, MS – Study Coordinator Nicolette Minas – Data/Protocol Coordinator 8-7682 8-1180 S9A06 Heme Malignancies Maria Baer, MD 8-3048 8-6896 410-389-0253 Aaron Rapoport, MD 8-1230 8-1975 3685 Ivana Gojo, MD 8-2596 8-6896 7815 Amy KImball 8-6373 8-6896 7672 Ann Zimrin, MD 8-2594 8-6896 6461 Stephanie Fleckinger RN – Study Coordinator 8-8739 8-1180 1948 S9A06 Debbie Nesbitt, RN – Study Coordinator 8-7558 8-1180 7262 S9A06 Kathleen Tiefenwerth-MS- Study Coordinator 8-6635.

8-1180 9469 S9A06 Dina Ioffe - Data Manager 8-7828 8-1180 7041 S9A06 Gene Whittaker- Data Manager 8-7520 8-1180 S9A06 Shannon Decker – Regulatory Coordinator 8-9161 8-2578 N9E34 GI /Head & Neck, Kevin Cullen,MD 8-5506 8-2578 Pandya, Naimish, MD 8-2567 8-6896 8993 Ann Zimrin, MD 8-2594 8-6896 6461 Jagdish Shetty, MS – Study Coordinator 8-7680 8-1741 0449 S9B Julieta Nacario- Data Management 8-7520 8-1741 S9B Shannon Decker – Regulatory Coordinator 8-9161 8-2578 N9E34 GU: Prostate, Bladder, Renal Cell Heather Manuel, MD 8-1119 8-6896 8778 Arif Hussain, MD 8-7225 8-0805 4987 Michelle Besche, RN – Study Coordinator N9E02 8-8610 8-8616 1835 Maha Khalil – Study Coordinator 9NE02 8-5009 8-8616 2019 Abdul Ruknudin -Study Coordinator at VA (VA phone5-4527) N9E02 8-8613 8-8616 3933 Leona Gittens, - Research Project Coordinator 8-8611 8-8616 8286 N9E02 N9E02 Jody Winkenwerder - GU Regulatory Coordinator 8-7340 8-1180 Pediatric Oncology Dr Teresa York 8-2808 8-0571 N5E16R Curt Milnes, RN 8-1787 8-0571 Phase I studies Judith Carter – Study Coordinator 8-3999 8-1741 5506 S9B Vera Kuffour-Manu– Study Coordinator (Group Leader) 8-2341 8-1741 1345 S9B Julieta Nacario –Data Coordinator 8-8612 8-1741 S9B Shannon Decker – Regulatory Coordinator 8-9161 8-2578 N9E34 Radiation Oncology 8-2331 8-6911 1401 Dr. Regine 8-2326 8-5279 2316 Dr. Suntha 8-8995 8-5279 1389 Dr. Amin 8-8018 8-7143 3242 Ritesh Kataria, MD, CCRC – Program Manager Nancy Kennedy, RN- Study Coordinator 8-2513 9-7143 8235 Susan Kopunek, RN - Study Coordinator 81681 8-7143 6178 Suzanne Grimm 8-7882 8-7143 4294 Svetlana Kudryasheva 8-7501 8-7143 4167 Samantha Chambers – Data Manager 8-8017 8-7143 Thoracic, Lung Martin Edelman, MD 8-2703 8-0805 410-389-2966 Petr Hausner, MD 8-2565, 2567 8-6896 5602 or 410-389-6836 Kim Csapo, RN – Study Coordinator 8-7332 8-1741 3253 S9B R. “Zak”, RN – Study Coordinator 8-9166 8-1741 1949 S9B Abdul Ruknudin – Study Coordinator at VA (VA phone:5-4527) N9E02 8-8613 8-8616 3933 Jody Winkenwerder - Thoracic Regulatory Coordinator 9NE02 8-7340 8-8616 Teresa Withers -Data Manager S9B 8-4499 8-1741 4441 Nicole Sealfon- Research Project Coordinator 8-8370 8-1740 IT, IDS PHARMA, REGULATORY & TECHNICAL SUPPORT STAFF Research Specimen Pharmacokinetics Coordinator STOLER LAB ROOM Marian Williams -Data Assistant, CAN 8-8669 8-8616 1828 S9B Teresa Withers 8-4499 8-1741 4441 CALGB Martin Edelman, MD 8-2703 8-1975 410-389-2966 N9E02 Colleen Smardon, RN 8-7496 8-8616 1832 Helen Cruz, RN, MS (VA Hospital) 5-7492 5-7936 410-447-3584 Computer and Data Base Specialists Arnold Hoffmann 8-7511 8-8596 N9E07B Data Safety Monitoring Michael Kleinberg, MD 8-2679, 5-6451 8-6896 410-351-4833 Maureen Klein, RN 8-7512 8-2578 2018 /410-389-2266 N9E36 Daytime pager 2882 N9E14 Investigational Drug Service Pharmacy: 8-5468 8-7326 24 hr. 410-748-1402 Myonghee Lee, Rh, PhD (mlee1@umm.edu) Regulatory Support Charit Villena, Regulatory/IRB Protocol Coordinator 8-4490 8-1180 N9E11 Terri Joneckis, Regulatory/CRC/IRB/SAE External Coordinator 8-2243 8-1180 REVISED 6/23/2010 @ 10:00 AM Clinical Investigator Handbook July 2010 Version - Page 154

Current Committee Membership (Committee membership subject to change without need for re-approval of entire investigator handbook.)

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CROC Members Kevin Cullen, M.D., Chair and Director H. Richard Alexander, M.D., Chair, CRC; Department of Surgery Nader Hanna, M.D., Head, Surgical Oncology Michael Kleinberg, M.D., Ph.D., Chair, DSM/QAC, Infectious Diseases & Clinical Epidemiology William Regine, M.D., Chair, Department of Radiation Oncology Edward Sausville, M.D., Ph.D., Associate Director for Clinical Research Maria Baer, M.D., Professor of Medicine, Hematologic Malignancies Martin Edelman, M.D., Professor of Medicine, Solid Tumors

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CRC Members H. Richard Alexander, M.D., Professor of Surgery, Chair CRC Maria Baer, M.D., Professor of Medicine, Hematologic Malignancies Martin Edelman, M.D., Professor of Medicine, Solid Tumors Olga Goloubeva, M.S., Biostatistician Ajay Jain, M.D., Assistant Professor of Surgery Aaron Rapoport, M.D., Professor of Medicine, Hematologic Malignancies William Regine, M.D., Professor of Radiation Oncology Renee Royak Schaler, Ph.D., Associate Professor of Epidemiology Edward Sausville, M.D., Ph.D., Professor of Medicine, Associate Director for Clinical Research Mohan Suntharalingam, M.D., Professor of Radiation Oncology Ming Tan, Ph.D., Professor of Epidemiology/Biostatistics Myounghee Lee, Investigational Drug Service Pharmacy Technology Research Review Committee (sub-committee of CRC) William Regine, M.D., Chair, Radiation Oncology Mohan Suntharalingam, M.D., Vice Chair, Radiation Oncology Alan Tomkinson, Ph.D., Director, Radiobiology Program Warren Dâ&#x20AC;&#x2122;Souza, Ph.D., Director, Physics Dept, Radiation Oncology Shahid Naqvi, Ph.D., Radiation Biologist Edward Sausville, M.D., Ph.D., Professor of Medicine, Associate Director for Clinical Research Ming Tan, Ph.D., Professor of Epidemiology/Biostatistics Suzanne Grim,Research Coordinator Ritesh Kataria,Research Specialist

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DSM/QAC Members Michael Kleinberg, M.D., Ph.D., DSM Chair, Associate Professor of Medicine, Infectious Diseases and Clinical Epidemiology Ivana Gojo, M.D., Associate Professor of Medicine, Hematologic Malignancies Petr Hausner, M.D., Associate Professor of Medicine, Solid Tumor Malignancies John Hess, M.D., Professor of Medicine, Pathology and Clinical Trials Ashraf Badros, M.D., Associate Professor of Medicine, Hematologic Malignancies Ming Tan, Ph.D., Professor of Epidemiology/ Biostatistics Laura Hearson, R.N., Patient Advocate and Nursing Katherine Tkaczuk, M.D., Associate Professor of Medicine, Solid Tumor Malignancies Ritesh Kataria, M.S., Patient Advocate and Radiation Oncology Edward Sausville, M.D., Ph.D., Professor of Medicine, Associate Director for Clinical Research Non Voting Colleen Smardon, R.N., Alternate DSM Coordinator Maureen Klein, R.N., Manager, Clinical Research Shared Service

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Glossary AE – Adverse events. Consult IRB policies and procedures for definitions and reporting requirements.

CALGB – Cancer and Leukemia Group B. One of a number of NCI-funded cooperative groups that sponsors clinical trials. Other cooperative groups include ECOG, RTOG, SWOG. CICERO – The IRB’s electronic submission and reporting system.

CRC – Clinical Research Committee. The committee that provides initial scientific review of all new cancer center protocols.

CROC – Clinical Research Oversight Committee. The committee that oversees policies and processes for clinical research at UMGCC. CRSS – Clinical Research Shared Service. The office that provides research nurse and data management support for clinical trials.

DSM/QAC – Data and Safety Monitoring/Quality Assurance Committee. The committee that provides independent review of ongoing clinical trials that do not have an external board to serve in that capacity.

GCRC – General Clinical Research Center. An NIH-funded facility at UM that can provide assistance with conduct of clinical trials.

IRB – Institutional Review Board. The body responsible for human subjects protection.

Oncore – The database system used by UMGCC to track clinical trials and accruals.

SAE – Serious adverse events. Consult the specific protocol to determine which AEs rise to definition of SAE. Consult IRB policies and procedures as well as sponsor procedures for reporting requirements.

TRRC – Technology Research Review Committee. A subcommittee of the CRC that reviews technology-related issues from Radiation Oncology.

UMGCC – The University of Maryland Marlene and Stewart Greenebaum Cancer Center

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