Transcript Human Gene Therapy: Risk Assessment and Regulatory

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
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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/PI’s/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/CV’s)
• Assess
– Containment level, facilities, procedures
– Develop emergency plans, report violations
Responsibilities: Biosafety
Officer
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IBC Member
Inspections
Report problems to IBC
Develop emergency plans
Advise on lab security
Responsibilities: Principal
Investigator
• Full compliance with Guidelines
• Can’t 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 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
Section III: Experiments
Covered by the Guidelines
• IBC Notice at time of initiation
– III-E-1: < 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
– < 50% viral genome, E.coli, B. subtilis,
S.cerevisiae, Purchase transfer of transgenic
rodents, extrachromosomal elements of gm+
organisms
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 remarkable.”
• 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 reactions.”
• 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
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
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 value)
• Financial conflict of interest (those with
shares in parent company)
FDA Response
• FDA request for detailed monitoring plans
from institutions and site visits
• Shutdowns
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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)
worldwide
– 62%
– 13%
– 9%
Cancer
single gene disorders
AIDS
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)
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
Adenoviruses
• Advantages
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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
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
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 nondividing cells
• 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
investigations
– safeguard public health while promoting novel
therapies
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
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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)
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NIH Requirement (funded locales)
safety
acute/chronic effects
risk to patient, contacts
exclusion criteria
adverse effects (stopping rules)
HGT Protocol Pathway
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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
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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 protocol?
– @ Yale - HGT Subcommittee
• Melanoma Trial
– oncologists, hematologists, immunobiologists
• Canavan’s Disease
– pediatric neurologists
– neurosurgeons
– ethicists
HGT Risk Assessment
• IBC HGT Review Team should also
include:
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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 SOP’s 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 cells)
• 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
environment?
– required precautions to prevent dissemination?
– safety protocols for pharmacy, healthcare staff?
– adequacy of clinical facilities?
– informed consent/clear communication of risks
to subjects
HGT Risk Assessment
• IRB Considerations:
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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 SAE’s and AE’s to related compliance
groups
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
• Don’t sell false hope
– Human Gene Transfer RESEARCH
– SUBJECTS not patients
– may or may not gain information
Success Stories
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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)
Conclusion
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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
Conclusion
• Responsibility of Regulators:
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ensure adequate process of review
approve only sensible, valid projects
ensure the ethical conduct of research
protect human subjects, healthcare workers, and
public
2007 Investigation of Serious
Adverse Event
• Death of patient enrolled in study involving
an AAV vector (Adeno-Associated Virus)
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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
• < 20 days post initiation of HGT Protocol
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copy of final protocol
NIH Grant # (if applicable)
copy of IRB and IBC approvals
written response to RAC recommendations
date of initiation of trial