CTSA - Online training- Data Safety and Monitoring in Clinical Research

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Education Module
Data Safety and Monitoring in Clinical Research

Introduction

Data and safety monitoring is mandated by the National Institutes of Health.  Every center/institute should have a system for the appropriate oversight and monitoring of the conduct of clinical trials.  It is vital that the safety of research participants is ensured and that the validity and integrity of data is protected. 

This module reviews participant and investigator obligations, study phases, key principles in data safety and monitoring, significant risk protocols, and independent data and safety monitoring boards.

Obligations

Participant Obligations in Clinical Research
Research participants should be fully informed of study requirements throughout the study.  Participants should comply with the rigors of the research protocol or be allowed to withdraw from study participation.

Investigator Obligations in Clinical Research

Investigators must protect the health and safety of clinical research participants.  Investigators must inform participants of information relevant to their continued participation and pursue research objectives with scientific diligence.

A Brief History of Data and Safety Monitoring

1979

  • Every clinical trial should have provision for data and safety monitoring
  • The size of the monitoring committee depended upon the nature, size, and complexity of the clinical trial
  • The principal investigator was expected to perform the monitoring function, but may have had help from others

1994

  • It was recommended that every clinical trial, including those that pose little likelihood of harm, have an external monitoring body

1998

  • Establishment of a Data Safety Monitoring Board (DSMB) is required for multi-site clinical trials involving interventions that entail potential risk to study participants
  • The functions and oversight of such activities are distinct from the requirement for study review and approval by an Institutional Review Board

Study Phases

Phase I – physiologic, toxicity, and dose-finding studies
Phase II – efficacy studies
Phase III – efficacy, effectiveness, and comparative trials

Principles of Data Safety and Monitoring
Monitoring should be commensurate with the degree of risk involved.  A data safety and monitoring committee should determine safe and effective conduct and recommend the conclusion of a clinical trial when significant benefits or risks have developed.

Risk associated with participation in clinical research must be minimized to the extent practical.  The size and complexity of a clinical trial will determine if a single person or committee is needed to oversee the study.

Data and safety monitoring is intended to protect the integrity of the system for monitoring trial data and participant safety.  Monitoring must be performed on a regular basis and conclusions of monitoring must be reported to the Institutional Review Board and the Research Subject Advocate (RSA) or RSA Committee.

The Institutional Review Board and/or the Research Subject Advocate may direct who shall perform monitoring activities and the composition of the monitoring group (i.e., the principal investigator is not to chair the Data and Safety Monitoring Board nor be the sole person conducting the monitoring).

Data and Safety Monitoring Plan

Many protocols are required to have a Data and Safety Monitoring Plan, which:

  • Monitors the progress of the research study and the safety of the participants;
  • Plans for assuring compliance with requirements for reporting adverse events;
  • Plans for assuring that any action resulting in a temporary or permanent suspension of the clinical trial is reported to all responsible parties; and
  • Plans for assuring protocol compliance and data accuracy.

The Data and Safety Monitoring Plan should include the following:

  • Committee chair and members
  • How frequently the study will be evaluated
  • Method of detecting adverse events
  • How adverse events will be scored
  • Adverse event reporting requirements
  • A description of interim efficacy analysis, if appropriate
  • The distribution of DSMB reports

Specifics of the plan will depend upon the nature, size, complexity, and risk of the clinical research trial.

Significant Risk Protocols

The definition or risk is a complex sum of individual contributors to the overall risk of participation in a study.  Risk to study subjects may be thought of as encompassing aspects of study design, potential for loss of confidentiality, and the nature of the study population involved.
The risk of the intervention is a function of the potential for adverse events and the severity of adverse events.  The potential for adverse events includes the expected frequency of adverse events.  When the frequency of adverse events is unknown or identifying the frequency is one of the endpoints of a trail (such as a Phase I trial), the risk is higher.  The severity of adverse events should also be considered independent of the frequency of adverse events.  Study procedures which are not expected to lead to frequent adverse events, but include the possibility of severe adverse events, confer higher risk.

The amount of experience with the study intervention also affects the risk, since the risk of adverse events may not be fully defined.  Participation of vulnerable subjects confers greater risk than non-vulnerable populations.  Vulnerable subjects include children under 18 years of age, prisoners, employees of the workplace, etc.  Normal volunteer populations require special consideration since any intervention confers greater risk than would be experienced by individuals not participating in a clinical research study.

Loss of confidentiality for study participants in genetic-related studies, studies of stigmatized conditions, or studies where loss of confidentiality could lead to social harms, may be considered high risk.  For example, a genetic study that might lead to a diagnosis of, or identify a predisposition for, a serious disease in study participants, would be considered high risk.  A study including known illegal drug users could be considered high risk since loss of confidentiality of study participants could lead to great social harm.

Independent Data and Safety Monitoring Board

An independent Data and Safety Monitoring Board is comprised of at least one member who is not directly involved with a given clinical research study.  This member should not be a member of the principal investigator’s or co-principal investigator’s division within a given department.  If the principal investigator of a study is a division director, the independent Data and Safety Monitoring Board cannot be comprised of more junior members of his/her division.

Certain types of clinical trials require an independent Data and Safety Monitoring Board.  All phase I trials, phase II trials (unless they involve low risk interventions), studies of devices or invasive techniques with which the principal investigator or community has little experience, and gene therapy trials all require independent Data and Safety Monitoring Boards.  Genetic studies, studies in vulnerable populations, and studies that involve administering agents manufactured on campus also require independent Data and Safety Monitoring Boards.  Vulnerable populations include children and adolescents under 18 years of age, prisoners, pregnant women, and decisional-impaired subjects.

Question and Answer

This question and answer section is designed to test your knowledge of audits in clinical research.  Answers are provided so that you can ensure you know the right answer.  No credit is given for completing these questions.

Question 1
Question.  True or false.  Data and safety monitoring is mandated by the National Institutes of Health?
Answer: True

Question 2
Question: True or false.  Monitoring should be commensurate with the number of research participants in a study.
Answer: False.  Monitoring should be commensurate with the degree of risk involved, not the number of study participants.

Question 3
Question: True or false.  Risk of an intervention is defined solely by the severity of adverse events that occur.
Answer: False. Risk is a complex sum of individual contributors to the overall risk of participation in a study.  The risk of an intervention is a function both of the potential for adverse events and their severity.  Risk also encompasses aspects of study design, confidentiality, and the nature of the study population involved.

Question 4
Question:  True or false.  Studies involving children under age 18 require an independent Data and Safety Monitoring Board?
Answer: True.  All studies involving vulnerable populations (i.e., children under age 18) require an independent Data and Safety Monitoring Board.

Acknowledgements

This module was adapted from a power point presentation available at the Indiana Clinical and Translational Sciences website.  The original power point is available at: http://www.indianactsi.org/coordinators/pastmeetings.