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 protocol-specific 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 UMGCCs 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.

Clinical Investigator Handbook July 2010 Version - Page 3

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.


PI must secure consensusof Disease Group HeadAND Assoc Dir Clin Res

re: resource allocation

Protocol Initiation Process

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 / BudgetProcess

PI work withAdmin and CRSS

staff

Regulatory Process(CRC, IRB, GCRC)

PI workwith CRSS staff

Approval to Initiate TrialOnly Once Contract, Budget and Regulatory Complete


PIDiseaseGroup or

AD Clin Res

CRC

IRB

GCRC**

CRSS

** - NCI sponsored investigational drug studiessee appropriate sections for full discussion of requirements

Protocol Initiation Overview of Regulatory

ManagerCRSS


10.31.09

DETAILED BUDGE OCESS FOR NEW

CLINICAL RESEARCH SHARED SERVICE GREENEBAUM CANCER CENTER

T & PROTOCOL UBMISSION PRSTRIALS

All new trials: GCC, Industry, NCI, Co-op group- PI presents protocol to disease group

Statemen at GCC. (Regulatory C o group head

CRSS Manager to verify Protoc within the capacity of CRSS.

t by Disease Group Head and AD, Clinical Research approving trial oordinator completes Disease Group Form & obtains signature f disease

olObtains signature of Dr Sausville; assigns GCC( local) protocol Number

PI submits all protocol and budget documents in ELECTRONIC FORMAT, to the manager of CRSS. Requir d: Protocol, Model Consent, Investigator Brochure, IND Safety Reports, FDA/ Sponsor uments e Doc

(See Regulatory document checklist),

NCI, Co p Group, PI Initiated

Industry Trials -o

REGULATORY Manager of CRSS will electronically submit: Service request

form to the SOM Center for Clinical Trials (CCT): CRSS will contact GCC Grants Office and work with Grants Admi ator to Formulate Budget:

nistrPROCESS

CRSS Rdesignated Specialty

bReg. Coordinator

Includes entering info into BRAAN: we B

CRC Review

CRC

Essenti (Terri eckis)

completes pre re ments and

**Ma ed to the IRB as soon as possible. Do not wait for completion of clinical trial

a

egulatory Contact by Disease

CRC Submission

(Clinical Research Committee Submission)

y Disease Group

b based IR

Approval

al Docum nts CoordinatoreJong Docu.

routes to sponsor)

IRB Submission (Institutional Review Board)

terials should be submitt

http://www.medschool.umaryland.edu/cct

greement negotiations

Manager ema and sponsor), contract, protoc alysis (signed)

to CCT & Office of Research & Development (legal) Fax: 410-706-4853

ils or faxes draft budget (internal ol, study calendar, & Medicare An

Email: [email protected]

CCT will produce first budget draft. ORD will prepare contact. CRSS/ Manager will review f r accuracy and communicate with

PI and Study Coordinator o

C , e f

GCC. CRSS manager obtains re d signatures on CTA, Internal

D.

CT and ORD, upon completion of budget & CTA negotiationsmails the CRSS Manager Grants / Contacts Administrator o

quirebudget, billing analysis and sends back to CCT and OR

Schedule of Event or Sponsors Draft Budget required for budget negotiations**

s

Grants Administra confirms budget and other grant items with PI.

tor

Grants Office routes proposal through SOMs Office of Research & Development.

ORD will sign and execute the agr

g letter has been received Routing Form has been submitted to the Office of

Resear and approval has been returned to the CC

eement provided that: Principal Investigator has signed the agreement A copy of the protocol has been received for

permanent record. IRB approval / Pendin

ch and Graduate StudiesT.

ORD forwards the executed agreement and protocol to the Office search and Development for activation of FAS/ Rof Re aven

A copy of the executed agree ent will be sent to the Department

account.m

business contact and the Principal Investigator.

Grants Office routes proposal through SOMs Office of Research & Development.


Committee Structure Governing Clinical Research

at UMGCC


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.


ClinicalTrial(Proposed)

IRBReviewhumanprotections

CRCReviewscientificmerit

priority

ClinicalResearchSSconductstudy

CRSSOversightCommitteeSSoperationaloversight

ensureequalaccessidentifyresourcesforSS

DSMmonitoring

qa

CRCaccrualmonitoringClinicalTrial

(Completed/Closed)

Role of UMGCC Committees inReview of Clinical Trials and of Clinical Research Shared Service


CICERO

The IRBs Electronic Submission System Example Submission with Comments


CRC

Clinical Research Committee


University of Maryland Marlene and Stewart

Effective: July 2010

Procedure No: CRC001

Subject: Clinical Research Committee (CRC)

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.

p1 Clinical Investigator Handbook July 2010 Version - Page 37

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


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.


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 PIs 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 Childrens 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.


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 Sponsors 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


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


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 110, 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.


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 CRCs 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 chairs 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 PIs 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.


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 PIs response to the CRC, and the CRCs 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 PIs 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 CRCs 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.


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.


CRC Packet Sample documents

Download from cancer center server drive G to ensure most current version


REGULATORY DOCUMENT CHECKLIST FOR

CRC AND IRB SUBMISSION

Regulatory Coordinator __________________

Protocol #__________________________ Regulatory Preparation By_________________

CRC SUBMISSION Study will not be reviewed unless all documents

are completed and submitted

Initial when complete

IRB SUBMISSION Initial when complete

Please provide CRC Committee with the following:

Ensure completion of the following prior to submitting to IRB:

CICERO Protocol Completed CICERO Protocol CICERO Consent Completed CICERO Consent Copy of Sponsors Protocol Attach the following in section Final

Additional Documents of CICERO:

Copy of Sponsors Model Consent 1. Copy of Sponsors Protocol Investigator Brochure 2. Copy of Sponsors model consent ONCORE Study Schedule 3. Sponsor approval of UM draft consent) 4. Investigator Brochure IB Complete and print the following (may be found in CRC folder of G Drive

5. ONCORE Study Schedule

1. Disease Group Review Form - signed by chair; should be provided by PI with protocol documents

6. Disease Group Review Form - signed by chair; should be provided by PI with protocol documents

2. Completed Regulatory documents checklist 7. CRC review letter 8. PIs 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)

19. DSMP - Data Safety Monitoring Plan 20. Web Posting Version date: 10/18/08 21. Eligibility Checklist

22. Signed scanned1572


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-investigators 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


Version date 05.29.2008

1

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. Sponsors 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)


Version date 05.29.2008

2

Does this study have competing studies for patients? No X Yes partial overlap

0636GCC

DSI MEL/MEL 2005-01; H-28562; HP-00042681

A Random-Assignment Study Of Hepatic Arterial Infusion Of Melphalan With Venous Filtration Via Peripheral Hepatic Perfusion (PHP) (Delcath System) Versus Best Alternative Care For Ocular And Cutaneous Melanoma Metastatic To The Liver

Alexander, H Richard

OPEN TO ACCRUAL 04/25/2008

0794GCC H-29873;

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

Approval for issuance of GCC protocol number: Approved Disapproved Dr. Edward Sausville Date

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 VAMC Is GCC Coordinating Center Yes X No 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 If yes, how many? 12

Phase: X I /II II III Other

Protocol: Approved to be submitted to CRC Disapproved Chair Date


Cancer Center Data and Safety Monitoring Plan

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 DSMC and IRB.

___ High

(Prospective review) All SAEs reported to the IRB, FDA (if appropriate affiliated research sites) and DSMC in a timely fashion. Summary of SAEs 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 SAEs reported to the IRB, FDA (if appropriate affiliated research sites) and DSMC in a timely fashion. Summary of SAEs 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 SAEs submitted to the IRB, FDA and sponsor. Summary of SAEs 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)


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:

HelpExclusion

Criteria:

Help

Contact Person Help

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

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

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 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


One copy of this document, signed and dated, must be given to the research subject Revised: October 19, 2007 Page 1 of 2

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: UMB IRB APPROVAL NUMBER:

RESEARCHERS NAME:

RESEARCHERS 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 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), DHHS-Department 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 Revised: October 19, 2007 Page 2 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.


C1D1 C1D2 C1D8 C1D15 C1D21 C2D1 C2D2 C2D8 C2D15 C2D21 C3D1 C4D1 C4D21C5D1 C6D1 C6D21 End ofOff StudyAdverse Events R R R R R R R R R R R R R R R RBlood ChemistriesCBC w/diff and platelets, Comprehensive chemistry panel C C C C C C C C C C C C C C CBone Marrow [3; 4] C C C C C C RConcomitant Medications C C C C C C C C C C C C C C C C C C CCorrelative studies (non PK, PD) [6] REKG C CMedical History CPKs [5] R R R R R RPerformance status [1] C C C C C C C C CPhysical Exam C C C C C C C C CPregnancy Test [1] R RQuestionnaires R R R R R RTreatment AdministrationSCH 727965 R R R R R RTreatment AdministrationMylotarg C CUrinalysis R RVital SignsBSA calculation, Diastolic BP (mmHG), Pulse (/min), Respiration Rate (/min), Systolic BP (mmHG), Temperature (C) [2] R R R R R R R R R

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 only6. See protocol for timepoints. Certain timepoints only if patient has consented to pharmacogenomic substudy. If no consent for PG, then only SCH 727965 patients.

Calendar Foot Notes1. 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.

Pre TTreatment (ALL pts)

Treatment 6 Cycles @21Days

Study No.: 0844GCC Short Title: Ph 2 of SCH 727965 in Relapsed and Refractory AMLStatus: New


UM/SOM/CCT PRELIMINARY MEDICARE COVERAGE ANALYSIS/QUALIFYING CLINICAL TRIAL

(Only for use with non-phase I trials)

Principal Investigator Signature Principal Investigator Printed Name Date Version #6 10/29/08 Page 1 of 1

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 IIDETERMINATION OF DEEMED TRIAL

Question Yes No If Yes, Specify 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)?

Part IIIMedicare 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.


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 [email protected]. 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 CHAIRS SUMMARY OF PROTOCOL Adequate

(may need minor revisions)

Not Adequate

Appropriate prioritization within research group X Biostatistical input & review X Scientific justification X Study design appropriate X Risks appropriate for nature of disease X Standard of care maintained X Potential of accruing at acceptable pace X Consent form X CICERO protocol information X Data and safety monitoring plan described X


DSM level recommended by the CRC:

Routine ___ High ____ Highest ____ Special _X_ External

H. Richard Alexander, M.D.

Chair, Clinical Research Committee Date cc: Edward A. Sausville, M.D., Ph.D.

Mary Quinn, R.N. Charit Villena


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 Date cc: Edward A. Sausville, M.D., Ph.D.

Mary Quinn, R.N. Charit Villena


UNIVERSITY OF MARYLAND

CLINICAL RESEARCH COMMITTEEProtocol Review Worksheet

Reviewer's Name: Date:

Protocol Title & Number:

PI:

Co-PI: Co-PI:

Statistician for In-House Studies:

Phase:

Anticipated Accrual:

I

Rate of Accrual:Rationale:

Has sufficient scientific rationale been provided?

Has the hypothesis been clearly stated and justified?Study Design:

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

Are the objectives stated clearly?

Is the treatment plan feasible?

Given the study background and proposed plan, is the study ethical forconduct?

Is there "prioritization" among competing trials?

Are the eligibility criterion clear and objective?Biostatistics:

Have appropriate measures been applied to answer the protocol objective?

Is there evidence of biostatistical input into the study design?

Is there a data and safety monitoring plan described?Scientific Basis:

Has relative importance and value of trial been presented taking intoconsideration "standard" therapy and competing trials?

Financial impact/additional tests/procedures

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

II HI

No

No

No

No

No

No

No

No

No

No

No

No

Other

N/A

N/A

Other Comments:

Action: ___ Approve___ Approve with minor modifications

___ Request major modifications___ DisapproveClinical Investigator Handbook July 2010 Version - Page 63

DSM/QAC

Data and Safety Monitoring/Quality Assurance


University of Maryland Greenebaum Cancer Center

Effective: July 2010

Procedure No: DSM001

Subject: Data & Safety Monitoring Plan

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:

Investigator-initiated protocols except those for which the IRB has granted a waiver of consent (e.g., retrospective chart reviews)


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 IRBs 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


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)


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 higher-risk 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


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.


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


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 PIs 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 SAEs 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. PIs 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.


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 investigator-initiated 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

clinical investigator handbook

Documents

introduction clinical

initiation clinical

clinical research functions

clinical trials

umgcc prms

university of maryland

associate director

committee structure