Data and Safety Monitoring Plancancer.ucsf.edu/itr/sm_files/DSMPNCI_Approved_09February... · 2017-01-20 · Data and Safety Monitoring Plan . Page 2 of 54 Approved by NCI 09/February2012

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Approved by NCI 09/February2012

Revision #2 submitted to NCI 11/01/2011

Approved by NCI 8/23/2007



University of California at San Francisco Helen Diller Family Comprehensive

Cancer Center

(UCSF HDFCCC)

Data and Safety Monitoring Plan

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Table of Contents

I. Introduction 3

II. Responsibilities of Cancer Center and Clinical Research Committees 3

III. Data and Safety Monitoring Plan: Required Elements 5

IV. Guidelines for Data and Safety Monitoring Implementation 6

V. Implementation of Reporting Requirements 6

VI. Monitoring Procedures 8

VII. Data Quality Control 10

VIII. Conflicts of Interest 11

APPENDICES

A. UCSF ITR Organizational Chart 13

B. List of Site Committees and Chairs 14

C. List of members of the Data and Safety Monitoring Committee 15

D. Data and Safety Monitoring Report (Subject Review) 16

E. Data and Safety Monitoring Report (Regulatory Review) 20

F. Model DSMP templates for investigators to insert into protocols

1. DSMP for Phase 1 Dose Escalation Study (Single Site) 23

2. DSMP for Phase 1/Pilot Study (Single Site) 25

3. DSMP for Phase 2 or 3 Study (Single Site) 27

4. DSMP for a CTEP Study (Phase 1 Dose Escalation) 29

5. DSMP for a CTEP Study (Phase 1/Pilot) 32

6. DSMP for a CTEP Study (Phase 2 or 3) 34

7. DSMP for a Behavioral Study (Single Site) 36

8. DSMP for a Multicenter Study (Phase 1 Dose Escalation) 38

9. DSMP for a Multicenter Study (Phase 1/Pilot) 42

10. DSMP for a Multicenter Study (Phase 2 or 3) 45

G. Guidelines for Establishing and Operating an External DSMB 48 H. Risk Assessment for Institutional Studies during DSMC Review 51

I. Policy for Verbal Notification of Newly Identified Risks 52

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Data and Safety Monitoring Plan

UCSF Helen Diller Family Comprehensive Cancer Center

I. Introduction

UCSF Helen Diller Family Comprehensive Cancer Center - Overview

The University of California at San Francisco Helen Diller Family Comprehensive Cancer

Center (HDFCCC) is a National Cancer Institute (NCI) designated matrix center conducting a

wide range of interdisciplinary research in the areas of laboratory, clinical, and population

sciences. The HDFCCC is led by the Director of the Center who is assisted by a Deputy

Director, and a Director’s Group which includes a Director of Clinical Sciences, a Director of

Population Science, a Director of Technology and a Director of Strategic Planning and Clinical

Services. The Director of Clinical Sciences serves as Director of the Investigational Trials

Resource (ITR), which is in charge of the oversight of clinical research at the HDFCCC.

Operational Definition of a Clinical Trial (NCI definition)

For purposes of the Data and Safety Monitoring Plan (DSMP), a clinical trial is operationally

defined as a prospective study involving human subjects designed to answer specific questions

about the effects or impact of particular biomedical or behavioral interventions. Therapeutic

clinical trials are defined as studies with therapeutic intent using drugs, radiation, surgery, other

biological agents, or behavioral or other interventions. Participants in these trials may be

patients with cancer or people without a diagnosis of cancer, but at high risk for developing

cancer.

In the area of molecular or imaging diagnostics, a study is considered a clinical trial if it uses the

information from the diagnostic test in a manner that affects medical decision-making for the

study subjects. By contrast, studies which do not use information from the diagnostic test in any

manner that can affect the outcome of study subjects, but whose objective is only the gathering

of data on the characteristics of a new diagnostic approach, are not considered clinical trials and

are not covered by this DSMP. An exception to this definition is made if performing the

diagnostic test itself imposes some risk on study subjects, in which case the study would be

considered a clinical trial.

II. Responsibilities of the Comprehensive Cancer Center and UCSF Clinical Research

Committees

Investigational Trials Resource (ITR) is responsible for the entire clinical research

enterprise within the HDFCCC, including the oversight of the Clinical Research Support

Office (CRSO), the Data and Safety Monitoring Committee (DSMC), and the Protocol

Review Committee (PRC) which is involved with Protocol Review and Monitoring

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Systems (PRMS). The ITR Steering Committee is responsible for developing overall

policy providing guidance and directions for PRMS, DSMC, and the CRSO.

Clinical Research Support Office (CRSO). The CRSO is responsible for providing

staffing and management of studies, including protocol preparation, and GCP

compliance. The CRSO is responsible for the office of record for clinical trials for the

HDFCCC, which maintains the regulatory records for institutional clinical trials, and

prepares PRC and IRB submissions,

Site Committees (SC) are responsible for reviewing the new protocols for

scientific merit and feasibility, generating new research ideas, and mentoring young

investigators. Research protocols must be reviewed and approved by the Site Committee

prior to submission to the PRC. Site Committees also set targeted annual accrual

expectations and evaluate accrual for all open studies. Site Committees will also close

trials with poor accrual to ensure appropriate utilization of resources. Additionally, Site

Committees will review and prioritize all protocols and protocol amendments before they

are submitted to the PRC. Site Committees are responsible for the real-time review of

toxicities in all open studies, The Site Committees meet weekly (Phase 1) to monthly

(Phase 2/3) to monitor accrual and toxicities on all clinical trials within their program.

(Appendix B).

Protocol Review Committee (PRC) is responsible for reviewing all HDFCCC clinical

trial protocols for scientific merit including clinical trial design, accrual, and the data and

safety monitoring plan. Any clinical trial protocols must be approved by the PRC before

submission to the UCSF IRB. The PRC meets monthly.

UCSF Committee on Human Research (CHR) is UCSF's Institutional Review Board

(IRB). At present, the CHR is comprised of four panels that share equal authority and

responsibility. The CHR reviews all HDFCCC protocols and determines final status

(approval/disapproval). It is the responsibility of the CHR to impose non-voluntary

closures of studies, and it may suspend clinical research trials for safety reasons

independent of the Data and Safety Monitoring Committee. However, if the Data and

Safety Monitoring Committee (DSMC) determines that a study should be closed, the

CHR will close that study and mandate that accrual be halted. This can occur either

through agreement with the investigators or by formal action by the DSMC or the CHR.

Data and Safety Monitoring Committee (DSMC) is responsible for monitoring and

auditing institutional clinical trials for data validity, trial conduct, and serious adverse

event (SAE) reporting. The risk assessment of the study is determined by the phase of

the trial, which in turn, designates the frequency of monitoring of the studies (see

Appendix H). The goal is to have Phase 1 studies monitored monthly by the DSMC,

dependent upon accrual, and beginning within one month of the initiation of enrollment.

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The DSMC must approve any dose escalation decision on a UCSF Institutional Phase 1

trial. While the DSMC has the ability to meet on an ad hoc or emergency basis, it

normally meets every six (6) weeks. In the event that a cohort dose escalation decision

needs to be made in between DSMC meetings, the DSMC Chair (or Vice Chair) has the

authority to approve the dose escalation. The dose escalations are approved by the

DSMC Chair or qualified alternate (i.e. Vice Chair) within two business days of the

request. Dose escalation decisions made by the Chair or Vice Chair require

confirmation by the full DSMC at the next DSMC meeting.

The goal for monitoring Phase 2 and 3 studies by the DSMC is twenty percent of the

enrolled subjects twice per year. The regulatory files for all studies are monitored for

regulatory compliance annually.

DSMC monitoring reports are reviewed by the DSMC Chair and committee at the DSMC

meeting following the monitoring visit(s). The DSMC may request additional data or add

recommendations. Once the monitoring report is approved by the DSMC Chair, the

report is sent to the PI. If serious non-compliance is identified during a monitoring visit,

the DSMC will recommend to the DSMC Chair that a voluntary hold on accrual be

implemented while a Corrective Action and Prevention Plan (CAPA) is being formulated.

If there is serious or repeated non-compliance to Good Clinical Practices (GCPs) or there

is an increased risk to subject safety, the DSMC may recommend that the CHR mandate

closure. The DSMC Chair reports to the ITR Director and also is a member of the ITR

Steering Committee.

III. Data and Safety Monitoring Plan: Required Elements

All clinical trials conducted at the UCSF Comprehensive Cancer Center must have a

satisfactory DSMP that is summarized in the protocol. These plans will be

reviewed by the PRC as part of the protocol approval process and are evaluated in

relation to the potential risks and scale of the trial. Low-risk behavioral trials also require

a DSMP and are evaluated by the PRC on a case-by-case basis.

Elements of a Data and Safety Monitoring Plan (DSMP) include:

A. Delineation of responsibilities:

For all therapeutic and non-therapeutic interventional trials, the Principal Investigator

(PI) is responsible for supervision of the protocol conduct, patient consent procedure

and enrollment, collection of data, including adverse event reporting and ensuring the

protocol has current IRB approval. The Principal Investigator is also responsible for

all reporting of safety-related events to the HDFCCC DSMC, the CHR, the FDA

(when the trial is conducted under an Investigational New Drug Application), the

participating sites for multicenter studies (when UCSF is the lead site), the federal

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regulators, and the NCI CTEP (as applicable). In addition, the PRC, on a case-by-

case basis, can request that the Principal Investigator convene an external Data and

Safety Monitoring Board (DSMB) (see Appendix G). This would usually involve

certain high-risk trials, such as gene-therapy, or knowledge of new safety information

that changes the risk-benefit ratio.

In Phase 3 trials without external auditors, an external Data and Safety Monitoring

Board (DSMB) must be appointed to review safety data at pre-specified intervals, or

at least annually. Recommendations of the DSMB for continuation of a trial will

normally replace and have precedence over the annual HDFCCC DSMC review.

B. Description of data and safety review process:

• Timetable for submission of reports to the UCSF HDFCCC DSMC as applicable

for the trial

• The timetable of the reporting of adverse events to the DSMC

• The closure of a study and/or notification of its participants when significant risks

are identified

IV. Guidelines for Data and Safety Monitoring Implementation

A. Principal Investigators will conduct review of data and patient safety at their Site

Committee meetings. Phase 1 trials will receive weekly review and Phase 2 and 3 trials

will receive monthly review. Minutes of these meetings and results will be kept, with

the discussion and conclusions documented in the minutes. The discussion should

include the following elements:

Screening, new subject enrollment, and accrual rates

A per subject review of:

o Significant toxicities as described in the protocol

o Grading of all significant toxicities

o Attribution of the relationship of the toxicity to the study drug

o Determination whether a toxicity was expected or unexpected

o Dose modifications per protocol

o Rate of occurrence of adverse events as compared to the investigators brochure or

package insert

B. Phase 3 Trials, certain high-risk trials, and trials enrolling greater than 300 subjects

must have an external DSMB. The PRC can request the DSMC to assist the PI to set up

an external DSMB for institutional trials. The PRC will not approve a therapeutic phase

3 trial sponsored by a cooperative group without a DSMB. The DSMB committee must

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be in place prior to opening the study. The composition of the committee, the frequency

of its meetings, and nature of the statistical evaluations to be conducted, and the review

procedures must be outlined in the research proposal.

C. Phase 1 - 3 non-therapeutic interventional clinical trials (including behavioral studies)

must have a DSMP that is directed toward anticipated risks of the study and is

commensurate with the level of risk to the participants. The DSMP must be included in

the research proposal and must be approved by the PRC prior to opening the study.

V. Implementation of Reporting Requirements

A. Suspected Adverse Reactions Considered “Serious” Reporting

Expedited suspected adverse reactions considered “serious reporting must be sent to

the DSMC, in addition to the regulatory institutions appropriate to the trial, per the

institution’s requirements (i.e. CHR, NCI, FDA, or cooperative groups).

All deaths, related to the study drug or study procedure, must be reported by the

Principal Investigator to the DSMC chair within one business day and the FDA

within 7 business days.

All suspected adverse reactions considered “serious”, regardless of the relationship

to the study will be tracked in OnCore®, the UCSF HDFCCC data management tool

All suspected adverse events considered “serious” will be reviewed every six weeks

by the DSMC.

The Principal Investigator is responsible for notifying all enrolled subjects of newly

identified risks that have not been incorporated into the CHR-approved informed

consent forms (ICF) (see Appendix I).

The Principal Investigator (or Study Chair) shall be responsible for notification of

other participating institutions if the clinical trial involves multiple institutions and

UCSF is the lead institution, according to the protocol.

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B. Study Progress

• The DSMC will use DSMC monitoring reports, protocol stopping rules, and

safety reports to determine whether a study warrants closure.

All DSMB reports and external audits must be submitted to the DSMC, whether

from appointed DSMBs or from cooperative groups.

The recommendations of the DSMC are forwarded to the Director of Clinical

Science. The Director of Clinical Science and the DSMC Chair will advise the

CHR of any serious non-compliance or continuous non-compliance issues.

The Principal Investigator is responsible for notification of all co-investigators,

the CHR, FDA (when the study is conducted under an IND), and any external

funding agencies of study suspected adverse events considered “serious”.

If the study is receiving NIH funding, the PI is responsible for notifying the NIH

of study closures.

VI. Monitoring Procedure

The DSMC determines when to monitor a study based upon the level of risk and accrual

as outlined in Appendix H. The DSMC Monitor manages the logistics associated with

the monitoring review sessions. Once the clinical trial is identified for monitoring, the

DSMC Monitor arranges for a selection of cases to monitor from among the subjects

registered in OnCore®, based upon the guidelines in Appendix H. OnCore® is the

clinical trials data management system used for electronic data capture and study

enrollment information, as well as other important data management functions. The

Principal Investigator and Study Coordinators are notified via e-mail in advance of a

scheduled monitoring session to arrange a mutually agreed upon time for the

monitoring session. The investigator and research staff are responsible for gathering all

of the materials needed for this review, including medical charts and other research

records requested. If there are multiple research sites, the sub-sites are responsible for

faxing over all documents to the coordinating site.

The DSMC Monitor reviews the regulatory documentation via iMeDRIS®, which is the

CHR database for managing regulatory reviews and submissions, to review the

following in single-site studies:

• Approval dates for protocols and amendments with no lapses in ongoing

approvals

• Approved informed consent forms (ICF)

• Approved study documents (i.e. patient diaries)

• Suspected adverse reactions considered “serious”, IND Safety Reports, and

protocol violations reported to CHR

• Approved single patient exceptions (SPE)

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Additionally, for multi-site studies, the DSMC uses iMedRIS® to review the following:

• Reviews that the protocol amendments and ICF changes have CHR approval prior

to distribution to the participating sites.

The DSMC Monitor reviews the medical records as the source document and verifies

data entry in the electronic case report form (OnCore®). The source document is

reviewed to ensure that there is adherence to the protocol and to verify if there are safety

issues with the conduct of the study. The following areas are examined and documented:

• Informed consent forms properly obtained

• Any required pre-study tests and procedures are obtained within the designated

pre-treatment time interval

• All eligibility criteria were met

• Adherence to treatment plan is documented including drug doses and drug

reductions and/or treatment holds, if indicated

• Accuracy, adequacy, completeness, and timeliness of data collection and

submission

• Appropriate and timely recording of adverse events (AEs) and reporting suspected

adverse reactions considered “serious” to the CHR

• Review of possible dose limiting toxicities (DLTs)

• Adherence to patient follow-up requirements

Following the completion of the monitoring session, the DSMC Monitor completes the

Monitoring Report (see Appendix D), which describes the findings of this monitoring

visit. The study is given an overall evaluation by the DSMC Monitor (and approved by

the DSMC Chair) of the following:

• Satisfactory (no follow-up required)

• Acceptable with follow-up items to be completed

• Significant findings with follow-up response to DSMC required

• Unsatisfactory, halt enrollment of new subjects, corrective action plan required

within 10 days to the DSMC. The DSMC Chair will notify the CHR regarding

the results of this audit/monitoring visit

This evaluation is based upon the findings of the monitoring session(s) and includes GCP

compliance issues, subject safety issues, and protocol adherence issues. In rating the

conduct of the study, the DSMC categorizes variances from the protocol as protocol

violations. Major Protocol Violations are variances from the clinical trial-specified

criteria or procedures that make the resulting data questionable and can affect patient

safety. Examples of these would include failure to obtain informed consent prior to study

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related procedures or treatment or not reporting dose limiting toxicities. Minor

Protocol Violations are those that do not affect the outcome or interpretation of the study.

Examples of these would include the investigator not grading the clinical significance of

an abnormal lab or ECG or a subject occasionally forgetting to take the study drug during

the study.

The significant findings of the DSMC Report are presented to the DSMC Chair

Committee and the committee votes on the following recommendations:

• Full Approval: Enrollment may continue; no outstanding questions regarding

toxicity and/or accrual

• Conditional Approval: Enrollment may continue conditionally upon a

satisfactory response by the Principal Investigator to the DSMC concerning study

conduct, toxicities, and/or accrual

• Suspension: Enrollment is immediately suspended pending Principal Investigator

response to DSMC concerns regarding serious protocol violations

• Closure: Study is closed due to unacceptable study conduct and toxicities

The DSMC Committee’s decision is sent to the study’s Principal Investigator in writing,

along with a copy of the monitoring report. If the Principal Investigator decides to appeal

the DSMC decision, he/she may do so in writing.

VII. Data Quality Control

A. Data Quality Audits

The DSMC will conduct audits for all single site and multisite therapeutic and

behavioral institutional trials. Audits will include a review of compliance for

regulatory adherence, review of staffing with roles and responsibilities of the PI,

nurses and data managers. For each study, a sample of enrolled patients will be

selected for chart review. Depending on the phase of the study, the audit will review,

at a minimum:

• Informed consent and eligibility

• Registration of the study in OnCore®

• Randomization documentation (if applicable)

• Adherence to the protocol: protocol deviations or violations

• Administration of drug, correct dose, and dose adjustments due to adverse

events,

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• Case report form completion/accuracy

• Recording of adverse events including CTC grading and attribution of

each event

• Reporting of adverse reactions considered “serious”

• Evaluation of disease progression and tumor measurement (where

applicable)

The results of these audits are reviewed by the DSMC. Serious instances of non-

compliance are referred by the DSMC Chair to the Director of Clinical Science and CHR

for further review and potential recommendation for protocol closure.

B. Post-Audit Quality Improvement Plan

The Post-Audit Quality Improvement Plan is required if serious issues of non-compliance

are discovered in the monitoring of therapeutic and behavioral institutional studies.

Overall, the Principal Investigator is responsible for the quality of the data in these

institutional studies. For multicenter studies, the Study Chair holds this responsibility.

The Post-Audit Quality Improvement Plan would involve halting additional accrual into

the study until an acceptable Corrective Action and Prevention Action for non-

compliance (CAPA) plan is developed by the PI and reviewed by the DSMC. This Post-

Audit Quality Improvement Plan would include re-training of the program staff, as well

as adjustment of workload and assignments of the program staff by the lead CRC. Audits

by the DSMC would be performed during this period to ensure that processes to achieve

good clinical practices (GCP) are maintained. The PI or Study Chair would be required

to wait for DSMC approval before resuming accrual. After accrual is resumed, the study

would be monitored more frequently for a period of one year. Phase 1 studies would be

monitored monthly and Phase 2/3 studies would be monitored every three months

(depending on accrual rates). If the audit shows improvement in compliance, the Phase 2

and 3 studies would be audited within another 3-6 months and Phase 1 studies would be

monitored monthly by the DSMC to ensure that this compliance is maintained.

VIII. Conflict of Interest

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The UCSF Office of Research monitors financial conflict of interest through submission

of contracts and grants. Conflict of interest in the course of internal monitoring by the

DSMC is avoided since the DSMC monitors are members of the ITR (Investigational

Trials Resource) and, thus, have no reporting relation to the investigator or sponsor and

do not participate in direct study management. However, if the DSMC Chair is the PI of

the institutional clinical study, this individual would be recused from their responsibility

as the DSMC Chair for this study and a qualified alternate (i.e. Vice Chair) would be

selected.

Additionally, statistical reviews are never performed by the same individual involved in

the study development and design. Applicants provide the name of the UCSF

biostatistician involved in institutional protocol development as part of the PRC

application; if that statistician sits on the PRC, the PRC Administrator will assign a

different statistician for review. As an additional measure, the name of the study

statistician is on the face page of the protocol template used by the Clinical Research

Support Office (CRSO).

With regards to potential conflict of interest for the Principle Investigators who are

members of the PRC, the PIs will not attend the meeting and, if they sit on the PRC, are

asked to leave the room during the review process (as are members who were otherwise

involved in the study design).

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Appendix A. UCSF Investigational Trials Resource (ITR) Organizational Chart

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Appendix B. UCSF HDF CCC Site Committees

Site Committee Chair/ Co-Chair

Breast John Park, MD/ Laura Esserman, MD

Skin/Endocrine/Gynecological/Other (SEGO) Adil Daud, MD/ Sue Yom, MD

Early Phase Pamela Munster, MD/ Mark Moasser, MD

Gastrointestinal Andrew Ko, MD/ Emily Bergsland, MD/

Genitourinary Charles Ryan, MD/ Kirsten Greene, MD

Hematopoietic Thomas Martin, MD/

Charalambos Andreadis, MD

Neurologic Michael Prados, MD/ Nicholas Butowski, MD

Oral, Head & Neck Annemieke Van zante, MD/ Jeanne Quivey, MD

Pediatric Oncology/Pediatric Leukemia Kate Matthay, MD Anu Banerjee, MD

Supportive Care Christine Miaskowski, RN/ Laura Dunn, MD

Thoracic Thierry Jahan, MD/ David Jablons, M.D.

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Appendix C. UCSF HDF CCC Data Safety Monitoring Committee

Alan Venook, MD Chair and Gastrointestinal Oncology

Andrew Ko, MD Vice Chair and Gastrointestinal Oncology

Thierry Jahan, MD Vice Chair and Thoracic Oncology

Adil Daud Cutaneous Oncology

Michael Prados MD Neurologic Oncology

Biljana Horn, MD Pediatric Malignancies

Michelle Melisko, MD Breast Oncology

Charles Ryan, MD Urologic Oncology

Weiyun Ai, MD Hematopoietic Malignancies

Robert Warren, MD Surgical Oncology

Vivian Weinberg, PhD Biostatistics Core

Monica Lee, Pharm. D. Investigational Pharmacy

Zoe Ngo, Pharm. D. Investigational Pharmacy

Data and Safety Monitors:

John F. McAdams, M.S., CCRC DSMC Monitor

Robert L. Kuhn, M.A., CCRP DSMC Monitor

Bernadette Paolini, R.N., CCRC DSMC Monitor

Maureen Lance, BSN, CCRC DSMC Monitor

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Appendix D. Data and Safety Monitoring Report (Subject Review)

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Revision #2 submitted to NCI 11/01/2011 and approved on 09February2012




Submitted to NCI July 2002

Page 18 of 54 Revision #2 submitted to NCI 11/01/2011 and approved on 09February2012












Appendix E. Data and Safety Monitoring Report (Regulatory Review)









Appendix F. Model DSMP templates for investigators to insert into protocols

Note to Investigators: These plans are meant as templates for your funding applications and for

your protocol preparation.

Please contact the DSMC for updated templates.

Page 23 of 54 Approved by NCI 09/February2012





Appendix F.1

Data and Safety Monitoring Plan for a Phase I Dose Escalation Institutional Study

The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and

Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and

subject safety for all HDFCCC institutional clinical studies. A summary of DSMC

activities for this study includes:

• Review of subject data in each cohort

• Review of suspected adverse reactions considered “serious”

• Approval of dose escalation by DSMC Chair (or qualified alternate)

• Monthly monitoring (depending on study accrual)

• Minimum of a yearly regulatory audit

Monitoring and Reporting Guidelines

Investigators will conduct continuous review of data and subject safety and discuss each

subject’s treatment at weekly Site Committee meetings. The discussions are documented

in the Site Committee meeting minutes. For each dose level, the discussion will include

the number of subjects, significant toxicities in accordance with the protocol, doses

adjustments, and observed responses.

All institutional Phase 1 therapeutic studies are designated with a high-risk assessment;

therefore, the data is monitored once per month as subjects are enrolled through the DLT

period.

Adverse Event Review and Monitoring

All clinically significant adverse events, whether or not unexpected, and whether or not

considered to be associated with the use of the study drug, will be entered into

OnCore®, UCSF’s Clinical Trial Management System.

All clinically significant adverse events entered into OnCore® will be reviewed on a

weekly basis at the Site Committee meetings. The Site Committee will review and

discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the

adverse event to the administration of the study drug(s).

In addition, all suspected adverse reactions considered “serious” are entered into

OnCore® and will be reviewed and monitored by the Data and Safety Monitoring

Committee on an ongoing basis and discussed at the DSMC meetings, which take place

every six (6) weeks.






If a death occurs during the treatment phase of the study or within 30 days after the last

administration of the study drug(s) and is determined to be related either to the study

drug(s) or to a study procedure, the Investigator or his/her designee must notify the

DSMC Chair or his qualified alternate within 1 business day of knowledge of this event.

The contact may be by phone or e-mail.

Dose Escalations

At the time of dose escalation, a written report will be submitted to the DSMC Chair (or

qualified alternate) describing the cohorts, dose levels, adverse events, safety reports, and

any Dose Limiting Toxicities observed, in accordance with the protocol. The report will

be reviewed by the DSMC Chair (or qualified alternate) and written authorization to

proceed or a request for more information will be issued within 2 business days of the

request. Approval for dose escalation by the DSMC (or qualified alternate) must be

obtained prior to implementation.

Increase in Adverse Event Rates

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in

the Investigator Brochure or package insert) is noted in the study, a report should be

submitted to the DSMC at the time the increased rate is identified. The report will

indicate if the incidence of adverse events observed in the study is above the range stated

in the Investigator Brochure or package insert.

If at any time the Investigator stops enrollment or stops the study due to safety issues, the

DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail.

The DSMC must receive a formal letter within 10 business days and the CHR must be

notified.

Data and Safety Monitoring Committee Contacts:

DSMC Chair: Alan Venook, MD

Phone (415) 353-2745

E-mail [email protected]

Box 1705

DSMC Monitors

Box 1297







Appendix F.2

Data and Safety Monitoring Plan for a Phase I Institutional/Pilot Study

The UCSF Helen Diller Comprehensive Cancer Center (HDFCCC) Data and Safety

Monitoring Committee (DSMC) is responsible for monitoring data quality and subject

safety for all HDF CCC institutional clinical studies. A summary of DSMC activities for

this study includes:

• Review of all subject data






subject’s treatment at weekly Site Committee meetings. These discussions are

documented in the Site Committee meeting minutes and will include the number of

subjects, significant toxicities as described in the protocol and observed responses.


therefore, the data is monitored once per month as subjects are enrolled.


All clinically significant adverse events, whether or not unexpected, and whether or not

considered to be associated with the use of the study drug, will be entered into


All adverse events entered into OnCore® will be reviewed on a weekly basis at the Site

Committee meetings. The Site Committee will review and discuss the selected toxicity,

the toxicity grade, and the attribution of relationship of the adverse event to the

administration of the study drug(s).






administration of the study drug(s) and is determined to be related either to the study drug

or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair






or his qualified alternate within 1 business day of knowledge of this event. The contact

may be by phone or e-mail.





indicate if the incident of adverse events observed in the study is above the range stated





notified.



Phone (415) 353-2745

Email [email protected]

Box 1705

DSMC Monitors

Box 1297







Appendix F.3

Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study



subject safety for all HDF CCC institutional clinical studies. A summary of DSMC


• Review of subject data


• Monitoring every six months (depending on study accrual)




subject’s treatment at monthly Site Committee meetings. These discussions are

documented in the Site Committee meeting minutes. The discussion will include the

number of subjects, significant toxicities in accordance with the protocol, and observed

responses.

All institutional Phase 2 or 3 studies are designated with a moderate risk assessment.

The data is monitored twice per year with twenty percent of the subjects monitored (or at

least three subjects if the calculated value is less than three).


All grade(s) 3-5 adverse events, whether or not unexpected, and whether or not

considered to be associated with the use of the study drug, will be entered into OnCore®,

UCSF’s Clinical Trial Management System.

All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly

basis at the Site Committee meetings. The Site Committee will review and discuss the

selected toxicity, the toxicity grade, and the attribution of relationship of the adverse

event to the administration of the study drug(s).

In addition, all suspected adverse reactions considered “serious” entered into OnCore®,

will be reviewed and monitored by the Data and Safety Monitoring Committee on an

ongoing basis and discussed at DSMC meetings, which take place every six weeks.







administration of the study drug(s) and it is determined to be related either to the study


DSMC Chair within 1 business day of knowledge of this event. The contact may be by

phone or e-mail.










notified



Phone (415) 353-2745


Box 1705

DSMC Monitors

Box 1297







Appendix F.4

Data and Safety Monitoring Plan with a Cancer Therapy Evaluation Program

(CTEP) (Phase 1 Dose Escalation Institutional Study) (NCI Drug Repository

Supplies Drug)

Oversight and Monitoring Plan

The UCSF-Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and





• Review of suspected adverse events considered “serious”







documented in the Site Committee meeting minutes. The discussions will include the


responses.



period.


All clinically significant adverse events, whether or not unexpected and whether or not





discuss the selected toxicity, the toxicity grade, and the attribution of relationship of

the adverse event to the administration of the study drug(s).

In addition, all suspected adverse reactions considered “serious” are entered in OnCore®,






and reviewed and monitored by the Data and Safety Monitoring Committee on an

ongoing basis and discussed at DSMC meetings, which take place every six weeks. The

suspected adverse reactions considered “serious” will also be reported to CTEP using the

Adverse Event Expedited Reporting System (AdEERS) form.






Dose Escalations

At the time of dose escalation, a written report will be submitted to the DSMC Chair (or

qualified alternate) describing the cohorts, dose levels, adverse events, safety reports, and

any Dose Limiting Toxicities observed, in accordance with the protocol. The report

will be reviewed by the DSMC Chair or qualified alternate and written authorization to

proceed or a request for more information will be issued within 2 business days of the

request. Approval for dose escalation by the DSMC (or qualified alternate) must be

obtained prior to implementation.










notified.



Phone (415) 353-2745







Box 1705

DSMC Monitors

Box 1297







Appendix F.5


(CTEP) (Phase 1 Institutional/Pilot Study) (NCI Drug Repository Supplies Drug)



subject safety for all UCSF HDF CCC institutional clinical studies. A summary of

DSMC activities for this study includes:








documented in the Site Committee meeting minutes and will include the number of

subjects, significant toxicities as described in the protocol and observed responses.



period.


All clinically significant adverse events, whether or not unexpected and whether or not





discuss the selected toxicity, the toxicity grade, and the attribution of relationship of

the adverse event to the administration of the study drug(s).

In addition, all suspected adverse reactions considered “serious” are entered in

OnCore®, and reviewed and monitored by the Data and Safety Monitoring

Committee on an ongoing basis and discussed at DSMC meetings, which take place

every six weeks. The suspected adverse reactions considered “serious” will also be

reported to CTEP using the Adverse Event Expedited Reporting System (AdEERS)

form.




















notified.



Phone (415) 353-2745


Box 1705

DSMC Monitors

Box 1297







Appendix F.6


(Phase 2 or 3 Institutional Study) (NCI Drug Repository Supplies Drug)



patient safety for all HDFCCC institutional clinical studies. A summary of DSMC




• Monitoring every six months (depending on study accrual)







responses.

All institutional Phase 2 or 3 studies are designated with a moderate risk assessment;

therefore, the data is monitored every six months, with twenty percent of the

subjects monitored (or at least three subjects if the calculated value is less than three).



considered to be associated with the use of study drug, will be entered into OnCore®,






In addition, all suspected adverse reactions considered “serious” are entered in

OnCore®, and reviewed and monitored by the Data and Safety Monitoring

Committee on an ongoing basis and discussed at DSMC meetings, which take place






every six weeks. The suspected adverse reactions considered “serious” will also be

reported to CTEP using the Adverse Event Expedited Reporting System (AdEERS)

form.






3.3 Review of Adverse Event Rates









notified.



Phone (415) 353-2745


Box 1705

DSMC Monitors

Box 1297


\






Appendix F.7

Data and Safety Monitoring Plan for a Behavioral Institutional Study



patient safety for all HDFCCC institutional clinical studies. A summary of DSMC




• Monitoring only when there are signs that subjects are at risk


Behavioral studies are characterized as low risk studies due to the study design being

based on interventions for the subject’s behavior as related to health, without

administration of drugs or complementary therapy that do not put the patient at

significant risk. The DSMC will not routinely monitor the study unless there are signs or

signals that patients are at risk. The signal for monitoring a behavioral study is two or

more suspected adverse reactions considered “serious” with attribution to study related

procedures in a six month period of time






responses.

3. Review and Oversight Requirements

3.1 Adverse Event Monitoring













In addition, all suspected adverse reactions considered “serious” entered into OnCore®,

will be reviewed and monitored by the Data and Safety Monitoring Committee on an

ongoing basis and discussed at DSMC meetings, which take place every six weeks.


administration of the study drug(s) and it is determined to be related either to the study


DSMC Chair within 1 business day of knowledge of this event. The contact may be by

phone or e-mail.










notified.



Phone (415) 353-2745


Box 1705

DSMC Monitors

Box 1297


mailto:[email protected]






Appendix F.8

Data and Safety Monitoring Plan for a Multicenter Institutional Study (Phase 1

Dose Escalation Institutional Study)











All institutional Phase 1 therapeutic studies are designated with a high risk assessment.

The data is monitored monthly as subjects are enrolled and includes all visits monitored

up through the Dose Limiting Toxicity (DLT) period. At the time of dose escalation, a

written report will be submitted to the DSMC Chair outlining the cohort dose, all

adverse events and suspected adverse reactions considered “serious”, and any Dose

Limiting Toxicity as described in the protocol. The report will be reviewed by the

DSMC Chair or qualified alternate and written authorization to proceed or a request

for more information will be issued within 2 business days of the request. The report is

then reviewed at the subsequent DSMC meeting. In the event that the committee does

not concur with the DSMC Chair’s decision, further study accrual is held while further

investigation takes place.

The Principal Investigator at the UCSF Coordinating Center will hold the role of Study

Chair. The Study Chair is responsible for the overall conduct of the study and for

monitoring its safety and progress at all participating sites. The Study Chair will conduct

continuous review of data and subject safety and discuss each subject’s treatment at

weekly UCSF Site Committee meetings. The discussions are documented in the UCSF

Site Committee meeting minutes. For each dose level, the discussion will include the

number of patients, significant toxicities in accordance with the protocol, doses

adjustments, and observed responses.

Multicenter communication






The UCSF Coordinating Center provides administration, data management, and

organizational support for the participating sites in the conduct of a multicenter clinical

trial. The UCSF Coordinating Center will also coordinate, at minimum, monthly

conference calls with the participating sites at the completion of each cohort or more

frequently as needed to discuss risk assessment. The following issues will be discussed

as appropriate:

• Enrollment information

• Cohort updates (i.e. DLTs)

• Adverse events (i.e. new adverse events and updates on unresolved adverse events

and new safety information)

• Protocol violations

• Other issues affecting the conduct of the study

Dose Level Considerations

The PI/Study Chair, participating investigators, and research coordinators from each site

will review enrollment for each dose level cohort during the regularly scheduled

conference calls. The dose level for ongoing enrollment will be confirmed for each

subject scheduled to be enrolled at a site. Dose level assignments for any subject

scheduled to begin treatment must be confirmed by the UCSF Coordinating Center via

fax or e-mail.

If a Dose Limiting Toxicity (DLT) arises in a subject treated at a study site, all sites must

be notified immediately by the UCSF Coordinating Center. The Study Chair has 1

business day (after first becoming aware of the event at either the UCSF Coordinating

Center or the participating site) in which to report the information to all participating

sites. If the DLT occurs at a participating site, the local investigator must report it to the

UCSF Coordinating Center within 1 business day, after which the UCSF Coordinating

Center will notify the other participating sites.

Adverse events reporting to the DSMC will include reports from both the UCSF

Coordinating Center, as well as the participating sites. The DSMC will be responsible for

monitoring all data entered in OnCore® at the UCSF Coordinating Center and the

participating sites. The data (i.e. copies of source documents) from the participating sites

will be faxed over to the UCSF Coordinating Center prior to the monitoring visits in

order for the DSMC to monitor the participating site’s compliance with the protocol,

patient safety, and to verify data entry.

3. Review and Oversight Requirements






3.1 Adverse Event Monitoring

All clinically significant adverse events (AEs), whether or not unexpected, and whether

or not considered to be associated with the use of study drug, will be entered into



weekly basis at the UCSF Coordinating Center’s Site Committee. All clinically

significant adverse events must be reported to the UCSF Coordinating Center by the

participating sites within 10 business days of becoming aware of the event. The Site

Committee will review and discuss the selected toxicity, the toxicity grade, and the

attribution of relationship of the adverse event to the administration of the study drug(s).





All suspected adverse reactions considered “serious” should be reported to the UCSF

Coordinating Center within 1 business day of becoming aware of the event or during

the next scheduled conference call, whichever is sooner.


administration of the study drug(s) and is determined to be related either to the

investigational drug or any research related procedure, the Study Chair at the UCSF

Coordinating Center or the assigned designee must be notified within 1 business day

from the participating site(s) and the Study Chair must then notify the DSMC Chair or

qualified alternate within 1 business day of this notification. The contact may be by

phone or e-mail.



the Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating

Center is responsible for notifying the DSMC at the time the increased rate is identified.

The report will indicate if the incidence of adverse events observed in the study is above

the range stated in the Investigator Brochure or package insert.

If at any time the Study Chair stops enrollment or stops the study due to safety issues, the



notified.








Phone (415) 353-2745


Box 1705

DSMC Monitors

Box 1297


Page 42 of 54






Appendix F.9

Data Safety Monitoring Plan for Multicenter Study (Phase 1 Institutional/Pilot

Study)

The UCSF-Helen Diller Family Comprehensive Cancer Center (HDF CCC) Data and


patient safety for all HDF CCC institutional clinical studies. A summary of DSMC







All institutional Phase 1 therapeutic studies are designated with a high risk assessment.

The data is monitored monthly as subjects are enrolled.



trial. The UCSF Coordinating Center will also coordinate monthly conference calls with

the participating sites to communicate the review of adverse events, safety data, and other

study matters.





weekly UCSF Site Committee meetings. The discussions are documented in the UCSF

Site Committee meeting minutes.




trial. The UCSF Coordinating Center will also coordinate, at minimum, monthly

conference calls with the participating sites or more frequently as needed to discuss risk

assessment. The following issues will be discussed as appropriate:


• Adverse Events (i.e. new adverse events and updates on unresolved adverse

events and new safety information)

Page 43 of 54






• Protocol Violations





participating sites. The data (i.e. copies of source documents) from the participating

sites will be faxed over to the UCSF Coordinating Center prior to the monitoring visits in




All clinically significant adverse events (AEs), whether or not unexpected, and whether

or not considered to be associated with the use of study drug, will be entered into


All adverse events entered into OnCore® will be reviewed on a weekly basis at the

UCSF Coordinating Center Site Committee meetings. All clinically significant adverse

events must be reported to the UCSF Coordinating Center by the participating sites

within 10 business days of becoming aware of the event or during the next scheduled

monthly conference call, whichever is sooner. The UCSF Site Committee will review

and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of

the adverse event to the administration of the study drug(s) from the UCSF Coordinating

Center and the participating sites.





All suspected adverse reactions considered “serious” should be reported to the UCSF

Coordinating Center within 1 business day of becoming aware of the event or during

the next scheduled conference call, whichever is sooner.







phone or e-mail.

Page 44 of 54






Review of Adverse Event Rates









notified.



Phone (415) 353-2745


Box 1705

DSMC Monitors

Box 1297


Page 45 of 54






Appendix F.10

Data and Safety Monitoring Plan for a Multicenter Study (Phase 2 or 3 Institutional

Study)



patient safety for all HDF CCC institutional clinical studies. A summary of DSMC




• Monitoring every six months (depending on patient accrual)



All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk

assessment. The data is monitored every six months, with twenty percent of the subjects

monitored (or at least three subjects if the calculated value is less than three).



trial. The UCSF Coordinating Center will also coordinate quarterly conference calls with

the participating sites to communicate the review of adverse events, safety data, and other

study matters.





monthly UCSF Site Committee meetings. The discussions are documented in the UCSF

Site Committee meeting minutes.




trial. The UCSF Coordinating Center will also coordinate, at minimum, quarterly

conference calls with the participating sites or more frequently as needed to discuss risk

assessment. The following issues will be discussed as appropriate:


Page 46 of 54






• Adverse Events (i.e. new adverse events and updates on unresolved adverse

events and new safety information)

• Protocol Violations





participating sites. The data (i.e. copies of source documents) from the participating sites

will be faxed over to the UCSF Coordinating Center prior to the monitoring visits in




All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not considered

to be associated with the use of study drug, will be entered into OnCore®, UCSF’s

Clinical Trial Management System.

All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis

at the UCSF Site Committee meetings. All clinically significant adverse events must be

reported to the UCSF Coordinating Center by the participating sites within 10 business

days of becoming aware of the event or during the next scheduled quarterly conference

call, whichever is sooner. The UCSF Site Committee will review and discuss the


event to the administration of the study drug(s) from the UCSF Coordinating Center

and the participating sites.

In addition, all suspected adverse reactions considered “serious” must be entered in

OnCore® and reported to the UCSF Coordinating Center within 1 business day. The

suspected adverse reactions considered “serious” will be reviewed and monitored by the

Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC

meeting, which take place every six (6) weeks.







phone or e-mail.


Page 47 of 54














notified.



Phone (415) 353-2745


Box 1705

DSMC Monitors

Box 1297


Appendix G.

Page 48 of 54






Guidelines for Establishing and Operating an External Data Safety Monitoring Board

(DSMB)

1. Membership

a. Monitoring activities should be conducted by experts in all scientific disciplines

needed to interpret the data and insure patient safety. Clinical trial experts,

biostatisticians, bioethicists, and clinicians knowledgeable about the disease and

treatment under study should be part of the monitoring group or be available if

warranted.

b. Voting members may be from within UCSF or from an outside institution, but the

majority should not be affiliated with UCSF. Members should view themselves

as representing the interest of patients and not that of the institution. Investigators

directly involved with the conceptual design or analysis of the particular trial are

not eligible to serve on the DSMB.

2. Meeting Procedures

a. Frequency

i. DSMB meetings will be held at least annually and more often depending

on the nature and progress of the trial being monitored.

b. Elements for Review

i. A written summary of status, toxicity and outcomes of the clinical trial

will be prepared by the study coordinator and reviewed by the principal

investigator and clinical trial statistician. The summary will be submitted

to DSMB members allowing sufficient review time prior to meeting.

ii. This summary will also address specific toxicity concerns as well as

concerns about the conduct of the trial. It may contain recommendations

for consideration by the DSMB concerning whether to close the trial,

report the results, or continue accrual or follow-up.

c. Meeting Structure

Meetings will be divided into three sessions as follows:

1) Open Session – members of the clinical trial team present review of the

trial conduct and answer questions from DSMB members. Focus is on

accrual, protocol compliance, and general toxicity.

Page 49 of 54






2) Closed Session – Includes DSMB members and the clinical trial

statistician(s). The statistician presents and discusses outcome results with

DSMB.

3) Executive Session – DSMB members only discuss the general conduct of

trial, all outcomes results including toxicities as described in the protocol,

all adverse events and develop recommendations.

3. Recommendations

a. It is the responsibility of the PI, the clinical trial statistician(s), and individual

DSMB members to ensure that the DSMB is kept apprised of non-confidential

results from other related studies that become available, and any programmatic

concerns related to the clinical trial being monitored. It is the responsibility of the

DSMB to determine the extent to which this information is relevant to its

decisions related to the specific trial.

b. DSMB recommendations will be given to the PI, sponsor, and the DSMC. The

DSMB must provide an adequate rationale for recommendations made to change

the trial for other than safety or efficacy reasons or for slow accrual.

c. The PI is responsible to implement the change recommended by the DSMB as

expeditiously as possible.

d. The sponsor must be informed of the reason for disagreement in the unlikely

situation that the PI does not agree with the DSMB recommendation.

e. The sponsor, DSMB Chair, and PI will be responsible for reaching a mutually

acceptable decision about the study.

4. Release of Outcome Data

a. In general, outcome data should not be made available to individuals outside of

the DSMB until accrual has been completed and all patients have completed their

treatment

b. The DSMB may approve the release of outcome data on a confidential basis to the

PI for planning the preparation of manuscripts and/or to a small number of others

for future trial planning purposes.

c. Any release of outcome data prior to the DSMB recommendation for general

dissemination of results must be reviewed and approved by the DSMB.

Page 50 of 54






5. Confidentiality

a. No communication, either written or verbal, of the deliberations or

recommendations of the DSMB will be made outside of the DSMB.

b. Outcome results are strictly confidential and must not be divulged to any non-

member, except as indicated about in Recommendations, until the

recommendations to release the results are accepted and implemented.

c. Each member of the DSMB, including non-voting members, must sign a

statement of confidentiality.

6. Conflict of Interest

a. DSMB members are subject to the UCSF policies regarding standards of conduct.

b. Individuals invited to serve on the DSMB (voting or non-voting) will disclose any

potential conflicts of interest, whether real or perceived, to the PI and the

appropriate institutional officials, in accordance with the UCSF Conflict of

Interest Policies. Conflict of interest can include professional interest, proprietary

interest, and miscellaneous interest as described in the NIH Grants Policy

Statement, Page 11-12, and 45 CFR Part 94.

c. Decisions concerning whether individuals with potential conflicts of interest or

the appearance of conflicts of interest may participate in the DSMB will be made

in accordance with the UCSF Conflict of Interest Policies.

d. Potential conflicts, which develop during a member’s tenure on a DSMB, must

also be disclosed and address in accordance with the UCSF Policies.

Page 51 of 54






Appendix H. Risk Assessment for Institutional Studies:

The table below lists the risk assessment for the institutional studies which are monitored by the

DSMC:

Risk

assignment

Study type Monitoring Surveillance

High

Institutional Phase 1

therapeutic

Monitor all subjects

once a month as

subjects are enrolled/

monitor through DLT

period

Real time monitoring

of AEs and SAE's

weekly at site

committees; DSMC

monitors SAE every six

weeks

High

All Institutional

therapeutic using

gene therapy or

vaccines regardless of

phase

Monitor once a

month as subjects are

enrolled/ monitor first

three

treatments/cycles


of AEs and SAEs

weekly at site

committees; DSMC


weeks

Moderate


therapeutic

Monitor twice a year

at 20% of subjects

enrolled in the six

months prior to

monitoring visit


of AEs and SAEs

monthly at site

committees; DSMC


weeks

Moderate


therapeutic

Monitor 20% of

yearly accrual during

the calendar year that

monitoring visit

occurs


of AEs and SAEs

monthly at site

committees; DSMC


weeks

Low

Behavioral studies/

early detection or

diagnostic

No routine

monitoring unless

requested by PI or 2

or more SAEs with

attribution to study

procedures in a six

month period of time

DSMC monitors for

SAEs every six weeks

Page 52 of 54






Appendix I. Policy for Verbal Notification of Newly Identified Risks for Research Subjects

Enrolled in therapeutic Oncology Clinical Trials

Page 53 of 54






Page 54 of 54






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