The Role of the IRB in Clinical Research

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The Role of the IRB in Clinical Research

• Karen J. Schwenzer, MD, FCCM
• Assoc. Professor of Anesthesiology Critical Care
  Medicine
• Chair, IRB-HSRSusan R. Hoffman, RN, BSN, CIP
• Director, IRB-HSR

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The IRB-HSR at the UVA is

• A group of lay people with no concept of patient
  care
• An inefficient, bureaucratic barrier to promotion
  and tenure
• A committee that will ultimately lead you to
  abandon a career in clinical research
• A committee designed to obstruct innovation and
  experimentation

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The IRB-HSR at UVA

• One of 3 local Institutional Review Boards.
• Provides oversight over biomedical research
  involving human subjects.
• Enables the FDA to assure that the University is
  in compliance with federal regulations.

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IRB Membership

• Oncology
• Cardiology
• Radiology
• Pediatrics
• Infectious Disease
• Surgery
• Anesthesiology
• Critical Care Medicine
• Pharmacy
• Behavioral Medicine

• HES
• Study Coordinators
• House staff
• Medical student body
• Vice Provosts Office
• Schools of Law and Nursing
• Chaplaincy
• Unaffiliated members
• Nonscientist members

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The Challenge of Self-Regulation

• Each IRB functions independently
• Federal oversight from the OHRP 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

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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 UVA
• Responsible for approving and continuingly
  reviewing all biomedical research projects
  involving human subjects
• Privacy Board (HIPPA)

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IRB Review

• A clinical study is ethical or not at its
  inception it does not become ethical because it
  succeeds in producing valuable data.
• It should be well designed according to sound
  scientific principles and be preceded by adequate
  laboratory and/or animal studies.

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Role of the IRB Review

• Determine if the scientific questions in the
  protocol have adequate merit to justify
  experimentation involving human subjects.
• Determine if the study design is adequate to
  answer the questions being asked.

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Result of IRB Review

• Changes may be imposed by the IRB either to
  improve the science of the study or to reduce the
  risks.
• The study is so flawed that no meaningful data,
  i.e. benefit will be obtained.
• Study objectives are trivial or a repeat of
  already accepted dogma

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Evaluate

• The appropriateness of the selected interventions
  
• The plans for minimizing bias (randomization,
  blinding, controls)
• The PI and co-investigators have the experience
  to conduct the study.

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Evaluate

• Recruitment practices
• Eligibility, inclusion and exclusion criteria
• Criteria for withdrawal
• Patient retention plans to minimize
  loss-tofollow up

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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.

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Selection of Research Subjects

• Benefits of the clinical study are distributed
  fairly.
• Morally acceptable for the burden of research,
  i.e. the risks, to fall on those most likely to
  benefit from the research.

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Vulnerable Populations

• Vulnerable
• Vulnerable to coercion to participate.
• Impaired capacity for informed consent.
• Are more likely than others to be willing to
  accept great risks in the hope that they will
  benefit from an experimental treatment.
• Vulnerable subjects should not be categorically
  excluded from studies

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Vulnerable Populations

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

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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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Special Populations

• Cognitively impaired, traumatized, critically
  ill, and comatose patients
• Students and employees
• Terminally ill

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Example 1Normal Healthy Volunteer

• RDBPC Trial of an investigational prophylaxis
  against experimentally-induced rhinovirus illness
• Male or female subjects 18-45 years of age
• One week confinement in local hotel
• 6 blood draws and 13 nasal washes
• 1350

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Competing Moral Principles

• Fulfillment of duties to research subjects
• Autonomy, protection of their welfare, fair
  treatment
• 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.

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Weighted Towards the Subject

• Duties to subjects takes precedence under most
  circumstances
• Informed consent
• Privacy
• Selection of subjects is equitable
• Additional safeguards for vulnerable populations
• Risks are minimized
• Risks are reasonable in proportion to anticipated
  benefits

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Financial Issues

• Compensation for Voluntary Subject
• Relative to time, effort, risk, and
  unpleasantness of the activities involved
• Subjects age and financial status influence
  IRBs reaction to the money offered
• Too large compensation may appear to be coercive.

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Example 2 - Phase II Trial

• Evaluation of the Efficacy of Vaccination with
  Synthetic Peptides in Patients with Advanced
  Colon Cancer
• 6 month study, 6 vaccinations, 12 blood draws,
  and a lymph node biopsy
• Withhold therapeutic treatment
• No direct benefit
• No compensation

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Financial Issues

• Subject is a Patient
• PI 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 remuneration may confuse subject to
  falsely believe that there is a long-lasting
  benefit

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Example 3 - Assent in Pediatric Trials

• 6 to 12 year olds with symptoms of sleep apnea.
• Still have tonsils and adenoids.
• 24-hour admission, physical examination,
  overnight sleep study, MRI study of the upper
  airway, and neurocognitive tests. Tests will be
  repeated 6 months after any treatment (i.e.
  tonsillectomy)
• Treatment is not covered by the study.
• 25 gift certificate for completing the first
  half of the study and a 75 gift certificate for
  completing the second half of the study.

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The Meaning of Assent

• A childs affirmative agreement to participate in
  research
• Those with developing capacity such as older
  children and adolescents can be invited to
  participate in research
• Assent also applies to an adult with impaired
  capacity though is functional

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Assent - continued

• Assent is about respect
• No child should be forced or coerced into
  participating in non-therapeutic research
• Even in therapeutic research, force and
  coercision should be used only as a last resort

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Example 4 - Cognitively Impaired Subject

• A 24-week, Multicentered RDBPC Trial of an
  investigational medication in patients with
  severe Alzheimer's Disease followed by a 12-week
  open label extension period
• 50 years of age with severe AD
• Caregiver must accompany subject to visits
• Monthly visits, lab tests, neuro testing
• Withhold other therapeutic medications

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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 Informational/Educational Techniques
• single sheet summaries or frequently asked
  questions 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 - New Device

• Analysis of safety and efficacy of
  sirolimus-eluting stents vs. standard stents in
  patients with CAD in a RDB trial
• Free stent if randomized to study stent.
  Otherwise subject is responsible for all costs of
  procedure.
• End point is MACE
• DSMB

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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.
• PI argues that protocol was approved by many
  other IRBs
• However, it may not be take it or leave it

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DSMBs

• Local IRB lacks information to provide oversight
  of continuations or modifications of trial. Shift
  oversight to DSMBs, which are not regulated by
  the Common Rule.
• Yet, local IRB and PI are held responsible for
  the safety of the study

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Who Pays for Research

• Financial Issues
• Who pays, and when?
• Who knows who pays?

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Financial Issues

• Patient pays investigator for participating in a
  study conducted during the course of routine
  delivery of health care
• Third party often involved insurance carrier
• Research vs. innovative therapy
• If the carrier refuses to pay for research,
  subject may incur a significant financial burden
  by participating in trial.

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Example 6 - Blood Draw Study

• Normal healthy volunteers
• 50 cc MWF for two weeks
• 10 per blood draw
• Is this study eligible for expedited review?

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Expedited Review

• Expeditable review means that the study can be
  approved by the IRB Chair.
• Expedited review and approval is available for
  protocols that involve only blood drawing or
  other minimal risk studies.

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Collection of blood samples by finger or heel
stick or venipuncture

• Healthy, nonpregnant adults who weigh at least
  110 lbs
• 550 ml in an 8 week period
• No more frequent than 2 times a week
• OR
• Other adults and children
• The lesser of 50 ml or 3 ml/kg in an 8 week
  period
• No more frequent than 2 times a week.

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Example 7 - Non-FDA Approved Indication

• Investigator-initiated RDBPC trial of intravenous
  ketamine for the prevention of postop nausea and
  vomiting
• Healthy subjects without history of PONV
  undergoing outpatient GYN procedure
• Rescue medication is provided in PACU
• Do you need an IND?
• Do you need a DSMP?

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Obtaining IND Exemption

• Not intended to support FDA approval of a new
  indication or a change in product labeling.
• Not intended to support a significant change in
  the advertising for the product.
• Does not involve a route of administration or
  dosage or use that significantly increases the
  risks associated with the use of the drug.
• The study is conducted in compliance with IRB
  regulation
• Check with the Clinical Trials Office

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Data Safety Monitoring Plan

• A DSMP is required for any protocol that involves
  an intervention.
• The IRB may determine a Data Safety Monitoring
  Board (DSMB) is needed if
• Phase I, II, or III study which involves high
  risk, multi-site, blinded, or a vulnerable
  population
• Device study requiring an IDE
• NIH Institute funding the protocol.

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Example 8 - Databases

• Two cohorts of patients, those with positive EBV
  infection results and those with negative
  results, will be linked by name, date of birth,
  gender, and SS to the diagnosis of Hodgkins
  lymphoma.
• Is this study exempt from IRB review?
• Is this study eligible for waiver of consent?
• It depends.

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Allowable Use of Identifiable Personal Health
Information

• 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 (OSP) and you track data
• If your privacy plan meets both the HIPPA Rule
  and the Common Rule for waiver
• Coded/linked, locked files, password protected

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Limited Data Set

• Strip some but not all of the PHI
• Less confidentiality risk for the subject
• Still need a Data Use Agreement for disclosures
  outside UVA
• Tracking of data is not required.

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Setting up a Database

• 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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Future Studies Using Data from A Database

• Submit a new protocol for review
• IRB determines if protocol is
• Exempt from IRB review - rarely
• Expeditable - usually
• If a Waiver or a Data Use Agreement is needed
• It depends on how you are taking the data out and
  with whom you are sharing it with

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PAM and ED

• Post Approval Monitoring
• Education

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Goals of PAM and ED

• to assure human subject safety
• to provide education to research professionals
• to identify strengths and areas for improvement
  in policies
• to enhance academic research practice

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PAM and ED

• Post Approval Monitoring
• Random
• For-cause
• PAM Subcommittee of IRB
• Exceptional
• Satisfactory
• Marginal
• Unsatisfactory

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PAM and ED

• Its not an audit
• Education plan is custom designed
• Remedial action
• Punitive action
• Re-reviewed in 6 months

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In Conclusion 18 Simple Rules for Surviving the
IRB

• Develop protocol idea.
• Write Protocol and Consent using the IRB PROTOCL
  BUILDER.
• Check to see if your study might be Expeditable
  or completely Exempt from IRB review.
• Complete the "Investigator's Agreement"
• Verify that all investigators/study coordinators
  have completed their IRB online training.

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• You may need an IND number-check with CTO
• You may need an IDE number-check with CTO
• If your study includes ionizing radiation, use
  the standard wording suggested by Radiation
  Safety Committee
• If your study involves the use of recombinant
  DNA, Biological Vectors, infectious agents, or if
  you are storing blood/tissue, submit application
  to the Biosafety Committee.
• If your study involves gene transfer, follow the
  UVA School of Medicine Policy on Gene Transfer
  Research Trials

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• If you ship specimens outside of UVA, all
  personnel performing these duties must complete
  DOT Training
• If youre using GCRC, review by the GCRC prior to
  IRB submission.
• If your study has an inclusion criteria that
  participants must have cancer, Protocol Builder
  may (or may not) direct you to the Cancer Center
  Protocol Review Committee.

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• Following the meeting you will receive a letter
  from the IRB explaining any changes which need to
  be made prior to final approval.
• APPROVED
• APPROVED PENDING MINOR MODIFICATIONS
• WITHHELD APPROVAL PENDING MAJOR MODIFICATIONS
• REJECTED

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• When all changes and approvals have been
  obtained, you will receive a signed IRB Approval
  Form and a stamped approved consent form. Only at
  this time can you begin to recruit or enroll
  subjects. The IRB must approve all modifications
• Report Adverse Events on-line
• Approximately 2 months prior to the expiration of
  a study, you will receive a Continuation Status
  form. This form should be completed and returned
  to the IRB office by the deadline.
• You are required to notify the IRB within 30 days
  of closure of the study.

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Future Directions

• Research with the cognitively impaired and the
  elderly
• Research with human embryos
• Genetic testing and screening, including families
  and children
• Organ transplant issues, including availability
  and xenografts

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Future - continued

• On-line review process
• Nationwide review of the Common Rule and current
  system
• Do we continue with the status quo or re-create a
  new national commission for bioethics?
• Battles over the free conduct of research vs. the
  politicization of research fetal, embryo,
  abortion

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