Practical Tips for Working Effectively With Your IRB

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Practical Tips for Working Effectively With Your
IRB

• Karen J Schwenzer, MD, FCCM
• Associate Professor of Clinical Anesthesiology
  and Critical Care Medicine
• Chair, Institutional Review Board-Health Sciences
  Research
• University of Virginia
• Charlottesville, Virginia

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I have disclosed that I do not have a financial
relationship or interest with any proprietary
entity producing healthcare goods or services in
conjunction with this conference.
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Outline

• Common stumbling blocks in protocol preparation
• Healthy normal volunteers
• Pediatrics
• Cognitively impaired subjects
• Investigation of a New Drug
• Investigation of a New Device
• Setting up a Database

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The Challenge of Self-Regulation

• Each institutional IRB functions independently
• Federal oversight from the Office of Human
  Research Protection
• Defines the Common Rule and implements the
  regulations (45 Code of Federal Regulations 46,
  subpart A)
• FDA has additional regulations governing new drug
  and device trials
• State statutes and local legal counsel

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IRB Role Responsibility

• Protect the rights welfare of human subjects
  recruited to participate in biomedical research
  activities conducted at or on behalf of your
  institution
• Responsible for approving and continuingly
  reviewing all biomedical research projects
  involving human subjects

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Model of Research Review

• PI writes proposal (or by committee developing
  multi-center trial)
• Scientific review of proposal
• External NIH or other sponsor
• Internal departmental review
• None IRB becomes de facto scientific reviewer
• Submit proposal to IRB
• Administrative review of proposal
• Conducted by IRB staff
• Communication with PI regarding
  administrative/regulatory deficiencies

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Model of Research Review -2

• Initial IRB review
• Conducted by IRB committee
• May involve input from experts/consultants
• May involve communication with other standing
  committees (COI, radiation safety, biosafety)
• Communication with PI regarding human subjects
  protection
• Study conducted
• Subject recruited, consent obtained, enrolled
• PI follows good clinical practice
• Ongoing/continuing administrative/IRB review of
  protocol

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Why IRBs Become Easy Targets for Perceived
Unfairness

• Superficial and hasty reviews of protocols
• Poor training of reviewers
• Favoritism
• Personal biases
• Conflicts of interest
• Investigators self-image and personal needs
• Clamping down on investigators because of fears
  from federal regulators
• Clamping down on investigators because of fears
  from within
• Timely fashion

From Keith-Spiegal. The IRB Paradox. Ethics and
Behavior 15(4)339. 2205
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Example 1Normal Healthy Volunteers

• RDBPC Trial of an investigational prophylaxis
  against experimentally-induced influenza illness
• Male or female subjects 18-45 years of age

• One week confinement in a local hotel
• 6 blood draws and 13 nasal washes
• 1350

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Competing Moral Principles

• Fulfillment of duties to research subjects
• Takes precedence under most circumstances
• Autonomy, privacy
• Fair treatment
• Minimize risks
• Good clinical practice standard

• Promotion of the general welfare of society
  through the conduct of research
• Research subjects have a moral responsibility to
  bear some of the risk in promoting the general
  welfare of society.
• Risks are reasonable in proportion to anticipated
  benefits

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Assessment of Anticipated Benefits

• Benefits to subject vs. Benefits to society
• Remuneration is not a benefit to be gained from
  research
• Research may be a personal rewarding experience,
  but this is not considered a benefit

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Financial Issues

• Moral interest in promoting the welfare of
  society supports paying research subjects
• Relative to time, effort, inconvenience, and
  unpleasantness of the activities involved
• Reimbursement for expenses, lost wages, and
  parking costs
• Prorated, completion bonus
• Subjects age and financial status influence
  IRBs reaction to the money offered

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Example 2 - Phase II Trial

• Evaluation of the Efficacy of Long Acting ß
  Agonist in Patients with Mild Persistent Asthma

• 4 month study, 18 visits, 12 blood draws
• Withhold therapeutic treatment except rescue
  albuterol
• 25 per visit prorated, free labs, tests, and
  free drug

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• Benefits
• Expressing a fact
• Expected or anticipated benefits of knowledge or
  improved health

• Risks
• Expressing probabilities
• Physical
• Psychological
• Social
• Economic

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Selection of Subjects

• Will the burdens of research fall on those most
  likely to benefit from the research?
• Are the benefits distributed fairly?
• Have you overprotected potential subjects so that
  they are denied opportunity to participate?

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Designing the Control Group

• Use a conventional or standard treatment
• Placebos may be used in clinical studies where
  there is no known or available alternative
  therapy that can be tolerated by subjects.
• Usual practice vs. Standard of care

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Conflict of Interest

• Subject is a patient
• Potential for conflict of interest if
  investigator is also patients treating
  physician.
• Investigator may reason that potential for
  therapeutic benefit is reason enough to
  participate.
• If the benefit is small, the IRB may feel
  remuneration is warranted
• Lack of payment may confuse subject to falsely
  believe that there is a long-lasting benefit

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Example 3 Evaluation of Factors Influencing Pain
in Children with CP

• 6 -17 year old children with CP
• Detailed anthropometric assessment,
  questionnaires, DEXA scan, wrist XRAY 3 times
  over one year.
• 30 gift certificate for each visit, 90
  total

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Vulnerable Populations

• Children
• Cognitively impaired
• Pregnant Women
• Fetuses
• Human in vitro Fertilization
• Prisoners

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Vulnerable Populations

• The IRB is mandated to apply a rigorous
  evaluation of the risk and benefits of the study
  when vulnerable subjects are asked to
  participate.
• If more than minimal risk is involved, some
  degree of benefit is usually required.

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What is Minimal Risk?

• the probability and magnitude of harm or
  discomfort anticipated in the research are not
  greater than those ordinarily encountered in
  daily life or during the performance of routine
  physical or psychological examinations or tests.
• (45CFR, part 46, secs. 102i and 111)

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Example 4 - Cognitively Impaired Subject

• Gene polymorphisms and the risk of the
  development and rupture of intracranial aneurysm
• Single blood draw
• Some subjects will be unconscious
• Request for surrogate consent
• Most genetic testing is considered greater than
  minimal risk

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Safeguards for Cognitively Impaired Subjects

• Use of an Independent Monitor
• Use of a Surrogate Decision-maker
• Use of Assent
• Use of summaries or FAQ sheet
• Use of Waiting Periods

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Virginia Statute on Surrogate Consent for Research

• Have animal and other pre-clinical studies been
  conducted which suggest that a potential for
  therapeutic benefit exists?
• Advance directive for research appointing
  surrogate decision maker for research.

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Example 5 - A Clinical Evaluation of the GORE
TAG Thoracic Endoprosthesis in the Primary
Treatment of Descending Thoracic Aortic Aneurysms

• Independent Data Safety Monitoring Board provides
  oversight of safety and efficacy of study

Patient is responsible for all costs of the
study, including graft, anesthesia, follow-up.
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Who Pays for Research

• Who pays, and when?
• Who knows who pays?
• Research vs. innovative therapy

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The Challenge of Multi-Centered or Cooperative
Group Trials

• Protocol was not developed locally.
• If local IRB requests changes to the study
  design, the sponsor could drop our institution
  and cause the loss of revenue and prestige.
• Investigator argues that protocol was approved by
  many other IRBs
• However, it may not be take it or leave it

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Data Safety Monitoring BoardWhat is this?

• Independent group of experts who advises the
  investigators, sponsor and local IRBs
• Reviews data, participant safety, efficacy,
  compliance to protocol
• Makes recommendations for modifications,
  continuation, or termination of study

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Example 6 - Blood Draw Study

• Normal healthy volunteers
• 150 cc once a month for 6 months
• 10 per blood draw
• Recruitment by approaching lab personnel and
  residents directly to volunteer
• Is this study eligible for expedited review?

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Expedited Review

• What is this?
• Expedited review and approval is available for
  protocols that involve only blood drawing or
  other minimal risk studies.

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Special Populations

• Terminally ill
• Students
• Employees
• Economically disadvantaged

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Example 7 - Non-FDA Approved Indication

• A Randomized Trial of Vitamins C and E and Beta
  Carotene in the Secondary Prevention of
  Cardiovascular Events in Women
• Women 40 years or older with a history of CVD
• Followed for 10 years
• Do you need an Investigational New Drug
  application (IND)?
• Do you need a Data Safety Monitoring Plan?

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Obtaining IND Exemption

• Not intended to support FDA approval of a new
  indication.
• Not intended to support a significant change in
  the advertising for the product.
• Does not involve a route of administration or
  dosage or patient population that significantly
  increases the risks of the drug.

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Data Safety Monitoring Plan What is this?

• Required for any protocol that involves an
  intervention.
• Risk assessment and adverse event grading and
  attribution scales.
• Monitoring plan - who, what, and how often
• Reporting plans
• Data accuracy and protocol compliance

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Example 8 - Hemoglobin Level and Outcomes
Database

• Prospective collection of existing data
• Is this considered human research?
• Is this study exempt from IRB review?
• Is this study eligible for waiver of consent?

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IRB May Waive the Requirement for Consent if

• You do not disclose data outside of UVA
• If you disclose data outside of UVA you need a
  Data Use Agreement with people you are sharing it
  with and you need to track where the data goes.
• If your privacy plan meets both the HIPAA Rule
  and the Common Rule for waiver
• Coded/linked
• Locked files
• Password protected

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Birmingham VA Medical Center

• Missing hard drive could affect 535,000 patients,
  1.3M doctors
• Information on the hard drive was being used in a
  nationwide study

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Another Way to Get a Waiver is to Create a
Limited Data Set

• Strip some but not all of protected health
  information (PHI), e.g. name, SS, DOB
• Still need a Data Use Agreement for disclosures
  outside institution
• Tracking of data is not required.

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Setting up a Database

• How do you do this?
• Expedited review by IRB.
• Data captured through review of medical records.
• Data captured through review of previous research
  data.
• Identifiable PHI is acceptable as long as data
  stays internal prefer linked and coded

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7 Principles of Human Research

• value
• validity
• fair subject selection
• favorable risk/benefit ratio
• independent review
• informed consent
• respect for enrolled participants