Meeting Todays Challenges: The Evolving Role of the IBC

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Meeting Todays Challenges The Evolving Role of
the IBC

• Claudia Mickelson, PhD
• MIT

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New AreasNew Biosafety Issues

• Gene therapy
• Transgenics
• Bioweapons
• Xenotransplantation
• DNA vaccines
• Pharmacogenomics

• vector safety, etc
• effect of transgene escape
• Public health
• zoonotic agents
• persistence, tolerance
• genetic privacy

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Framework of Oversight

• Federal
• -HHS, including NIH, FDA, OHRP, OLAW
• Recent Pending
• -CDC
• -USDA
• -DOJ

• Institution
• IRB
• IBC
• IACUC
• Investigator

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Recent NIH Initiatives

• Public access to SAE reports,harmonization of
  definition and timing with the FDA
• Establishment of GTSAB
• Revision of HGT Protocol review process
• Development of GTPC
• Long term patient follow up

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Recent NIH Initiatives

• Changes to RG classifications for certain viral
  and bacterial agents.
• Guidance on Ad vector use
• Development of GEMCRIS
• NIH effort on IBC professional development

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Recent Changes Role of IBC

• Human Gene Transfer Research
• Serious Adverse Event Reporting
• Review and Oversight of Human Xenotransplantation
  Research
• Review and Oversight of Select Agent Research

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Role of the Institutional Biosafety Committee

• balancing risk/protection
• and
• scientific quality

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Role of the Institutional Biosafety Committee

• Reflection of the responsibility of the
  institution to ensure the safe conduct of
  biological research
• Provide a mechanism for public scrutiny of and
  access to biological research
• minimally driven by specific research or funding
  source

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The IBC

• Not just rDNA but drugs, toxins, infectious
  agents, vaccines, xenotransplantation
• An early warning system
• Identification of appropriate pre-clinical
  studies
• Assessment of pre-clinical data

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Comparison of Local Oversight Roles
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IRB, IACUC IBC Overlap Areas

• Human Gene Therapy
• Xenotransplantation

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HGT Clinical Trials Unique

• Age of participants a reversal of the normal
  process
• Severity of the underlying illness
• Complexity of therapeutic drug and safety
  issues
• Potential for long term effects
• Need for collaboration IBC, IRB, IACUC

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Strategies in Gene Therapy

• gene replacement and/or supplementation
• enhancement of immune function
• immunization
• suicide genes
• augment conventional therapies

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Gene Transfer Trial by Disorder
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Scientific Issues in Gene Transfer

• vector safety
• cell tissue specificity
• transgene expression regulation
• secondary effects of insertion expression
• shedding exposure of non-patients
• Genotype/phenotype correlation
• long term effects of gene transfer

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Ethical Public Issues

• Patient Safety Informed Consent Process
• Public access to Serious Adverse Event data
• Conflict of Interest, researchers institutions
• in utero Gene Transfer
• Germ line Gene Transfer
• Enhancement

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Collaboration IBC and IRB

• Timing is everything
• Various models
• Sequential review
• Joint subcommittee
• Separate review of sections

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Preclinical Studiestest of construct, proof of
concept IBC and IACUC?

• adequate model of disease
• safety in vivo
• efficacy in vivo
• biodistribution, toxicity, secondary effects
• development of quantitative end points
• Identification of possible surrogate end points

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The Role of the IBC

• Scientific quality of protocol, does the
  preclinical data support the initiation of a
  human trial as the next logical most reasonable
  step
• Does the preclinical animal data address and
  resolve as many safety issues as feasible (are
  tests in more than one species needed)
• Is the patient monitoring program sufficient,
  consistent,
• Will/can meaningful data be acquired

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Clinical Trial Review Risk/ Benefit Assessment

• Potential risks harm to study participants,
  close contacts, community
• Potential Benefits development of therapies for
  serious/life threatening conditions
• Assessment do the potential benefits outweigh
  the potential risks

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IBC IRB Collaboration

• Is the Informed Consent document clear, and
  adequate, without technical jargon?
• Are preclinical results clearly explained (what
  they do and do not show)?
• Is information about SAE, outcomes of other
  trials, other patients presented clearly

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Xenotransplantation The IBC, IACUC and IRB

• Background
• Safety Issues
• Examples of clinical trials

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Resurgence of interest in Xenotransplantation
NEED

• shortage of human/fetal organs or tissues
• no therapies
• new immune suppressive drugs, assays and reagents
• better immune suppression regimens

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Xenotransplantation

• Transplantation or implantation into a human
  recipient or live cells/tissues/ organs from a
  nonhuman source
• Human body fluids/cells/tissues or organs that
  have had ex vivo contact with live nonhuman
  animal cells, tissues, or organs

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Barriers to Clinical Trials

• Immunological recognition of non-self
• hyperacute rejection
• acute vascular rejection

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Barriers to Clinical Trials

• zoonoses
• inadvertent infections
• poorly characterized products
• inability to treat cellular preps to inactivate
  possible contaminants

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Safety Issues in Xenotransplantation

• Public Health community concerns
• New zoonotic infectious agents totally new
  situation, time of exposure due to
  transplantation, evolution of host range to
  include humans
• Individual concerns
• Infectious agents, transmission to other members,
  no blood or tissue or organ donation

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Ethical Issues in Xenotransplantation

• The barriers are so high, what criteria must be
  met for the first organ transplant trials
• Use of animals
• Lifelong follow up

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XenotransplantationTypes of Trials

• Ex vivo maintenance of a barrier
• In situ implantation into the body, such as
  porcine fetal neuronal cells as a treatment for
  PD, other neurodegenerative diseases

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IBC IACUC

• Assessment and review to ensure appropriate
• Animal selection screening
• Donor animal quarantine testing
• GMP cell processing product testing
• Patient education informed consent
• Patient surveillance program
• SAE review process, DSMB

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IBC Role in Monitoring

• Preclinical studies, assess adequacy of testing
• Objectives assess, minimize, health impact and
  risks to participants, close contacts, health
  care workers, community
• Plans must include periodic life-time testing,
  archiving of specimens, adverse event reporting
  pre-and post marketing

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IRB, IACUC, IBC Collaboration

• Within Appendix M/PHS Guidelines
• Other areas where enhanced cooperation might
  strengthen institutional review process?

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Goal

• Mutually supportive and interactive assessment of
  risks to participants, families, staff,
  investigators, and the community

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Conclusions

• Increasing complexities
• Greater expertise
• Increasing demands for oversight

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Conclusions

• Recognize the integral role of IBC
• Increasing Responsibilities it has worked well
  for over 26 years, how adaptable is it
• Need for Increased Resources, Training, and
  Support for Central Role