data and safety monitoring in clinical trials harvey murff, m.d., m.p.h. gcrc, vanderbilt university...

Data and Safety Monitoring in Data and Safety Monitoring in Clinical TrialsClinical Trials

Harvey Murff, M.D., M.P.H.Harvey Murff, M.D., M.P.H.

GCRC, Vanderbilt University Medical GCRC, Vanderbilt University Medical CenterCenter

Today’s TopicsToday’s Topics

I.I. History of DSMP/BsHistory of DSMP/Bs

II.II. Who requires whatWho requires what

III.III. Current requirementsCurrent requirements• Data and Safety Monitoring PlansData and Safety Monitoring Plans• Data and Safety Monitoring BoardsData and Safety Monitoring Boards

Evolution of Human Subjects Evolution of Human Subjects

Protection in Research StudiesProtection in Research Studies

1940 1950 1960 1970 1980 1990 2000

Occurrence

Regulatory Response

Nuremberg Trials

Nuremberg Code

AMA Code of Research Ethics

Jewish Chronic Disease H Lew-Medicine

Research Institute Survey

Declaration of Helsinki

Kefauver-Harris Amendment to

FDC Act US PHS requires

independent review

Beecher reportWillowbrook

Tuskegee

National Research Act

Belmont Report

Common Rule

Plutonium Experiments

Jessie Gelsinger

Ellen Roche

OIG “A Time for Reform”

IOM “Responsible

Research”

ACHRE formed

““What experience and history teach is What experience and history teach is this -- that people and governments never this -- that people and governments never

have learned anything from history”have learned anything from history” Georg W.F. HegelGeorg W.F. Hegel

(1770-1831)(1770-1831)

DefinitionsDefinitions

Data Safety Monitoring Data Safety Monitoring Plan (DSMP)Plan (DSMP)– describes how the study describes how the study

investigators plan to investigators plan to oversee research subject oversee research subject safety and how adverse safety and how adverse events will be characterized events will be characterized and reportedand reported

– The intensity and frequency The intensity and frequency of monitoring should be of monitoring should be tailored to fit the expected tailored to fit the expected risk level, complexity, and risk level, complexity, and size of the particular studysize of the particular study

Data and Safety Data and Safety Monitoring Board Monitoring Board (DSMB/DMC)(DSMB/DMC)– A group of individuals with A group of individuals with

pertinent expertise that pertinent expertise that review on a regular basis review on a regular basis accumulating data from accumulating data from ongoing an clinical trialongoing an clinical trial

– Advises sponsor regarding Advises sponsor regarding safety of current and future safety of current and future participants and validity participants and validity and scientific merit of the and scientific merit of the trialtrial

Study Risk DefinitionsStudy Risk Definitions

Minimal-risk:Minimal-risk: Non-therapeutic trials such as survey research, questionnaires, blood samples, Non-therapeutic trials such as survey research, questionnaires, blood samples, or observations. or observations.

One standard definition isOne standard definition is: : A study where the magnitude of harm or discomfort is A study where the magnitude of harm or discomfort is not greater than that encountered in daily life or the performance of routine not greater than that encountered in daily life or the performance of routine physical or psychological examinations or tests.physical or psychological examinations or tests.

Moderate-risk:Moderate-risk:

Phase II or phase III multi-intuitional industry sponsored trials with Phase II or phase III multi-intuitional industry sponsored trials with independent data monitoringindependent data monitoring

High-risk:High-risk:

Clinical trials with investigational agents, phase I clinical protocols, Clinical trials with investigational agents, phase I clinical protocols, investigator initiated INDs, manufacturing of product on campus, some phase investigator initiated INDs, manufacturing of product on campus, some phase II clinical trials, and investigator initiated phase III clinical trials.II clinical trials, and investigator initiated phase III clinical trials.

History of DSMB’sHistory of DSMB’s

Soon after the era of modern randomized clinical Soon after the era of modern randomized clinical trials began (1950’s)trials began (1950’s)

NIH external advisory group (Greenberg report) NIH external advisory group (Greenberg report) first introduced the concept of a formal committeefirst introduced the concept of a formal committee

Coronary Drug Project (CDP)Coronary Drug Project (CDP)– Evaluated 5 different lipid-lowering treatmentsEvaluated 5 different lipid-lowering treatments– 8000 patients over 5 years8000 patients over 5 years– DMC recommended termination of high- and low- dose DMC recommended termination of high- and low- dose

estrogen and dextrothyroxineestrogen and dextrothyroxine– Began developing new statistical tools for repeated Began developing new statistical tools for repeated

testing testing

History of DSMB’sHistory of DSMB’s

After the CDP, DSMB became a more frequent After the CDP, DSMB became a more frequent component to large, multi-center trials sponsored component to large, multi-center trials sponsored by NIH by NIH

VA began to include the use of DMC’s with VA began to include the use of DMC’s with formal guidelines developed in mid-70’sformal guidelines developed in mid-70’s

NCI began adopting DMC’s in early 1980’sNCI began adopting DMC’s in early 1980’s– Still considered valuable despite being completely Still considered valuable despite being completely

independent and using open therapiesindependent and using open therapies Adopted more frequently by industry in early Adopted more frequently by industry in early

1990’s1990’s

How Independent DSMB might favor How Independent DSMB might favor Industry-sponsored trialsIndustry-sponsored trials

Amyotrophic lateral sclerosis trialAmyotrophic lateral sclerosis trial– Ciliary neurotrophic factor (CNTF)Ciliary neurotrophic factor (CNTF)– ALS CNTF Treatment Study (ACTS)ALS CNTF Treatment Study (ACTS)

» Utilized complete independent DSMBUtilized complete independent DSMB

» DMC terminated trial due to adverse effectsDMC terminated trial due to adverse effects

» Shareholders sued company stating they had been Shareholders sued company stating they had been misleadmislead

» Sponsors successful defense rested in being blinded Sponsors successful defense rested in being blinded to these resultsto these results

Why the increasing use of DMC’sWhy the increasing use of DMC’s

Growing number of industry-sponsored trials with Growing number of industry-sponsored trials with mortality and major morbidity endpointsmortality and major morbidity endpoints

Increasing collaboration between industry and Increasing collaboration between industry and government in sponsoring major clinical trialsgovernment in sponsoring major clinical trials

Heightened awareness within scientific Heightened awareness within scientific community of problems in clinical trial conductcommunity of problems in clinical trial conduct

Requirements for DSMB’sRequirements for DSMB’s

NIHNIH– Typically require DSMBTypically require DSMB

» Protocols that generate Protocols that generate blinded/randomized datablinded/randomized data

» Multicenter protocols; Multicenter protocols;

> minimal risk> minimal risk

» Gene transfer protocolsGene transfer protocols

– May require DSMBMay require DSMB» Pose > minimal riskPose > minimal risk

» Protocols requiring special Protocols requiring special scrutinyscrutiny

High public interestHigh public interest Vulnerable populationsVulnerable populations

FDAFDA– Risk to trial participantsRisk to trial participants

» Study endpointStudy endpoint

» Large trials of long-Large trials of long-durationduration

» Fragile populationsFragile populations

– PracticalityPracticality» Short trialsShort trials

– Assurance of scientific Assurance of scientific validityvalidity

» Inclusion of new scientific Inclusion of new scientific knowledge without adding knowledge without adding biasbias

http://ohsr.od.nih.gov/info/rinfo_18.php3 Guidance for Clinical Trials Data Monitoring Committes

Requirements for DSMB’sRequirements for DSMB’s

Is the trial intended to provide definitive information about Is the trial intended to provide definitive information about the effectiveness and/or safety of a medical interventionthe effectiveness and/or safety of a medical intervention

Are there prior data to suggest that the intervention being Are there prior data to suggest that the intervention being studied has a potential to induce potentially unacceptable studied has a potential to induce potentially unacceptable toxicitytoxicity

Is the trial evaluating mortality or another major endpoint, Is the trial evaluating mortality or another major endpoint, such that inferiority of one treatment arm has safety as such that inferiority of one treatment arm has safety as well as effectiveness implicationswell as effectiveness implications

Would it be ethically important for the trial to stop early if Would it be ethically important for the trial to stop early if the primary question addressed has been definitively the primary question addressed has been definitively answered, even if secondary questions or complete safety answered, even if secondary questions or complete safety information were not fully addressedinformation were not fully addressed

Ellenberg, 2002

Which Studies Require DSMB?Which Studies Require DSMB?

Clinical Research?

Yes No

Phase III or Multicenter

Yes No

Blinded, high-risk intervention, or vulnerable population?

Yes No

IRB + DSMPIRB + DSMP + DSMB

What is the best way to monitor What is the best way to monitor your trial?your trial?

Data and Safety Monitoring Data and Safety Monitoring Plans (DSMP)Plans (DSMP)

NCRR minimal required content for DSMPNCRR minimal required content for DSMP– Adverse event (AE) grading and attribution scaleAdverse event (AE) grading and attribution scale

– Plan for unanticipated AE reportingPlan for unanticipated AE reporting

– Plan for annual reporting of AEsPlan for annual reporting of AEs

– Plan for safety review (by whom and at what frequency)Plan for safety review (by whom and at what frequency)

Other content might be necessary Other content might be necessary depending on the protocoldepending on the protocol– Such as evaluations of the progress of the study, Such as evaluations of the progress of the study,

assessments of data quality and timeliness and assessments of data quality and timeliness and participant recruitment, accrual and retentionparticipant recruitment, accrual and retention


Adverse event (AE) grading and attribution scaleAdverse event (AE) grading and attribution scaleExample of scale:Example of scale:

0 = No adverse event or within normal limits0 = No adverse event or within normal limits1 = Mild AE, not requiring treatment1 = Mild AE, not requiring treatment2 = Moderate AE, resolved with treatment2 = Moderate AE, resolved with treatment3 = Severe AE, resulted in inability to carry on normal 3 = Severe AE, resulted in inability to carry on normal activities and required professional medical attentionactivities and required professional medical attention4 = Life-threatening or disabling AE4 = Life-threatening or disabling AE5 = Fatal AE5 = Fatal AE

Or specific definition:Or specific definition: “A serious adverse event will be defined “A serious adverse event will be defined as an adverse event that is fatal, immediately life-threatening, as an adverse event that is fatal, immediately life-threatening, permanently (or significantly) disabling, requires permanently (or significantly) disabling, requires hospitalization, prolongs an existing hospitalization or is a hospitalization, prolongs an existing hospitalization or is a congenital anomaly or birth defect (in an offspring)”.congenital anomaly or birth defect (in an offspring)”.


Plan for unanticipated AE reportingPlan for unanticipated AE reporting

Requirements:Requirements:

1)1) Description of how adverse events will be Description of how adverse events will be detected ( such as laboratory tests or detected ( such as laboratory tests or

interviews)interviews)

2)2) A description of who will be collecting these A description of who will be collecting these AE (PI, Research Nurse)AE (PI, Research Nurse)

3)3) Specification of who will be notified of an Specification of who will be notified of an AE (IRB, NIH, FDA, PI, GCRC)AE (IRB, NIH, FDA, PI, GCRC)


Plan for annual reporting of AEsPlan for annual reporting of AEsThis recommendation is for studies lasting greater than one year, This recommendation is for studies lasting greater than one year, however studies with shorter durations still need a however studies with shorter durations still need a pre-specifiedpre-specifiedtime frequency specified regarding event reportingtime frequency specified regarding event reporting

Requirements:Requirements:1) Specify how often reports will be prepared1) Specify how often reports will be prepared2) Specify who will prepare the report2) Specify who will prepare the report3) Specify where these reports will be sent (IRB, NIH, FDA, 3) Specify where these reports will be sent (IRB, NIH, FDA, GCRC)GCRC)4) Specify what data will be sent to the IRB4) Specify what data will be sent to the IRB

Remember, all reports should be copied to the GCRCRemember, all reports should be copied to the GCRC


Plan for safety review (by whom and at what frequency)Plan for safety review (by whom and at what frequency)

1)1) Identify who will be performing the safety reviews Identify who will be performing the safety reviews (collecting adverse events, reviewing them, and reporting (collecting adverse events, reviewing them, and reporting them)them)

» Is the reviewer (either individual or committee) independent of Is the reviewer (either individual or committee) independent of the study sponsor or study investigators?the study sponsor or study investigators?

2)2) Interval of safety reviewInterval of safety review» Dependant on the nature and progress of the study, but Dependant on the nature and progress of the study, but

must be performed regularlymust be performed regularly

You interval for safety review should be appropriate You interval for safety review should be appropriate to the level of risk entailed in the studyto the level of risk entailed in the study

DMSB ChecklistDMSB Checklist

Preliminary DSMP ChecklistPreliminary DSMP Checklist1)1) Is some form of study risk assessment?Is some form of study risk assessment?2)2) Is there a description of the anticipated adverse events?Is there a description of the anticipated adverse events?3)3) Is there a description of how adverse events will be detected Is there a description of how adverse events will be detected

and monitored at a research subject level?and monitored at a research subject level?4)4) Is there an adverse event grading and attribution scale Is there an adverse event grading and attribution scale

described?described?5)5) Is there a plan for the reporting of adverse events?Is there a plan for the reporting of adverse events?6)6) Is there a plan for annual reporting of adverse events?Is there a plan for annual reporting of adverse events?7)7) Is there a description of who will be performing safety Is there a description of who will be performing safety

reviews for the study and how often these will be reviews for the study and how often these will be reviewed?reviewed?8)8) Has preliminary criteria for decision making regarding Has preliminary criteria for decision making regarding

continuation, modification or termination of the clinical continuation, modification or termination of the clinical study been documentedstudy been documented

Generic DSMP ExampleGeneric DSMP Example

PURPOSE:PURPOSE: The Data Safety Monitoring Plan is written to ensure the safety of the participants and verifying The Data Safety Monitoring Plan is written to ensure the safety of the participants and verifying

the validity and integrity of the data.the validity and integrity of the data.ASSESSING TOXICITY:ASSESSING TOXICITY:Toxicity will be graded according to NCI’s Common Toxicity Criteria II (CTC II). The Toxicity will be graded according to NCI’s Common Toxicity Criteria II (CTC II). The

investigator will try to determine relationship of toxicity to test drugs as not related, possibly investigator will try to determine relationship of toxicity to test drugs as not related, possibly related, or definitely related using standard criteria for clinical trials. All grades of toxicity related, or definitely related using standard criteria for clinical trials. All grades of toxicity will be noted. will be noted.

ADVERSE EVENT REPORTING:ADVERSE EVENT REPORTING: All “unanticipated” adverse events related to the experimental procedures will be reported to the All “unanticipated” adverse events related to the experimental procedures will be reported to the

IRB, GCRC, FDA and NIH institute in an expedited manner if they are Grade 2 and above in IRB, GCRC, FDA and NIH institute in an expedited manner if they are Grade 2 and above in severity. If the study is done under an IND with the FDA, then the FDA definition of severe severity. If the study is done under an IND with the FDA, then the FDA definition of severe adverse event will be used as well and any related and unexpected SAEs will be reported adverse event will be used as well and any related and unexpected SAEs will be reported within 15 days. Unanticipated patient deaths are reportable within 7 days. Twithin 15 days. Unanticipated patient deaths are reportable within 7 days. The expedited he expedited report sent to other organizations can be copied to the GCRC. The investigator will continue report sent to other organizations can be copied to the GCRC. The investigator will continue to follow or obtain documentation of the resolution course of such an event. to follow or obtain documentation of the resolution course of such an event.

A copy of the annual report of adverse events to the IRB will be copied to the GCRC. This report A copy of the annual report of adverse events to the IRB will be copied to the GCRC. This report will include a statement similar to the following: will include a statement similar to the following:

Generic DSMP Second Example -contGeneric DSMP Second Example -cont

The most common side effects seen in patients treated with <<Drug Name, Treatment The most common side effects seen in patients treated with <<Drug Name, Treatment Name>> included the following ………Name>> included the following ………

CONFIDENTIALITY:CONFIDENTIALITY:<<Add appropriate wording>><<Add appropriate wording>>DATA AND SAFETY MONITORING:DATA AND SAFETY MONITORING:The clinical research coordinator [if there is one, or the PI]The clinical research coordinator [if there is one, or the PI] is responsible for collecting and is responsible for collecting and

recording all clinical data. As these results are collected, all toxicities and adverse events recording all clinical data. As these results are collected, all toxicities and adverse events will be identified and reported to the principle investigator. Adverse events will be will be identified and reported to the principle investigator. Adverse events will be reported as described above. The principle investigator will determine relationship of the reported as described above. The principle investigator will determine relationship of the event to the study drug and decide course of action for the study participant. event to the study drug and decide course of action for the study participant.

Monitoring will be conducted annually via Internal Audits and annually via an appointed Monitoring will be conducted annually via Internal Audits and annually via an appointed External Auditor [if appropriate]. <<Add appropriate wording. What will be monitored? External Auditor [if appropriate]. <<Add appropriate wording. What will be monitored? List acceptable criteria if applicable. >>List acceptable criteria if applicable. >>

All expedited adverse event reports will be reviewed by the General Clinical Research All expedited adverse event reports will be reviewed by the General Clinical Research Center (GCRC) Data Safety Monitoring Board (DSMB) in its convened meetings. The Center (GCRC) Data Safety Monitoring Board (DSMB) in its convened meetings. The annual summary of all adverse events and any audit reports will be reviewed annually by annual summary of all adverse events and any audit reports will be reviewed annually by the GCRC DSMB. the GCRC DSMB.

Data and Safety Monitoring Data and Safety Monitoring BoardsBoards

What are they and when are they What are they and when are they necessary?necessary?

Data and Safety Monitoring Data and Safety Monitoring Boards (DSMB)Boards (DSMB)

Duties of DSMB:Duties of DSMB:– Review the research protocol and plans for data safety Review the research protocol and plans for data safety

and monitoringand monitoring

– Evaluate the progress of the trial with periodic Evaluate the progress of the trial with periodic assessments of data quality and timeliness, participant assessments of data quality and timeliness, participant recruitment, accrual and retention, participant risk recruitment, accrual and retention, participant risk versus benefit, and reports from related studiesversus benefit, and reports from related studies

– Make recommendations to the IRB and investigators Make recommendations to the IRB and investigators concerning continuation or conclusion of the trialconcerning continuation or conclusion of the trial


Elements of a DSMB:Elements of a DSMB:– 1) Description of the DSMB chair and members1) Description of the DSMB chair and members

– 2) Meeting structure2) Meeting structure

– 3) Adverse event reporting requirements3) Adverse event reporting requirements

– 4) A description of interim efficacy analysis, if 4) A description of interim efficacy analysis, if appropriate appropriate

– 5) Study stopping rules, if appropriate5) Study stopping rules, if appropriate

– 6) How and to whom DSMB reports will be 6) How and to whom DSMB reports will be distributed distributed


Description of the DSMB chair and membersDescription of the DSMB chair and membersBoard membership:Board membership:

• Varying recommendations as to the appropriate number Varying recommendations as to the appropriate number but a minimal number is 3but a minimal number is 3

• For studies with large numbers of patients the DSMB For studies with large numbers of patients the DSMB should include a statisticianshould include a statistician

• Should include qualified people knowledgeable about Should include qualified people knowledgeable about the studies content but not directly involved in the the studies content but not directly involved in the studystudy


Describe meeting structureDescribe meeting structure• frequency (based on risk and subject accrual rate)frequency (based on risk and subject accrual rate)

• character (open, closed, private, public)character (open, closed, private, public)

• the PI may participate in open sessions but cannot be the PI may participate in open sessions but cannot be present for closed sessionspresent for closed sessions

• specify that minutes will be recorded and kept specify that minutes will be recorded and kept confidentialconfidential

• method for disseminating DSMB reports and method for disseminating DSMB reports and recommendationsrecommendations

Important Factors in Interim Important Factors in Interim Decision-MakingDecision-Making

1.1. Recruitment rate and completion scheduleRecruitment rate and completion schedule

2.2. Baseline characteristics and risk profile Baseline characteristics and risk profile

3.3. Baseline comparabilityBaseline comparability

4.4. Compliance to interventionCompliance to intervention

5.5. Data completeness and follow-upData completeness and follow-up

6.6. Internal consistency (outcomes/safety profile)Internal consistency (outcomes/safety profile)

7.7. External consistencyExternal consistency

8.8. Statistical issues for interim analysesStatistical issues for interim analyses

9.9. Ethical issuesEthical issues

10.10. Impact of early terminationImpact of early terminationDeMets, 1990

Statistical Techniques for Interim MonitoringStatistical Techniques for Interim Monitoring

ProblemProblem– For one-sided superiority on non-inferiority For one-sided superiority on non-inferiority

trial, upper bound on the false positive error trial, upper bound on the false positive error rate is 2.5%rate is 2.5%

– Multiple tests will lead to a false-positive rate Multiple tests will lead to a false-positive rate substantially higher than thissubstantially higher than this

– Interim testing must be performed at a more Interim testing must be performed at a more conservative levelconservative level

Statistical Techniques for Interim MonitoringStatistical Techniques for Interim Monitoring

MethodsMethods– Haybittle ApproachHaybittle Approach

» Use a highly-conservative level of significance (P = 0.001)Use a highly-conservative level of significance (P = 0.001)

– Pocock ApproachPocock Approach» Same significance level for all analysis (including final) Same significance level for all analysis (including final)

designed to reach the desired false positive error ratedesigned to reach the desired false positive error rate

– O’Brien-Flemming ApproachO’Brien-Flemming Approach» Varies level of significance used for testing as trial progressesVaries level of significance used for testing as trial progresses

» Group Sequential BoundaryGroup Sequential Boundary

Suggestions on how a DSMB meeting Suggestions on how a DSMB meeting might be conductedmight be conducted

Initially an open session is conducted Initially an open session is conducted • members of the clinical trial may be presentmembers of the clinical trial may be present• may focus on accrual, protocol compliance, and general toxicity may focus on accrual, protocol compliance, and general toxicity

issuesissues• no outcome results discussed during this sessionno outcome results discussed during this sessionFollowed by a closed sessionFollowed by a closed session• DSMB members onlyDSMB members only• outcome results discussedoutcome results discussed• statistical reports (if necessary)statistical reports (if necessary)Finally an executive sessionFinally an executive session• DSMB members onlyDSMB members only• discuss the general conduct of the trialdiscuss the general conduct of the trial• all outcomes (including toxicities and AE)all outcomes (including toxicities and AE)• develop recommendations and vote if necessarydevelop recommendations and vote if necessary

Examples of Advantages of DSMBExamples of Advantages of DSMB

SafetySafety– Gamma interferon in chronic granulomatous Gamma interferon in chronic granulomatous

diseasedisease» Biological markers (1 month trial) versus clinical Biological markers (1 month trial) versus clinical

markers (12 month trial)markers (12 month trial)

» DMC recommended 12 month trialDMC recommended 12 month trial

» At 6 month analysisAt 6 month analysis No effect on biologic outcomes (superoxide production)No effect on biologic outcomes (superoxide production) Substantially affected rate of recurrent infections Substantially affected rate of recurrent infections


SafetySafety– Cardiac Arrhythmia Suppression Trial (CAST)Cardiac Arrhythmia Suppression Trial (CAST)

» Trial initially designed with one-sided 0.05 level of Trial initially designed with one-sided 0.05 level of significancesignificance

» DMC recommended traditional 0.025 false positve DMC recommended traditional 0.025 false positve raterate

» Set both “upper boundary” for treatment benefit and Set both “upper boundary” for treatment benefit and “lower boundary” for treatment harm“lower boundary” for treatment harm

» Boundary for harm crossed rapidly and trial stoppedBoundary for harm crossed rapidly and trial stopped


Study QualityStudy Quality– Nocturnal Oxygen Therapy Trial (NOTT)Nocturnal Oxygen Therapy Trial (NOTT)

» Continuous versus nocturnal oxygen Continuous versus nocturnal oxygen supplementation on survival in COPDsupplementation on survival in COPD

» During course of trial key subgroup displayed During course of trial key subgroup displayed significant effect in favor of continuous O2 significant effect in favor of continuous O2 supplementationsupplementation

» Subsequent investigation revealed that two centers Subsequent investigation revealed that two centers were late in filing data reports and only submitted were late in filing data reports and only submitted mortality data for nocturnal O2 therapymortality data for nocturnal O2 therapy

» Benefit disappeared as files updatedBenefit disappeared as files updated


Study QualityStudy Quality– Major, international placebo-controlled trial of Major, international placebo-controlled trial of

intervention in an acute care settingintervention in an acute care setting– At interim analysis, primary efficacy endpoint At interim analysis, primary efficacy endpoint

sufficiently negative ruling out any possible sufficiently negative ruling out any possible treatment benefittreatment benefit

– DMC carefully analyzed reported dataDMC carefully analyzed reported data» Determined that treatment codes had been reversed Determined that treatment codes had been reversed

in data reportin data report» Re-analysis demonstrated benefitRe-analysis demonstrated benefit

Please do not hesitate to Please do not hesitate to contact me with any questions contact me with any questions

or concernsor concernsHarvey MurffHarvey Murff

(w) 327-4751 ext-6823(w) 327-4751 ext-6823

(p) 835-9617(p) 835-9617

Email: Email: [email protected]@med.va.gov

OrOr

[email protected]@vanderbilt.edu

data and safety monitoring in clinical trials harvey murff, m.d., m.p.h. gcrc, vanderbilt university...

Documents

safety monitoring plansdata

safety monitoring boardsdata

safety monitoring plans

safety of current

frequency of monitoring

research subject safety

particular study data

current requirements