The Role of the Human Investigation Committee in Clinical Research

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The Role of the Human Investigation Committee in
Clinical Research

• Karen J. Schwenzer, M.D.Associate Professor of
  AnesthesiologyChair, HICThea
  Grover-PatrickAssistant Director, HIC Office

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The HIC 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 HIC at UVA

• One of 3 local Institutional Review Boards.
• Provides oversight over research involving human
  subjects.
• Composed of clinicians, scientists,
  nonscientists, and community members
• Enables the FDA to assure that the University is
  in compliance with federal regulations.

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HIC Role Responsibility

• Role is to protect rights welfare of human
  subjects recruited to participate in biomedical
  research activities conducted at or on behalf of
  UVA
• Responsible for approving and continuing all
  biomedical research projects involving human
  subjects
• Privacy Board (HIPPA)

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HIC Membership

• Biomedical Ethics
• Study Coordinators
• House staff
• Medical student body
• Vice Provosts Office
• Schools of Law and Nursing
• Chaplaincy
• Community members without a scientific
  background 

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

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Common Federal Rule

• The US Dept of Health and Human Services
  published Basic DHHS Policy for the Protection
  of Human Research Subjects in 1981 - 45 Code of
  Federal Regulations 46, subpart A
• Common Rule, nearly identical to the DHHS
  regulations, was accepted by 16 federal
  departments and agencies in 1991

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The Challenge of Self-Regulation

• Each IRB functions independently
• OHRP Office of Human Research Protection
• Defines the Common Rule and implements the
  regulations
• FDA has additional regulations governing new drug
  and device trials

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Exceptions to the Federal Rule

• Waiver of Consent
• Minimal risk
• More than minimal risk if research could not be
  practically carried out without the waiver
  (Emergency Use)
• Surrogate Consent
• Non-therapeutic with minimal risk
• Children
• Vitally important knowledge

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What is Minimal Risk?

• the probability and magnitude of harm or
  discomfort anticipated in the research are not
  greaterthan 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 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 Volunteer 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 Melanoma Peptides in Patients with
  Advanced Melanoma
• 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 - Therapeutic Pediatric Trial

• Analysis of safety and efficacy of a pneumococcal
  vaccine vs. placebo in a randomized double-blind
  trial in infants.
• Infants receive either pneumoccocal vaccine or
  placebo at 6, 10 and 14 weeks of age
• End point is incidence of first episode of
  invasive pneumococcal disease.

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Example 4 - Assent in Pediatric Trials

• 6 to 12 year olds with symptoms of sleep apnea.
• Should 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.
• 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 5 - 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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Surrogate Consent

• Is it clear that individuals cannot give informed
  consent?
• Have animal and other pre-clinical studies been
  conducted which suggest that a potential for
  therapeutic benefit exists?
• Does study involve specimen collection that will
  cause no more than minimal risk (i.e. leftover or
  lt50 cc in 8 weeks)?

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Example 6 - 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 consent?
• Is this study eligible for waiver of consent?
• What about HIPAA?

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Allowed Use of Identifiable Personal Health
Information

• Consent/authorization required
• Waiver of Consent required
• If disclosing data outside of UVA
• All disclosures must be tracked
• Exceptions
• Internal Use only
• Database
• Preparatory to Research

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Limited Data Setor Coded/Linked PHI

• Consent/authorization NOT required
• Waiver of Consent NOT required, nor is tracking
  of data if disclosed outside UVA
• Data Use Agreement for disclosures
• Exceptions
• Internal Use only
• Preparatory to Research

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Databases

• Expedited protocols capturing PHI
• Data captured through review of clinical
  records/medical records
• Accessed subsequently by other protocols
• Data Use Agreement

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Example 7 - 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 defined as failure of the target
  vessel, as defined as death from cardiac causes,
  MI, or revascularization.
• 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 elsewhere
• 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 8 - 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 HIC Chair. The study can begin
  prior to the next meeting of the full HIC.
• 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 per kg in an 8 week
  period
• No more frequent than 2 times a week.

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Example 9 - Graduate Medical Education

• You have developed a new computer-based learning
  module for residents to learn fiberoptic
  intubation
• You want the residents to do a pre and post
  written test
• Is this study exempt from consent?
• Are residents a vulnerable population?

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Exempt Research

• Research involving instructional strategies,
  effectiveness of instructional techniques or
  curricula.
• Research involving the use of educational tests,
  surveys, interviews or observations.
• Research involving the collection or study of
  existing data, documents, records, pathological
  specimens or diagnostic specimens.
• Research designed to study public benefit or
  services programs
• Tests and food quality evaluation and consumer
  studies

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Example 10 - 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 or GU procedure
• Rescue medication is provided in PACU
• Do you need an IND?
• Do you need a DSMP?

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Obtaining IND Exemption

• 1. Not intended to support FDA approval of a new
  indication or a change in product labeling.
• 2. Not intended to support a significant change
  in the advertising for the product.
• 3. Does not involve a route of administration or
  dosage or use that significantly increases the
  risks (or decreases the acceptability of the
  risks) associated with the use of the drug.
• 4. The study is conducted in compliance with IRB
  regulation

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Data Safety Monitoring Plan

• A DSMP is required if the protocol includes an
  intervention.
• The HIC will determine if a Data Safety
  Monitoring Board or Committee (DSMB/DSMC) 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 this protocol.

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Responsibilities of the PI

• Follow the procedures listed under Submission
  Process
• If your study requires collaboration from another
  area, it is customary to name a person from that
  department as a sub-investigator.
• Abide by the Investigators Agreement

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Investigators Agreement

• No subjects will be recruited until you have
  received the signed HIC Approval Form.
• Any advertisements used to recruit subjects will
  be approved by the HIC prior to use.
• Any modifications of the protocol or consent form
  needs prior written approval by the HIC
• All subjects will sign a copy of the consent form
  that has an HIC approval stamp.

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• Any deviation or adverse events that are serious,
  unexpected and related to the study or a death
  occurring during the study will be reported
  promptly to the HIC in writing.
• Continuation forms will be returned on time.
• HIC office will be notified within 30 days of a
  change in the PI or of closure of the study.
• No one will be allowed to work on the protocol
  until they have completed the HIC On-line training

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In Conclusion 18 Simple Rules for Surviving the
HIC

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

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• You may need an IND number
• You may need an IDE number
• If your study includes ionizing radiation, use
  the standard wording suggested by the 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
  HIC submission.
• If your study has an inclusion criteria that
  participants must have cancer, and the study is
  not sponsored by NIH, ACS, NSF or a Cancer
  Cooperative Group, your study must be reviewed by
  the Cancer Center Protocol Review Committee.

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• Following the meeting you will receive a letter
  from the HIC explaining any changes which need to
  be made prior to final approval.
• APPROVED
• WITHHELD APPROVAL 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 HIC Approval
  Form and a stamped approved consent form. Only at
  this time can you begin to recruit or enroll
  subjects. The HIC 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 HIC office by the deadline.
• You are required to notify the HIC 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 submission and review process
• Review and evaluate 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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