Data Safety and Monitoring Plans for the GCRC

The purpose of data and safety monitoring is to protect subjects participating in a research trial from harm and to maintain the validity and integrity of the data produced. It is the Principal Investigator’s (PI) responsibility to prepare the Data and Safety Monitoring Plan (DSMP) and see that it is carried out as described.

Every study submitted to the GCRC is required to have a DSMP which should be tailored to the level of complexity and risk to participants and should include the following elements: 

• A description of who is monitoring the study and at what frequency.

• A description of the specific risks inherent to the study and steps taken to monitor and ameliorate them.

• An adverse event grading and attribution scale

• Plans for reporting of adverse events/unanticipated problems. (The DSMP should simply state who is responsible for the reporting of events/problems, the time frame for reports, and to whom the reports will be sent.)

• A description of the procedures that insure confidentiality and accuracy of all data study records, including hard copy and computer files.

Data and Safety Monitoring Plans- Examples

Representative DSMPs that may be modified for use with GCRC protocols are provided.  Three separate examples are given, each reflecting a protocol of differing risk or complexity.  The GCRC risk grading scale is listed here.

DSMP for Minimal Risk Study

Procedures performed during this study are H & P (includes interval history, physical exam and anthropometric measurements) at Baseline, 3 months, 6 months, 12 months and 24 months; DXA at Baseline, 6 months, 12 months and 24 months. Past medical records will be reviewed and recorded at the first visit.

Risks of radiation exposure are minimal. Exposure is approximately 3 μSv for one DXA scan. Thus, total radiation exposure over two year study period will be 12 μSv. Background radiation in Oklahoma is 3000 μSv/year. Risks of having the medical record tracked in a computer database are minimal but could include loss of privacy.

The PI will monitor the study for unexpected problems and adverse events by querying the subjects’ parents at each visit. The investigators will meet every 6 months to assess the progress of the study.  Adverse events will be recorded and classified using the following grading and attribution scale. (Grading = Mild, Moderate, Severe; Attribution = Definite, Probable, Possible, Unlikely, Unrelated). Unanticipated problems and adverse events will be reported as per IRB and GCRC policies.  The IRB and GCRC will be notified promptly should a significant unanticipated problem or outcome occur.

Data will be monitored by the PI for quality by comparing data in the Case Report Forms to data in the source documents. Information will be kept in a secure database that is password protected. Records will be kept secure, and the subject’s name will not be shown in any summary of results.

DSMP for Low or Moderate Risk Study

Subjects in this trial undergo periodic medical evaluation including the recording of medical history, physical examination, anthropometric measures, and blood sampling during dynamic tests of carbohydrate metabolism. The latter include oral and intravenous glucose tolerance measures and measures of insulin sensitivity (FSIVGTT). Risks include bruising or infection at the site of blood sampling and hypoglycemia during the FSIVGTT. Symptomatic hypoglycemia will be treated with rapid infusion of glucose intravenously. An experienced nurse will monitor the subject throughout the procedure and a study investigator will be available by pager.

Dr.___________, in the division of ____________, will serve as an independent study monitor for the study. Drs. X, Y, and Z (PI and Co-investigators) will be primarily responsible for monitoring data quality and adverse events. Interim analysis on a quarterly basis will focus on accrual and drop-out rates. The monitor will review recruitment and adverse events/unanticipated problems every 6 months and report to PI. The independent monitor will review serious adverse events and significant unanticipated events as they occur.

Adverse events/unanticipated problems will be recorded and classified using the following grading and attribution scale. (Grading = Mild, Moderate, Severe; Attribution = Definite, Probable, Possible, Unlikely, Unrelated). Unanticipated problems and adverse events will be reported as per IRB and GCRC policies. Should a significant unanticipated problem or outcome occur, the IRB and GCRC will be notified promptly.

All adverse events and unanticipated problems will be reported to the IRB in summary form at the time of the annual progress reports or at the close of the study, whichever occurs first. Similarly, these reports also will be provided to the NIH/FDA/ other regulatory agency along with any investigator-initiated or IRB-mandated protocol changes based on this information, per NIH/FDA/other regulatory agency guidelines.

Data (such as lab values and anthropometric measurements) will be entered from source documents into Case Report Forms by the study coordinator. The PI will review Case Report Forms entries for accuracy by comparison with the source documents. Data will be checked against normal values. Research records and source documents will be maintained in a research chart and stored in the investigator's locked file cabinet, or in password-protected electronic files. No patient identifiers will be published.  

DSMP for Moderate or High Risk Study

Study Description

This study is a multi-site, placebo-controlled study to determine the safety and efficacy of Investigational Drug XYZ. The following procedures occur during the study: A thorough Medical history and Physical Exam is obtained at baseline. Additional physical examinations, blood tests, magnetic resonance (MRI) or CT scan of the brain and abdomen, chest x-ray, pulmonary function tests, and questionnaires are performed per protocol.

The study will be monitored by an independent Data and Safety Monitoring Board (DSMB) composed of individuals free from conflicts of interest with the PI and sponsor.  The minimal number for this study is 4 and will include a biostatistician and an oncologist.  The DSMB will convene prior to study initiation for a formal review of the protocol and periodically thereafter to assess research subject safety and study progress.  A copy of the DSMB charter is attached.

After baseline tests, eligible subjects are randomized to study drug XYZ or placebo distributed by the OUHSC Investigational Pharmacy. Dosing escalation is dependent upon observations from prior subjects who will enter into one of 3 separate cohorts.   Follow-up visits occur at three weeks, three months, six months, nine months, twelve months, eighteen months and twenty-four months after starting study drug. At each follow-up visit, subject will have a history and physical examination performed and blood tests repeated. MRI or CT scans will be repeated after six months, twelve months, and twenty-four months.

Dose Escalation/Stopping Rule:   An interim analysis of safety will be conducted after the first 10 subjects have completed 6 months of study.  Subsequent cohorts of subjects will not be enrolled at an escalated dose if there is an unacceptable safety profile, as defined by the DSMB, based on the data obtained from the prior cohort of subjects. Alternatively, the DSMB may elect to terminate enrollment prior to reaching the protocol specified number of subjects per cohort for safety concerns.

The principal expected risk is that chronic treatment with XYZ, given daily, is associated with an increase in serum lipid levels, particularly triglycerides.  Triglyceride levels above 1000 mg/dl will prompt dose reduction and above 1500 mg/dl, withdrawal from the study.

Adverse Event Grading and Attribution Scales

The following definitions for grading will be used (Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (Publish Date August 9, 2006)):

Grade 1 – Mild AE

Grade 2 – Moderate AE

Grade 3 – Severe AE

Grade 4 – Life threatening or disabling

Grade 5 – Death related AE

The relationships are categorized (attribution scale) as:

Definite – The adverse event is clearly related to the investigational agent(s).

Probable – The adverse event is likely related to the investigational agent(s).

Possible - The adverse event may be related to the investigational agent(s).

Unlikely - The adverse event is doubtfully related to the investigational agent(s).

Unrelated - The adverse event is clearly NOT related to the investigational agent(s).

Each sign or symptom reported is documented on the case report form to include the start date and time of onset (if known), stop date, outcome of event and any interventions given.

Unanticipated problems and adverse events will be reported as per IRB and GCRC policies. Should a significant unanticipated problem or outcome occur, the IRB and GCRC will be notified promptly along with the DSMB.

Data Security

Data will be entered from source documents into Case Report Forms by the study coordinator. The PI will review Case Report Forms entries for accuracy by comparison with the source documents. Data will be checked against normal values. Research records and source documents will be maintained in a research chart and stored in the investigator's locked file cabinet, or in password-protected electronic files. No patient identifiers will be published.