Defining and Reporting Protocol NonCompliance

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Defining and Reporting ProtocolNon-Compliance

• Joseph C. Milbrandt, PhD
• Director
• Center for Clinical Investigation and
  Therapeutics
• OSF Saint Francis Medical Center
• Peoria, IL 61637

2
Background

• Federal Regulations require that all protocol
  deviations and/or instances of noncompliance with
  IRB regulations be reported to the IRB by the
  principal investigator as soon as the violations
  are discovered.
• A protocol violation/deviation is any action
  involving a research subject (or potential
  subject) which is outside the specific protocol
  guidelines.
• These violations are usually a direct result of
  poor investigator training.
• Innocent Ignorance

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Background

• Protocol deviations/violations emerge when there
  is a variance in a research study between the
  protocol (reviewed and approved by the IRB) and
  the actual activities performed by the research
  team.
• When such instances are discovered, the IRB must
  act promptly and ensure investigator action
  regarding compliance with human subject
  protection requirements and, if necessary, halt
  enrollment into a study.

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Recourse

• The IRB has the authority to terminate approval
  of research not conducted in accordance with IRB
  requirements or that has been associated with
  unexpected serious harm to subjects.
• The IRB also can sanction, suspend, or terminate
  approval if there are serious or continuing
  investigator non-compliance with the policies,
  requirements or determinations of the IRB.

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Protocol Deviations(Minor Protocol Violations)

• Non-compliance with any research regulation that
  usually does not
• have any substantive effect on the safety or
  well-being of research participants
• change the risk/benefit ratio
• affect the value of the data collected (meaning
  the violation does not confound the scientific
  analysis of the results)
• result from willful or knowing misconduct on the
  part of the investigator(s)
• violate any basic ethical principles

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Protocol Deviations(Minor Protocol Violations)

• Common deviations include
• unreported minor modifications in the IRB
  approved protocol or consent documents
• failure to perform certain study-related tasks
• failure to obtain official IRB notice of an
  amendment approval prior to enrolling research
  subjects under a revised protocol
• failure to perform follow-up visits according to
  the protocol
• lapses in approval for continuing review
• exceeding IRB approved enrollment numbers
• Examples
• Patient visit outside study window by two days.
• Missing first urine collection.

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Protocol Deviations(Minor Protocol Violations)

• Typical IRB response
• Administrative Review
• Notation in IRB study file.
• Report to Full Committee as informational item
  only.

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Protocol Violations(Serious Protocol Violations)

• Serious protocol violations include actions of
  noncompliance that
• have or pose a significant risk of substantive
  harm to research participants
• cause damage to the scientific integrity of the
  data collected
• result from evidence of willful or knowing
  misconduct on the part of the investigator
• ignore the established research, medical, and
  ethical principles

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Protocol Violations(Serious Protocol Violations)

• Examples
• patients enrolled prior to IRB notification of
  approval or after expiration of approval
• enrolling a subject outside the
  inclusion/exclusion criteria.
• use of an unapproved or expired informed consent
  document
• inadequate/improper informed consent procedures
• consenting of vulnerable subjects without a
  legally authorized/guardians signature
• poor comprehension by the study subjects due to
  study complexity and/or ICD language
• record keeping and documentation failures
• incorrect study medication or dosing
• wrong laboratory procedure or timing of procedure
• breach of confidentiality
• loss of drug or device

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Protocol Violations(Serious Protocol Violations)

• Typical IRB Response
• Notation in IRB study file.
• PI must provide detailed action plan to prevent
  future occurrences.
• Will be reviewed by Full Committee.
• IRB may suspend accrual of subjects.
• IRB may terminate the protocol.
• Extremely serious or repeated violations (usually
  more than 3) can result in the complete
  suspension of an Investigators Privileges.

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Protocol Exceptions

• Protocol Exceptions
• Applies to cases in which a single subject will
  be entered into a study even if this subject
  doesnt meet the eligibility criteria.
• Requires IRB approval prior to subject enrollment
• The IRB does not have to recognize a sponsor's
  approval to enroll a subject outside the
  inclusion/exclusion criteria.
• Requests should include
• An explanation of why this protocol is the best
  choice for this individual
• A description of the criteria that makes this
  person ineligible to enroll in this trial
• Documentation of approval by the trial sponsor
  (if there is one) to provide an exception

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Identification of ProtocolNon-Compliance

• Investigator/Research staff
• Investigator Peers
• Audits/monitoring by Sponsor, FDA, IRB, and/or
  compliance programs.
• Medical/Hospital staff caring for the subject.
• Hospital ancillary services
• Complaints by participant or family member

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Quiz

• Is the following example considered a protocol
  violation or a protocol deviation?
• Subject was randomized to kit number 003, but kit
  004 was mistakenly used.

14
Quiz

• Is the following example considered a protocol
  violation or a protocol deviation?
• Subject was given study drug (FDA approved for
  another indication) from pharmacy stock instead
  of the study drug supplied by the sponsor.

15
Quiz

• Is the following example considered a protocol
  violation or a protocol deviation?
• A subject returns for a 30 day follow-up visit
  for an acute IV antibiotic study. The protocol
  required a chemistry panel, but it was not done
  due to poor patient venous access.

16
Quiz

• Is the following example considered a protocol
  violation or a protocol deviation?
• Subject consented to participate in a study.
  Baseline labs were drawn and indicated the
  patient had an abnormal platelet count which
  excluded them from the study. Patient was not
  randomized to treatment.

17
Quiz

• Is the following example considered a protocol
  violation or a protocol deviation?
• In an ongoing study, a subject was enrolled using
  an updated consent form which had been submitted
  to the IRB. The approval letter was pending.
  The consent form changes provided by the sponsor
  were only administrative.