Human Gene Therapy: Risk Assessment and Regulatory Requirements

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Human Gene Therapy Risk Assessment and
Regulatory Requirements

• And Overview of the NIH rDNA Guidelines
• EMD 545b
• Lecture 10

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NIH Guidelines for Research Involving rDNA
Molecules (April, 2002)
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NIH Guidelines - April 2002

• NIH - OBA (Office of Biotechnology Activities)
• Outline scope of regulated rDNA work and required
  containment levels (changes approved by NIH-OBA)
• Applicability
• NIH Sponsored Institutions
• NIH Supported projects (US Abroad)

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Responsibilities Institution

• Ensure full conformity with Guidelines
• Establish an IBC
• Appoint a BSO (if necessary)
• Ensure adequate expertise for protocol review
  (plant, animal, human gene transfer)
• Training (IBC/BSO/PIs/Lab staff)
• Health Surveillance (BL3/Large scale)

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Responsibilities - IBC

• 5 members (2 from community)
• Expertise (rDNA, biosafety, containment, legal)
• Annual report to NIH-OBA (roster/CVs)
• Assess
• Containment level, facilities, procedures
• Develop emergency plans, report violations

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Responsibilities Biosafety Officer

• IBC Member
• Inspections
• Report problems to IBC
• Develop emergency plans
• Advise on lab security

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Responsibilities Principal Investigator

• Full compliance with Guidelines
• Cant start/modify non-exempt work w/out approval
• Report violations w/in 30 days
• Make initial determination of containment
• Instruct/train lab staff
• Supervise safety performance

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Section III Experiments covered by the NIH
Guidelines

• Require approval before initiation
• III-A Transfer significant drug-resistant trait
  (IBC/RAC review/NIH Director)
• III-B Cloning toxins (IBC/NIH-OBA)
• III-C Human gene transfer (IBC/IRB/FDA
  NIH-OBA registration)
• III-D Risk group 2-4 restricted, defective
  virus in cell culture, animals, plants, large
  scale

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Section III Experiments Covered by the
Guidelines

• IBC Notice at time of initiation
• III-E-1 lt 2/3 viral genome
• III-E-3 Production of transgenic rodents
• III-E-2 Whole plants

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Section III Exempt Experiments

• III-F-1 through III-F-6
• not in organisms/viruses, PCR, known exchangers,
  in/out of same host
• Appendix C-1 through C-VI
• lt 50 viral genome, E.coli, B. subtilis,
  S.cerevisiae, Purchase transfer of transgenic
  rodents, extrachromosomal elements of gm
  organisms

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Appendices to NIH Guidelines

• Appendix B Classification of Etiologic Agents on
  the Basis of Hazard
• Appendix F Containment for toxin experiments
• Appendix G Biosafety containment levels (in
  vitro experiments)
• Appendix H Shipment

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Appendices to NIH Guidelines

• Appendix K Large Scale containment
• Appendix M Human gene transfer
• Appendix P Plants (biocontainment for rDNA
  plant experiments)
• Appendix Q Animal Biosafety containment levels

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Human Gene Therapy

• Gene Therapy Any clinical therapeutic procedure
  in which genes are intentionally introduced into
  human somatic cells
• Gene transfer The deliberate transfer of
  recombinant DNA, or DNA or RNA derived from rDNA
  into human subjects. NIH

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Notable Quotes

• Gene therapy has clearly matured from the point
  of Gee-Whiz to getting down to hard work.
• Putting genes into people is no longer a worry.
  We know there are no ill effects. Now we can
  think of genes as drugs, and that is quite
  remarkable.
• Dr. Ronald Crystal, Cornell Medical School
• USA Today, 6/10/99

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Notable Quotes

• The conclusions from these trials are that gene
  therapy has the potential for treating a broad
  array of human diseases and that the procedure
  appears to carry a very low risk of adverse
  reactions.
• Dr. W. French Anderson
• Nature, April 30, 1998

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September 17, 1999

• 1st reported death attributed to a HGT Protocol
  UPENN OTC Trial
• subject may have not been properly informed of
  risk
• not a suitable candidate for the trial
• NIH OBA request for unreported adverse and
  serious adverse events (11/99)
• 650 previously unreported AE and SAE received by
  NIH, including unexplained deaths

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Lack of Oversight

• Insufficient monitoring once HGT protocols begin
• Beth Israel Hospital (Boston) 7 subjects 3
  unreported deaths and 1 SAE
• Tufts Univ. (Boston) 2 deaths, 1 unexplained,
  but PI claim unrelated to study

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Fox Guarding the Hen House
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Rationale for Delayed Reporting

• Reports to FDA (private), not to NIH (public)
• PI decision SAE unrelated to study drug
• Competition between companies
• Financial implications of negative news (stock
  value)
• Financial conflict of interest (those with shares
  in parent company)

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FDA Response

• FDA request for detailed monitoring plans from
  institutions and site visits
• Shutdowns
• Duke
• LA VA Hospitals
• Oklahoma State
• Univ. Colorado Health Sciences Center
• Others

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Additional Adverse Events

• Vector associated leukemia - France
• 2002- HGT Trials suspended after 2nd case of
  leukemia caused by integration of defective
  retroviral vector in host chromosome

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Cellular HGT

• Somatic cells
• non-reproductive
• genetic information not passed to next generation
• Germ line cells
• sperm/egg cells
• currently not allowed

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Categories of HGT Research

• ex vivo
• cells removed from patient
• incubated with vector
• altered cells returned to patient
• in vivo
• direct injection into affected tissues
• systemic delivery

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HGT Protocols

• 1st U.S. trial 1990 ADA
• 400 trials in past 10 years (3,000 patients)
  worldwide
• 62 Cancer
• 13 single gene disorders
• 9 AIDS

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Delivery Vehicles for HGT

• Viruses
• murine retroviruses (46)
• adenoviruses (22)
• Other vectors
• adeno-associated virus, vaccinia virus,
  herpesvirus
• Cationic liposomes (non-viral delivery)
• naked plasmid DNA or RNA (gene guns)

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Murine Retroviruses

• Advantages
• stable infection
• long-term expression
• will infect dividing cells only
• Disadvantages
• insertional mutagenesis
• activate an oncogene/shut off tumor suppressor
• recombine with host retrovirus

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Murine Retroviruses

• Before 2002 adverse events
• 10 year experience
• no adverse events (800 patients)
• no malignancies
• no replication competent retroviruses
• FDA has dropped requirement for lifetime
  monitoring of patients

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Adenoviruses

• Advantages
• capacity for large genetic insert
• high level of expression
• can also infect non-dividing cells
• does not integrate into host genome
• Disadvantages
• potential recombination with host adenovirus
• inflammation, immune response

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Adenoviruses

• Last decade
• minimal viral shedding from subjects
• standard precautions adequate (replace isolation
  practices)
• consideration of using replication competent
  vectors with adequate isolation and monitoring of
  subjects

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Liposomal Vectors

• Positive charged lipid particle
• Advantages
• capacity for very large genetic insert
• safe
• ease of mass production
• Disadvantages
• low efficiency
• poor specificity

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Other Vectors

• Lentiviral vectors (HIV) can infect non-dividing
  cells
• Vaccinia (HGT vaccines)
• Baculovirus (insect virus)
• Salmonella
• No bounds on imagination of investigators

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Oversight of HGT Research

• Food and Drug Administration (FDA)
• Sole authority of approval of HGT protocols
• Center for Biologics Evaluation Research (CBER)
• drugs/biological products intended for use in
  human subjects
• Investigational New Drug application (IND)
• 21 CFR Part 312 Subpart B

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Oversight of HGT Research

• Objectives of the FDA
• ensure safety/rights of research subjects
• ensure scientific quality of clinical
  investigations
• safeguard public health while promoting novel
  therapies

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Oversight of HGT Research

• National Institutes of Health (NIH)
• applicable to entities that receive NIH funding
• DHHS Office of Human Research Protection (OHRP)
• regulations that protect human subjects/control
  research risks
• Office of Biotechnology Activities
• mandatory registration of HGT Protocols
• national repository

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Oversight of HGT Research

• NIH
• Recombinant DNA Activities Committee (RAC)
• public notification/participation in discussion
• review 10 of submitted HGT protocols
• NIH Guidelines for Research Involving rDNA,
  Appendix M
• Points to Consider for Human Gene Therapy

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Oversight of HGT Research

• History of NIH RAC Involvement
• 1990 - 1996 Approval authority
• 1996 - 2000 can recommend RAC review to FDA
• October, 2000 RAC review prior to local
  institutional approval to ensure public
  notification and adequate risk assessment

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Local Oversight for HGT

• Institutional Review Board (IRB)
• Ensure compliance with FDA and NIH OHRP
  requirements to protect human subjects.
  Federally mandated for any work with humans.
• Informed Consent
• risk/benefit evaluation on behalf of subject
• conflict of interest (financial implications)
• ethical issues (false hope)
• review of adverse effects

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Local Oversight for HGT

• Institutional Biosafety Committee (IBC)
• NIH Requirement (funded locales)
• safety
• acute/chronic effects
• risk to patient, contacts
• exclusion criteria
• adverse effects (stopping rules)

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HGT Protocol Pathway

• PI submission to IRB, IBC and NIH OBA
• OBA/NIH RAC filter public review?
• RAC comments to IBC, IRB, FDA, OHRP
• IBC/IRB approval
• PI application for FDA IND
• Final FDA approved protocol to NIH OBA, IBC, IRB
• Adverse Effects reported

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HGT Risk Assessment

• IBC Review Process
• NIH Guidelines, Appendix M
• Composition of IBC
• molecular biologists
• infectious disease experts
• immunologists, relevant expertise as needed
• biosafety/containment representation
• occupational health
• community representation

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HGT Risk Assessment

• Can your existing IBC efficiently review the HGT
  protocol?
• _at_ Yale - HGT Subcommittee
• Melanoma Trial
• oncologists, hematologists, immunobiologists
• Canavans Disease
• pediatric neurologists
• neurosurgeons
• ethicists

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HGT Risk Assessment

• IBC HGT Review Team should also include
• IRB members
• hospital pharmacy
• infection control representatives
• clinical virologists
• legal
• ethicists

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HGT Risk Assessment

• IBC Questions to the PI
• why is disease a good candidate for HGT?
• objective/quantitative disease measures present?
• alternative therapies?
• what cells have been targeted for HGT?
• describe methods, reagents, full sequence of
  inserted DNA, steps to derive construct

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HGT Risk Assessment

• IBC Questions for the PI
• preparation of the vector in compliance with FDA
  21 CFR Part 211 (Good Manufacturing Practices)?
• clean room facility requirements met?
• Trained personnel?
• Documented/validated SOPs and equipment?
• QA/QC program in place?
• Sterility testing (RCV/adventitious agents)?

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HGT Risk Assessment

• IBC Questions for the PI
• adequacy of pre-clinical studies (best animal or
  cellular model)?
• observed toxicity/efficacy?
• chronic effects (time followed after treatment)?
• accuracy/efficiency of delivery system?
• affect target cells only (spread to reproductive
  cells)
• transient of stable infection

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HGT Risk Assessment

• IBC Questions to PI
• determination that sequences have been expressed?
• expected benefits or adverse effects
• length of follow-up for subjects
• post-mortem studies?

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HGT Risk Assessment

• IBC Questions for PI
• can DNA spread from subject to contacts or
  environment?
• required precautions to prevent dissemination?
• safety protocols for pharmacy, healthcare staff?
• adequacy of clinical facilities?
• informed consent/clear communication of risks to
  subjects

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HGT Risk Assessment

• IRB Considerations
• risk/benefit of protocol
• protect subjects from coercion/undue influence
• confidentiality/disclosure of information
• verification or informed consent process
• verify eligibility/withdrawal criteria
• ongoing monitoring of subjects
• annual renewal of protocol

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Adverse Effects

• Serious Adverse Effect (SAE)
• FDA
• report immediately if related to study drug
• NIH
• ANY SAE reportable immediately to all related
  compliance groups
• Annual Data Report
• includes SAEs and AEs to related compliance
  groups

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Approval of HGT Protocols

• IRB/IBC Coordination
• NIH OBA registration/FDA IND approved
• PI sign-off/acceptance of responsibilities
• contingencies outlined on approval letter
• oversight/monitoring
• informed consent/eligibility, adverse events,
  stopping criteria

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HGT Report Card

• The efficiency of gene transfer and expression
  in human patients is, however, still
  disappointingly low.
• W. French Anderson, Nature, 1998

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HGT Report Card

• Not really therapy (treatment)
• Few clinically significant results
• Dont sell false hope
• Human Gene Transfer RESEARCH
• SUBJECTS not patients
• may or may not gain information

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Success Stories

• US ADA 1990 (Anderson)
• French ADA 1999
• Cancer (marker gene) Deisseroth, 1993
• Herpes TK, brain tumor, 1993 (Blaise)
• SHH (activator), heart disease, hair growth
  (Crystal)

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Conclusion

• HGT a promising field
• Human genome project will feed fire
• build on successes, share information
• Goal
• cost-effective approach
• improved delivery and expression of gene
• sustained expression of therapeutic gene

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Conclusion

• Responsibility of Regulators
• ensure adequate process of review
• approve only sensible, valid projects
• ensure the ethical conduct of research
• protect human subjects, healthcare workers, and
  public

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2007 Investigation of Serious Adverse Event

• Death of patient enrolled in study involving an
  AAV vector (Adeno-Associated Virus)
• Focus of NIH OBA Meeting
• AAV not a known human pathogen?
• Dose?
• AAV as cause of event indeterminable

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Institutional Approval of HGT Protocols

• Review of location, personnel
• Infection control
• SAE notification

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Institutional Approval of HGT Protocols

• Certificate of Analysis to institution from
  sponsor or designated lab
• GMP Compliance statement from sponsor
• FDA approval letter on file
• Copy of final FDA authorized protocol

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Institutional Approval of HGT Protocols

• Data Safety Management Board
• Periodic review of patient safety information
• Report to IRB and IBC
• Annual Renewal of HGT Protocol
• Report changes in protocol

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Additional NIH Requirements

• lt 20 days post initiation of HGT Protocol
• copy of final protocol
• NIH Grant (if applicable)
• copy of IRB and IBC approvals
• written response to RAC recommendations
• date of initiation of trial