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appendix a performance status criteria

| ECOG Performance Status Scale                                                                                                                                  | Karnofsky Performance Scale                                                          |                                                                  |                                                                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                          | Descriptions                                                                         | Percent                                                          | Description                                                            |
| 100                                                                                                                                                            | Normal, no complaints, no evidence                                                   |                                                                  |                                                                        |
| Normal activity. Fully active, able                                                                                                                            | of disease.                                                                          |                                                                  |                                                                        |
| 0                                                                                                                                                              | to carry on all pre-disease  performance without restriction.                        | 90                                                               | Able to carry on normal activity;  minor signs or symptoms of disease. |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or                              | 70                                                                                   | Cares for self, unable to carry on                               |                                                                        |
| sedentary nature (e.g., light                                                                                                                                  | normal activity or to do active work.                                                |                                                                  |                                                                        |
| housework, office work).                                                                                                                                       | 80                                                                                   | Normal activity with effort; some  signs or symptoms of disease. |                                                                        |
| 1                                                                                                                                                              | Requires occasional assistance, but                                                  |                                                                  |                                                                        |
| 60                                                                                                                                                             | is able to care for most of his/her                                                  |                                                                  |                                                                        |
| 2                                                                                                                                                              | needs.                                                                               |                                                                  |                                                                        |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours. | 50                                                                                   | Requires considerable assistance and  frequent medical care.     |                                                                        |
| In bed >50% of the time. Capable                                                                                                                               | 40                                                                                   | Disabled, requires special care and  assistance.                 |                                                                        |
| 3                                                                                                                                                              | of only limited self-care, confined  to bed or chair more than 50% of  waking hours. | 30                                                               | Severely disabled, hospitalization  indicated. Death not imminent.     |
| 100% bedridden. Completely                                                                                                                                     | 20                                                                                   | Very sick, hospitalization indicated.  Death not imminent.       |                                                                        |
| 4                                                                                                                                                              | disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.         | 10                                                               | Moribund, fatal processes  progressing rapidly.                        |
| 5                                                                                                                                                              | Dead.                                                                                | 0                                                                | Dead.                                                                  |  
| APPENDIX B   | LUGANO AND LYRIC RESPONSE CRITERIA (31, 32)                                                                                                      |                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
|--------------|--------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Criteria     | CR                                                                                                                                               | PR                                                                                                                                                                                                                                                                                              | PD PET-CT score 4 or 5 with an increase in intensity of uptake  from baseline and/or new FDG-avid foci consistent with  lymphoma at interim or end-of-treatment assessment. OR  On CT, an individual node/lesion must be abnormal with:  LDi >1.5 cm and increase by ≥50% from PPD nadir and an  increase in LDi or SDi from nadir 0.5 cm for lesions ≤2 cm  1.0 cm for lesions >2 cm                                                                                                                                                                                                                                                                                                                                                       |
| Lugano       | PET-CT,  score 1, 2, or  3 *with or  without a  residual mass  on 5PS†  OR  on CT, target  nodes/nodal  masses must  regress to  ≤1.5 cm in  LDi | PET-CT  score 4 or 5  with reduced  uptake  compared  with baseline  and residual  mass(es) of  any size. OR  On CT ≥50% decrease in  SPD of up to  6 target  measurable  nodes and  extranodal  sites                                                                                          | In the setting of splenomegaly, the splenic length must  increase by >50% of the extent of its prior increase beyond  baseline (eg, a 15-cm spleen must increase to >16 cm). If no  prior splenomegaly, must increase by ≥2 cm from baseline.  New or recurrent splenomegaly New or clear progression of preexisiting nonmeasured  lesions Regrowth of previously resolved lesions A new node >1.5 cm in any axis or a new extranodal site  >1.0 cm in any axis; if <1.0 cm in any axis, its presence  must be unequivocal and must be attributable to lymphoma Assessable disease of any size unequivocally attributable to  lymphoma AND/OR new or recurrent involvement of the bone marrow As with Lugano with the following exceptions: |
| LYRIC        | Same as                                                                                                                                          | Same as                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Lugano       | Lugano                                                                                                                                           | IR IR(1): ≥50% increase in SPD in first 12 weeks IR(2): <50% increase in SPD with a. New lesion(s), or b. ≥50% increase in PPD of a lesion or set of lesions at any  time during treatment IR(3): Increase in FDG uptake without a concomitant  increase in lesion size meeting criteria for PD |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
table of contents
1 introduction

The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC DSMP) outlines the pocedures for conducting a DF/HCC Multi-Center research protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC that will be participating in the research protocol.
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1.1 purpose

To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center protocol will comply with Federal Regulations, Health Insurance Portability and Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.
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1.2 multi-center data and safety

DF/HCC Multi-Center Protocol: A research protocol in which one or more outside institutions are collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates.  
Lead Institution: One of the Dana-Farber/Harvard Cancer Center consortium members (DanaFarber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center (BIDMC), Boston Children's Hospital (BCH), Brigham and Women's Hospital (BWH)) responsible for the coordination, development, submission, and approval of a protocol as well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.). The Lead Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also typically serves as the Coordinating Center for the DF/HCC Multi-Center Protocol. DF/HCC Sponsor: The person sponsoring the submitted Multi-Center protocol. Within DF/HCC, this person is the Overall Principal Investigator who takes responsibility for initiation, management and conduct of the protocol at all research locations. In applicable protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory agencies. The DF/HCC Sponsor has ultimate authority over the protocol and is responsible for the conduct of the study at DF/HCC and all Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC Overall Principal Investigator; however, both roles can be filled by two different people. Participating Institution: An institution that is outside the DF/HCC and DF/PCC consortium that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator. The Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and responsibility for the overall conduct of the study. Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol.  
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring highquality standards are used for data collection and the ongoing management of clinical trials, auditing, and data and safety monitoring. ODQ also coordinates quality assurance efforts related to multi-center clinical research. DF/HCC Research Informatics for Operations (RIO): A group within DF/HCC responsible for providing a comprehensive data management platform for managing clinical trial data.
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2 general roles and responsibilities

For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the Participating Institutions are expected to adhere to the following general responsibilities:
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2.1 df/hcc sponsor

The DF/HCC Sponsor, Dr. Eric Jacobsen, will accept responsibility for all aspects of conducting a DF/HCC Multi-Center protocol which includes but is not limited to:
Oversee the coordination, development, submission, and approval of the protocol as well as subsequent amendments.  
Ensure that the investigators, study team members, and Participating Institutions are qualified and appropriately resourced to conduct the protocol.  
Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.  
Ensure all Participating Institutions are using the correct version of the protocol.  
Ensure that each participating investigator and study team member receives adequate protocol training and/or a Site Initiation Visit prior to enrolling participants and throughout trial's conduct as needed.  
Ensure the protocol will be provided to each participating site in a language understandable to all applicable site personnel when English is not the primary language.  
Monitor progress and overall conduct of the study at all Participating Institutions.  
Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable reporting requirements are met.  
Review data and maintain timely submission of data for study analysis. Act as the single liaison with FDA (investigator-held IND trials), as applicable.  
Ensure compliance with all requirements as set forth in the Code of Federal Regulations, applicable DF/HCC requirements, HIPAA requirements, and the approved protocol.  
Commit to the provision that the protocol will not be rewritten or modified by anyone other than the DF/HCC Sponsor.  
Identify and qualify Participating Institutions and obtain accrual commitments prior to extending the protocol to that site.  
Monitor accrual and address Participating Institutions that are not meeting their accrual requirements.
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2.2 coordinating center

The general responsibilities of the Coordinating Center may include but are not limited to:
Assist in protocol development.  
Maintain FDA correspondence, as applicable.  
Review registration materials for eligibility and register participants from Participating Institutions in the DF/HCC clinical trial management system (CTMS).  
Distribute protocol and informed consent document updates to Participating Institutions as needed.  
Oversee the data collection process from Participating Institutions. Maintain documentation of Serious Adverse Event (SAE) reports and deviations/violation submitted by Participating Institutions and provide to the DF/HCC Sponsor for timely review and submission to the DFCI IRB, as necessary.  
Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions.  
Provide Participating Institutions with information regarding DF/HCC requirements that they will be expected to comply with.  
Carry out plan to monitor Participating Institutions either by on-site or remote monitoring.  
Maintain Regulatory documents of all Participating Institutions which includes but is not limited to the following: local IRB approvals/notifications from all Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all sites, all SAE submissions, Screening Logs for all sites, IRB approved consents for all sites Conduct regular communications with all Participating Institutions (conference calls, emails, etc) and maintain documentation all relevant communications.
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2.3 participating institution

Each Participating Institution is expected to comply with all applicable federal regulations and DF/HCC requirements, the protocol and HIPAA requirements. The general responsibilities for each Participating Institution may include but are not limited to:
Document the delegation of research specific activities to study personnel. Commit to the accrual of participants to the protocol.  
Submit protocol and/or amendments to their local IRB.  
Maintain regulatory files as per sponsor requirements.  
Provide the Coordinating Center with regulatory documents or source documents as requested.  
Participate in protocol training prior to enrolling participants and throughout the trial as required (i.e. teleconferences).  
Update Coordinating Center with research staff changes on a timely basis.  
Register participants through the Coordinating Center prior to beginning research related activities.  
Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements and to the Coordinating Center, in accordance with DF/HCC requirements.  
Submit protocol deviations and violations to local IRB per institutional requirements and to the DF/HCC Sponsor in accordance with DF/HCC requirements.  
Order, store and dispense investigational agents and/or other protocol mandated drugs per federal guidelines and protocol requirements.  
Have office space, office equipment, and internet access that meet HIPAA standards.  
Participate in any quality assurance activities and meet with monitors or auditors at the conclusion of a visit to review findings.  
Promptly provide follow-up and/or corrective action plans for any monitoring queries or audit findings.
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3 df/hcc requirements for multi-center

The following section will clarify DF/HCC Requirements and further detail the expectations for participating in a DF/HCC Multi-Center protocol.
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3.1 protocol distribution

The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent amended protocols to all Participating Institutions.
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3.2 protocol revisions and closures

The Participating Institutions will receive notification of protocol revisions and closures from the Coordinating Center. It is the individual Participating Institution's responsibility to notify its IRB of these revisions.  
**Non life-threatening revisions:** Participating Institutions will receive written notification of protocol revisions regarding non life-threatening events from the Coordinating Center. Non-life-threatening protocol revisions must be IRB approved and implemented within 90 days from receipt of the notification.  
**Revisions for life-threatening causes:** Participating Institutions will receive immediate notification from the Coordinating Center concerning protocol revisions required to protect lives with follow-up by fax, mail, e-mail, etc. Life-threatening protocol revisions will be implemented immediately followed by IRB request for approval.  
**Protocol closures and temporary holds:** Participating Institutions will receive notification of protocol closures and temporary holds from the Coordinating Center. Closures and holds will be effective immediately. In addition, the Coordinating Center, will update the Participating Institutions on an ongoing basis about protocol accrual data so that they will be aware of imminent protocol closures.
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3.3 informed consent requirements

The DF/HCC approved informed consent document will serve as a template for the informed consent for Participating Institutions. The Participating Institution consent form must follow the consent template as closely as possible and should adhere to specifications outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated Multi-Center Protocols. This document will be provided separately to each Participating Institution. Participating Institutions are to send their version of the informed consent document and HIPAA authorization, if a separate document, to the Coordinating Center for review and approval prior to submission to their local IRB. The approved consent form must also be submitted to the Coordinating Center after approval by the local IRB for all consent versions. The Principal Investigator (PI) at each Participating Institution will identify the physician members of the study team who will be obtaining consent and signing the consent form for therapeutic protocols. Participating institutions must follow the DF/HCC requirement that only attending physicians obtain informed consent and re-consent for all interventional drug, biologic, or device research.
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3.4 irb documentation

The following must be on file with the Coordinating Center:
Initial approval letter of the Participating Institution's IRB.  
Copy of the Informed Consent Form(s) approved by the Participating Institution's IRB.  
Participating Institution's IRB approval for all amendments. Annual approval letters by the Participating Institution's IRB.
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3.5 irb re-approval

Verification of IRB re-approval from the Participating Institutions is required in order to continue research activities. There is no grace period for continuing approvals. The Coordinating Center will not register participants if a re-approval letter is not received from the Participating Institution on or before the anniversary of the previous approval date.
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3.6 participant confidentiality and authorization

In 1996, congress passed the first federal law covering the privacy of health information known as the Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the physical or mental health of an individual is called Protected Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be used or disclosed. In order for covered entities to use or disclose protected health information during the course of a study, the study participant must sign an authorization statement. This authorization statement may or may not be separate from the informed consent document. The Coordinating Center, with the approval from the DFCI IRB, will provide a consent template, with information regarding authorization for the disclosure of protected health information.  
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials.  
However, because of the nature of these trials, certain protected health information must be collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather than limited data sets with data use agreements.
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3.6.1 df/hcc multi-center protocol confidentiality

All documents, investigative reports, or information relating to the participant are strictly confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be de-identified. It is recommended that the assigned protocol case number (as described below) be used for all participant specific documents. Participant initials may be included or retained for cross verification of identification.
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3.7 df/hcc multi-center protocol registration

3.7.1 Participant Registration and Randomization To register a participant, the following documents should be completed by the Participating Institution and e-mailed to the Coordinating Center:
Megan Forsyth Dana-Farber Cancer Institute 450 Brookline Ave Boston, MA 02215 Megan_Forsyth@DFCI.HARVARD.EDU Phone: 857-215-1405 Fax: 617-632-6625  
Copy of required laboratory tests including: All screening evaluations. Signed informed consent document Signed DFCI eligibility checklist HIPAA authorization form (if separate from the informed consent document)
Other appropriate forms (e.g., Eligibility Screening Worksheet, Registration form)
The Coordinating Center will review the submitted documents in order to verify eligibility and consent. To complete the registration process, the Coordinating Center will:
Register the participant on the study with the DF/HCC Clinical Trial Management System (CTMS).  
Upon receiving confirmation of registration, the Coordinating Center will inform the Participating Institution and provide the study specific participant case number, and, if applicable, assigned treatment and/or dose level.
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treatment or other protocol-specific interventions

Registration can only occur during normal business hours, Monday through Friday from 8:00 AM to 5:00 PM Eastern Standard Time.
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3.7.2 initiation of therapy

Participants must be registered with the DF/HCC CTMS before the initiation of treatment or other protocol-specific interventions. Treatment and other protocol-specific interventions may not be initiated until the Participating Institution receives confirmation of the participant's registration from the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must be notified of any violations to this policy.
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3.7.3 eligibility exceptions

No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be permitted. All Participating Institutions are required to fully comply with this requirement.
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3.8 df/hcc protocol case number

At the time of registration, the following identifiers are required for all subjects: initials, date of birth, gender, race and ethnicity. Once eligibility has been established and the participant successfully registered, the participant is assigned a unique protocol case number. Participating Institutions should submit all de-identified subsequent communication and documents to the Coordinating Center, using this case number to identify the subject. 3.8.1 Protocol Deviations, Exceptions and Violations Federal Regulations require an IRB to review proposed changes in a research activity to ensure that researchers do not initiate changes in approved research without IRB review and approval, except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC requires all departures from the defined procedures set forth in the IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB. For reporting purposes, DF/HCC uses the terms "violation", "deviation" and "exception" to describe departures from a protocol. All Participating Institutions must adhere to these requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for reporting to their local IRB.
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3.8.2 definitions

Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved protocol which is *prospectively approved* prior to its implementation. Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g. enrollment of a participant who does not meet all inclusion/exclusion criteria. Protocol Violation: Any protocol deviation that was not *prospectively approved* by the IRB prior to its initiation or implementation.
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3.8.3 reporting procedures

DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical record and/or regulatory documents to describe all protocol exceptions, deviations and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol violations/deviations are promptly reported per DFCI IRB guidelines. Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. The Participating Institution must submit the deviation request to the Coordinating Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is submitted to the Participating Institution IRB, per institutional policy. A copy of the Participating Institution's IRB report and determination will be forwarded to the Coordinating Center within 10 business days after the original submission. The deviation may not be implemented without all required approvals. All protocol violations must be sent to the Coordinating Center in a timely manner. The Coordinating Center will provide training for the requirements for the reporting of violations. Coordinating Center: Upon receipt of the violation/deviation report from the Participating Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. Subsequently, the Participating Institution's IRB violation/deviation report will be submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will forward all violation reports to CTEP via an internal DF/HCC process, as applicable.
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3.9 safety assessments and toxicity

The study teams at all participating institutions are responsible for protecting the safety, rights and well-being of study participants. Recording and reporting of adverse events that occur during the course of a study help ensure the continuing safety of study participants. All participants receiving investigational agents and/or other protocol mandated treatment will be evaluated for safety. The safety parameters include all laboratory tests and hematological abnormalities, physical examination findings, and spontaneous reports of adverse events reported by participants. All toxicities encountered during the study will be evaluated according to the NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating Center. Additional safety assessments and toxicity monitoring will be outlined in the protocol. 3.9.1 Guidelines for Reporting Serious Adverse Events Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed in protocol section 7.  
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating Center following the DFCI IRB Adverse Event Reporting Policy. The Coordinating Center will maintain documentation of all Participating Institution Adverse Event reports and be responsible for communicating to all participating investigators, any observations reportable under the DFCI IRB Reporting Requirements. Participating Institutions will review and submit to their IRB according to their institutional policies and procedures 3.9.2 Guidelines for Processing IND Safety Reports The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports are distributed to the Participating Institutions. Participating Institutions will review and submit to their IRB according to their institutional policies and procedures.
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3.10 data management

DF/HCC RIO develops case report forms (CRF/eCRFs), for use with the protocol. These forms are designed to collect data for each study. DF/HCC RIO provides a web based training for all eCRF users.
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3.10.1 data forms review

Data submissions are monitored for timeliness and completeness of submission. If study forms are received with missing or questionable data, the submitting institution will receive a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, or designee. Responses to all queries should be completed and submitted within 14 calendar days. Responses may be returned on the written query or on an amended paper case report form, or in the case of electronic queries, within the electronic data capture (eDC) system. In the case of a written query for data submitted on a paper case report form, the query must be attached to the specific data being re-submitted in response. If study forms are not submitted on schedule, the Participating Institution will periodically receive a Missing Form Report from the Coordinating Center noting the missing forms.
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4 requisitioning investigational drug

The ordering of investigational agent is specified in the protocol section 8.1. Participating Institutions should order their own agent regardless of the supplier.  
If the agent is commercially available, check with the local Director of Pharmacy and/or the Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the agent can be ordered once the protocol is approved by the local IRB. If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent according to state and federal requirements. The local IRB should be kept informed of who will supply the agent so that any regulatory responsibilities can be met in a timely fashion.
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5 monitoring quality control

The quality control process for a clinical trial requires verification of protocol compliance and data accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality control oversight for the protocol.
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5.1 ongoing monitoring of protocol

The Participating Institutions may be required to submit participant source documents to the Coordinating Center for monitoring. Participating Institution may also be subject to on-site monitoring conducted by the Coordinating Center.  
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating Institutions are complying with regulatory and protocol requirements, data quality, and participant safety. Monitoring will occur before the clinical phase of the protocol begins, continue during protocol performance and through study completion. Additional monitoring practices may include but are not limited to; source verification, review and analysis of the following: eligibility requirements of all participants, informed consent procedures, adverse events and all associated documentation, study drug administration/treatment, regulatory files, protocol departures, pharmacy records, response assessments, and data management. Participating institutions will be required to participate in monthly Coordinating Center initiated teleconferences. E-mails highlighting overall protocol progress and important announcements will be distributed regularly.  
On-Site Monitoring: Participating institutions will be required to participate in monitoring one onsite visit. At this time, source documentation verification (SDV) will be conducted by having access to participants' complete medical record and source documents. Access to the site regulatory binder and site's pharmacy records will also be required. Remote Monitoring: Participating Institutions will be required to forward de-identified copies of participants' eligibility packetsand informed consent documents to the Coordinating Center to aid in source data verification within 30 days of subject enrollment. Source verification of all case report form data will occur remotely once per patient. At the time of visit, participating institutions will be required to forward de-identified copies of the participant's medical record to the Coordinating center for review.
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5.2 monitoring reports

The DF/HCC Sponsor will review all monitoring reports for on-site and remote monitoring of Participating Institutions to ensure protocol compliance. The DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that are unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local regulations. Participating Institutions may also be subject to an audit as determined by the DF/HCC Sponsor.
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5.3 accrual monitoring

Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual requirements for each participating institution. Accrual will be monitored for each participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations may be subject to termination. It is expected that a minimum accrual of at least 2 patients per site annually will occur.
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6 auditing quality assurance

Auditing is a method of Quality Assurance and involves the systematic and independent examination of all trial related activities and documents. Audits determine if evaluated activities were appropriately conducted and whether data was generated, recorded and analyzed, and accurately reported per the protocol, applicable Standard Operating Procedures (SOPs), and the Code of Federal Regulations (CFR).
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6.1 df/hcc internal audits

All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, approximately 3-4 participants would be audited at the site over a 2-day period. If violations which impact participant safety or the integrity of the study are found, more participant records may be audited.
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6.2 audit notification

It is the Participating Institution's responsibility to notify the Coordinating Center of all external audits or inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will forward a copy of final audit and/or re-audit reports and corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the audit date.
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6.3 audit reports

The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee would forward the final audit report and corrective action plan to the DFCI IRB as applicable.
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6.4 participating institution performance

The DF/HCC Sponsor and the DFCI IRB are charged with considering the totality of an institution's performance in considering institutional participation in the protocol. Participating Institutions that fail to meet the performance goals of accrual, submission of timely and accurate data, adherence to protocol requirements, and compliance with state and federal regulations, may be recommended for a six-month probation period. Such institutions must respond with a corrective action plan and must demonstrate during the probation period that deficiencies have been corrected, as evidenced by the improved performance measures. Participating Institutions that fail to demonstrate significant improvement will be considered by the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB may terminate a site's participation if it is determined that a site is not fulfilling its responsibilities as described above.