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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)

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Human Gene Therapy: Risk Assessment and Regulatory Requirements

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

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

  3. 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)

  4. 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/PI’s/Lab staff) • Health Surveillance (BL3/Large scale)

  5. 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

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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. Fox Guarding the Hen House

  19. 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)

  20. 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

  21. 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

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

  23. 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

  24. 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

  25. 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)

  26. 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

  27. 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

  28. 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

  29. 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

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

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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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)

  39. 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

  40. 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

  41. 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

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

  43. 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

  44. 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)?

  45. 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

  46. 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?

  47. 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

  48. 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

  49. 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

  50. 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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