OHRPP October 2010

Data and Safety Monitoring

Laurie Shaker-Irwin, Ph.D., M.S.

Research Subject Advocate

Assistant Professor of Medicine

Office of Research Participant Advocacy (ORPA)

UCLA General Clinical Research Center

OHRPP October 2010

Goals

Understand the importance of data and safety monitoring in all research studies involving humans

Be able to identify the contents of a data and safety monitoring plan and selection of monitors

Know that safety monitoring is contingent upon the type and complexity of the research study and enrollment rates

OHRPP October 2010

“Teen Dies Undergoing Gene Therapy” (Washington Post 1999)

• Dose-finding gene transfer study of ornithine transcarbamylase deficiency • Attenuated adenovirus vector• Fever shortly after gene infusion • Liver failure after 1 day• Multisystem organ failure and brain death after 4 days, despite aggressive measures

OHRPP October 2010

Safety

Quality

Integrity

Trust

OHRPP October 2010

Current Events in Clinical Research

• Data call into question HIV study results (WSJ 10/09)

• Doctor rebuked over research (LAT 01/10) ; Lancet retracts study tying vaccine to autism (WSJ 02/10)

• Doctor is accused of faking painkiller studies (LAT 01/10)

• Violations at brain lab may have wide fallout (LAT 07/10)

• U.S. Apologizes for Syphilis Tests in Guatemala (NYT 10/10)

OHRPP October 2010

Definition of Data and Safety Monitoring (DSM)

Systematic review of the data and adverse events at regular intervals to assess the ongoing safety of the participants and the integrity of the overall study

Data and Safety Monitoring methods are usually detailed in a specific Data and Safety Monitoring Plan (DSMP)

OHRPP October 2010

Fundamental Principles of Data Monitoring

Safeguard the interest of study participants

Preserve the integrity and credibility of the study

Ensure that definitive and reliable results be available in a timely manner to the medical community and to the public

Ellenber g S, Fleming T, DeMets D. Data Monitoring Committees in Clinical TrialsJohn Wiley & Sons, Ltd. 2002

OHRPP October 2010

Regulations

NIH Guidelines Federal Regulations 45 CFR 46.111(a)

(6)FDA Guidelines IRB Review

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Important Common Elements of DSMPs

Description of the collection, review and reporting mechanisms for adverse events and safety information to the study monitors, IRB, FDA, sponsor (NIH, industry), and other applicable offices, agencies

Description of any setpoints/guidance for modifying or stopping the study

Description of the quality assurance efforts

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Important Study Considerations for Development of a DSMP

Risk to ParticipantsType and Complexity of StudyOther Factors

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Types of Risk

Physical PsychologicalSocialEconomic

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Likelihood of Risk

Probable ImprobableTheoretical

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Type and Complexity of Study

Intensity of the intervention

(e.g. type of agent, dose escalation, early phase

studies)

Vulnerability of the population

(e.g. age, cognitive function, disease condition, healthy volunteers, pregnant women)

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Other Factors Related to DSMP Preparation

BlindedPlacebo-controlled Multi-centerNew science Investigator IND Investigator experience DSM oversight by external entities

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Nuts and Bolts of the DSMP

Deciding on the Monitoring BodySelection of Monitor(s) Content of MonitoringFrequency of MonitoringDecision-Making Criteria/GuidelinesReporting Mechanisms

Sample DSMP

“An independent DSMB will be established to monitor the course of the clinical study. The responsibilities of the board will be to review, control, and assess the adverse events and other safety data and to give advice when considered necessary regarding the management of the trial and the trial protocol, always trying to ensure the safety and well-being of the study patients and the trial integrity”

OHRPP October 2010

Sample DSMP (continued)

The members of the DSMB will be experts who are independent of the sponsor and the CRO. The procedures and responsibilities for the collection, analysis, and review of the data by the DSMB as well as communication and documentation of their opinions and recommendations will be defined in the DSMB charter which will be agreed upon and written before the trial starts”.

OHRPP October 2010

OHRPP October 2010

DSMB Responsibilities

Evaluate research protocol and monitoring plans

Regularly review data Make recommendations to sponsor, IRB, and

investigators regarding the continuation, modification or conclusion of the trial.

Maintain confidentiality of the data

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Biostatistical Considerations

WHAT: Primary vs. Secondary endpoint decisions WHEN: Short-term vs. long-term treatment effects

determines when to analyze the data HOW: Subgroup analysis, where certain groups

have different responses than others (e.g. by gender or a specific risk factor)

WHAT ELSE? Available external information from other research.

JUPITER Trial 2008

Stopped after 1.9 years of follow-up; rosuvastatin significantly reduced the primary end point (disease and death from cardiovascular outcomes) by 44%, compared with placebo. There was a 55% reduction in nonfatal MI, a 48% reduction in the risk of nonfatal stroke and a 47% reduction in the risk of MI/stroke/CV death

OHRPP October 2010

JUPITER Trial (continued)

“Nine of the 14 authors have financial ties to the sponsor and the principal investigator has personal conflict of interest as a co-holder of the patent for the CRP test. The chair of the DSMB, which made the recommendation to stop the trial for efficacy, also comes in for criticism on this front, with others saying he has been and still is involved in many other industry-sponsored lipid-lowering trials, raising issues of conflicts of interest.”

OHRPP October 2010

ACCORD - 2008

ACCORD DSMB stated that a medical treatment strategy to intensively lower blood sugar below current guidelines increased the risk of death compared to standard blood sugar lowering treatment in type 2 diabetes patients at high risk for cardiovascular disease. Result: Transition everyone over to standard treatment

OHRPP October 2010

Testosterone 2010

Clinical trial of testosterone found a higher rate of adverse cardiovascular events, such as heart attacks and elevated blood pressure, in a group of older men receiving testosterone gel compared to those receiving placebo. Due to these events, the treatment phase of the trial was stopped, however evaluation of participants continues

OHRPP October 2010

Communicating with Participants about DSMB Decisions

Maintain confidentiality until it is absolutely necessary to disclose to the public

Notify all participants as quickly as possible and document notification

Follow-up with hardcopy notice of changes to study, if applicable

Ensure that all methods used in communicating study information have been reviewed by the IRB.

OHRPP October 2010

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Goals of Quality Assurance

Accrual Rates and Recruitment SourcesEligibility CriteriaInformed ConsentsAccuracy of DataCompleteness of DataConfidentiality of Data

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Clinical Research Problems and Events

Investigational drug research requires an effective system for collecting accurate and timely data on unanticipated problems and adverse events.

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Events in Data and Safety Monitoring: Adverse Events, Incidents, Unanticipated Problems

Protection and safety of study subjects Greater understanding of overall safety profile

of the study Recognition of dose-related toxicities Appropriate modification of study protocols Improvements in study design and/or

procedures Adherence to regulatory requirements

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Event Follow-up and Reporting Requirements

Recognize eventsRecord all details of events Evaluate in context of study as to

relationship and contextReport per policy to: data and safety

monitors, IRB, campus departments, FDA, and sponsors

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Some Problems Observed with Event Reporting

Inaccurate/inadequate or missing source documents (medical records)

Delegation of event identification and review to unqualified personnel

Insufficient follow up of events to determine resolution

Events that are not reported to the IRB/other agencies in a timely fashion

OHRPP October 2010

Problems Observed with Event Reporting (continued)

Description is not sufficientLess serious aspects are described and

more serious aspects are omittedMissing concomitant drugsData on reports do not match data on

source documents or case report forms

(c) January 2009

Remember…..

Knowing is not enough, we must apply.

Willing is not enough, we must do

J.W. Goethe