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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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Presentation on theme: "Human Gene Therapy: Risk Assessment and Regulatory Requirements And Overview of the NIH rDNA Guidelines EMD 545b Lecture #10."— Presentation transcript:

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, st 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 – : Approval authority – : 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

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

52 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

53 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)

54 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

55 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

56 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

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

58 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

59 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

60 Additional NIH Requirements < 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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