What the GCRC Can Do for You: Research Subject Advocate

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What the GCRC Can Do for YouResearch Subject
Advocate

• RSA Donald M. Mock, M.D., Ph.D.
• RSA Assistant Cindy Henrich, M.A.
• Phone [phone]
• http//www.uams.edu/gcrc/

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Primary Responsibilities of the Research Subject
Advocate

• Provide assurance to the PI of the GCRC grant,
  Aubrey Hough, M.D., that appropriate efforts are
  being made at the GCRC to protect the
  participating research subjects

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Three Principal Activities

• Evaluate Data and Safety Management Plans (DSMPs)
• Chair the Data and Safety Monitoring Board (DSMB)
• Conduct audits of active GCRC protocols for
  documentation of adherence to DSMP

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Historical Context

• In 1999, the death of a young man in a gene
  transfer clinical trial triggered an examination
  of safety by the Food and Drug Administration
  (FDA).
• Major medical centers had human research shut
  down for noncompliance.

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Historical Context

• In 1999, the Office of Human Research Protections
  (OHRP) inspected a number of medical centers for
  compliance with human subject regulations.
• FDA sent every gene transfer researcher a letter
  requesting numerous records for each study,
  including audit results and plans, evidence of
  compliance with Good Clinical Practice.

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Historical Context

• In April 2000, investigations into irregularities
  and IRB procedures resulted in the suspension of
  Federal funding at seven institutions.
• In September 2000, the NCRR mandated a part-time
  RSA position and an RSA assistant for GCRCs.

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I. Why Would You Need the RSA Office/Research
Support in CTSA?

• The NIH policy for data and safety monitoring of
  all clinical intervention studies requires
  ongoing oversight and monitoring to ensure the
  safety of participants and the validity and
  integrity of the data.
• So, you need a DSMP.
• We can help you with your DSMP.

• http//grants.nih.gov/grants/guide/notice-files/no
  t98-084.html
• http//grants.nih.gov/grants/guide/notice-files/NO
  T-OD-00-038.html

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Who Must Have a DSMP?

• All clinical trials require a general description
  of the data and safety monitoring plan as part of
  the research application to NIH and to UAMS IRB.
• All GCRC protocols must have a DSMP.

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Six Elements of a DSMP

• Risk Assessment
• Monitoring
• Interim Study Analysis
• Reporting
• Data Accuracy and Protocol Compliance
• Conflict of Interest

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1. Risk Assessment

• Adverse event grading
• Serious
• Non-serious
• Attribution
• Probably related
• Possibly related
• Remotely related
• Unrelated
• Experience with the drug or protocol

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Risk Assessment

• Adult Risk Levels
• Minimal Risk (AM)
• Greater than Minimal Risk (AGM)
• Pediatric Risk Levels
• P1. Risk not greater than minimal
• P2. Risk greater than minimal but with prospect
  of direct benefit to the subject
• P3. Risk greater than minimal with no prospect of
  direct benefit but likely to yield knowledge
  about the subjects disease
• P4. Research not otherwise approvable but
  offering an opportunity to understand prevent, or
  alleviate a serious problem affecting the health
  or welfare of children

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2. Monitoring

• Who will monitor the study?
• Investigator /- clinical coordinatorThe buck
  stops with the PI
• DSMB?
• How often will the study be monitored? Monitoring
  should be commensurate with risk, size, and
  complexity.
• What specific elements will be monitored?
• Choose wisely and be realistic.

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Monitoring

• Who will be informed of the results of monitoring
  and within what time frame?
• How will abnormal results be handled?
• How will normal results be handled?
• For example, will the subject be notified, and ,
  if so, how and within what time frame?

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3. Interim Study Analysis

• Why conduct an interim study analysis?
• Clinical trials in which clinical implications or
  safety issues may dictate that the trial should
  be stopped early need an Interim Study Analysis.
• positive or negative findings

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4. Reporting Plans
How will the IRB, the RSA, and the GCRC
administration be informed of SAEs, AEs, and
other safety concerns?

• Annual reporting of adverse events to the IRB and
  other required agencies
• http//www.uams.edu/irb/IRB.asp
• Jimmie L. Valentine, PhD, IRB Chair
• Include plans to inform the GCRC administration
  and the RSA if the IRB or any other body
  temporarily or permanently suspends the study.

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Reporting Plans

• PI is required to report all of the following
  (within the noted time-frame) to the IRB, the
  CAVHS R D Committee, the GCRC RSA, and other
  appropriate agencies
• Adverse events, usually upon annual continuing
  review
• Serious and unexpected adverse events, within 7
  days
• Death, within 3 days if patient is in the study.
  (Death during long-term follow-up, not
  protocol-related should be reported w/in 60 days
  of PIs notification.

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Reporting Plans

• Protocol deviations immediately if the deviation
  represents a significant alteration of the
  approved protocol and/or it effects the safety
  and welfare of the patient. Otherwise, report at
  the time of continuing review.
• Protocol violations (more serious than
  deviations) within 10 days
• Amendments to approved protocol within 30 days
• Restrictions, suspension or termination of the
  study within 3 days
• Any other activity which involves a potential or
  actual unanticipated risk to patients within 7
  days

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Reporting Plans

• An adverse event is not defined in the IRB
  Investigators Handbook.
• A serious adverse event is defined as any event
  that is life-threatening, results in persistent
  or significant disability, results in or prolongs
  hospitalization (even as a precautionary measure
  for observation), represents other significant
  hazard, or results in death.

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5. Data Integrity and Protocol Compliance

• How will adherence to the protocol be assured?
• How will data be handled?
• How will it be stored?
• Who will have access to it?
• How will security be addressed?

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6. Conflict of Interest

• Describe any possible conflicts of interest for
  the study personnel, particularly the PI.

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II. Data Safety Monitoring Board (DSMB)

• Provide safety reviews for all qualified clinical
  research studies utilizing the GCRC.
• Some funding agencies require DSMB charter
• http//www.uams.edu/gcrc/gcrc2/RSA/DSMPDSMB.asp

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Reasons to Use a DSMB

• Vulnerable population
• Risk level to participants is high
• Multicenter (probably an outside DSMB)
• Mortality or morbidity as an endpoint
• Co-morbidity of the study population
• Likelihood of uncovering significant benefit or
  harm from protocol treatment before conclusion of
  the study

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Criteria to be Monitored by the GCRC DSMB

• Study must be investigator-initiated (category A
  or B)
• All subjects must be studied at UAMS (UAMS
  Hospitals Clinics, VAH/GCRC, and ACH
  facilities)
• Less than 100 subjects/year unless approved by
  the RSA

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DSMB Membership

• Donald M. Mock, MD, PhD
• Professor of Biochemistry Molecular Biology and
  Pediatrics
• Non-voting Member
• K. David Straub, MD, PhD
• Professor of Internal Medicine and Biochemistry
• Chair GCRC Advisory Committee and DSMB
• Current member of UAMS IRB
• Voting Member
• Fred Faas, MD
• Professor of Medicine
• Former Chair of UAMS IRB
• Current member of UAMS IRB
• Voting member

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DSMB Membership

• Jeffrey R. Kaiser, MD, MA
• Assistant Professor Pediatrics, Section of
  Neonatology
• Voting member
• Mario Cleves, PhD
• Associate Professor Dept of Pediatric
• Senior Biostatistician
• Voting Member
• Alison Oliveto, PhD
• Professor and Vice Chair for Research, Dept. of
  Psychiatry
• Voting member
• Cynthia Witkowski, BSN, RN
• GCRC Nurse Manager
• Nonvoting member
• Cindy Henrich, MA
• RSA Assistant
• Nonvoting member

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Data and Safety Monitoring Report(DSMR)

• Attachments
• Abstract
• Data and Safety Monitoring Plan

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III. Chart Audits

• The purpose of audits by the RSA office is to
  ensure a process that genuinely enhances subject
  safety and data integrity without unduly impeding
  clinical research.

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Annual Audits

• Goals
• 100 of all protocols that have experienced one
  or more study-related SAEs
• 33 of all protocols judged by the UAMS IRB to be
  Adult Greater than Minimal Risk or Pediatrics
  Category 2-4
• 20 of all protocols judged by the IRB to be
  Adult Minimal Risk or Pediatrics Category 1

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Audit Procedure

• Five subjects from the previous 12-month interval
  are chosen.
• Inactive studies are not included.
• Study choice and subject choice are random.
• Exceptions
• No PI will be audited more than once in an
  auditing cycle.
• Unless an audit uncovers gross negligence.

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Education about Compliance and Documentation

• Seminars to educate PIs, study coordinators, and
  other research staff about subject safety and
  data management
• Consensus meetings
• Education Compliance- not Gotcha!