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Human Gene Therapy: Risk Assessment and Regulatory Requirements


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Title: Human Gene Therapy: Risk Assessment and Regulatory Requirements

Human Gene Therapy Risk Assessment and
Regulatory Requirements
  • And Overview of the NIH rDNA Guidelines
  • EMD 545b
  • Lecture 10

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

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)

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

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

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

Section III Experiments covered by the NIH
  • 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

Section III Experiments Covered by the
  • 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

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

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

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

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

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
  • Dr. Ronald Crystal, Cornell Medical School
  • USA Today, 6/10/99

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
  • Dr. W. French Anderson
  • Nature, April 30, 1998

September 17, 1999
  • 1st reported death attributed to a HGT Protocol
    UPENN OTC Trial
  • subject may have not been properly informed of
  • 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

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

Fox Guarding the Hen House
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
  • Financial conflict of interest (those with shares
    in parent company)

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

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

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

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

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

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

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

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

  • 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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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)?

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
  • transient of stable infection

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?

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

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

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

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

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

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

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

  • 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

  • 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

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

Institutional Approval of HGT Protocols
  • Review of location, personnel
  • Infection control
  • SAE notification

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

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

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
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