NIH Office of Biotechnology Activities

2. NIH Office of Biotechnology Activities • Within the Office of Science Policy, Office of the Director, NIH • Five programs: • Recombinant DNA (RAC) • Genetics (SACGHS) • Xenotransplantation (SACX) • Biosecurity (NSABB) • Outreach and Education

3. Recombinant DNA Program • Oversee recombinant DNA research, including human gene transfer • Manage the Recombinant DNA Advisory Committee (RAC) • Administer the NIH Guidelines for Research Involving Recombinant DNA Molecules • Partner with Institutional Biosafety Committees in the oversight of recombinant DNA research

4. Recombinant DNA Program • Disseminate information on technical and policy matters concerning recombinant DNA research • RAC recommendations on clinical protocols • Interpretations of the NIH Guidelines • Scientific symposia and policy conferences • Develop and contribute to public policy on recombinant DNA research • Interagency oversight of biotechnology

5. A Brief History of Recombinant DNA Oversight • Emergence of recombinant DNA technology (Mid 1970’s) • Concerns among both scientific community and general public • Public health and safety • Environmental impact • Potential ethical and social implications

6. A Brief History of Recombinant DNA Oversight • NAS Committee Report (July 1974); called for • a moratorium on certain experiments • development of NIH guidelines for conduct and review of recombinant DNA experiments

7. A Brief History of Recombinant DNA Oversight • Asilomar Scientific Summit (1975) • Premise: Scientists taking responsibility for the risks of their own research activities • Outcomes • Reaffirmation of the need for guidelines • Establishment of a new federal oversight committee

8. A Brief History of Recombinant DNA Oversight • NIH Recombinant DNA Molecule Program Advisory Committee • First federal advisory committee • Launched process of developing NIH guidelines for recombinant DNA oversight • Made recommendations about local oversight • NIH grants using rDNA be awarded only after review of risks by an institutional “biohazards” review committee • Review of physical containment and facilities • Consideration of local circumstances

9. Published in July 1976 Established responsibilities of investigators and institutions The First NIH Guidelines

10. Local Community Involvement • Local communities (e.g., Cambridge) begin establishing their own oversight frameworks • Local review and citizen involvement key characteristics of oversight

11. First Major Revisions (1978) • Relaxed certain restrictions deemed no longer scientifically necessary, while: “...increasing significantly public access to information about recombinant DNA research activities and increasing public participation in the administration of the guidelines in local communities.” (HEW Secretary Califano)

12. Enhancing Public Access (1978) • At least two, and no less than twenty percent, of IBC members had to represent the general public and have no connection to the institution • “Important records” of IBC’s had to be publicly available • In addition to minutes: MUAs, reports of violations, and other materials submitted to the federal government • “Major actions” only on advice of RAC and after public and Federal agency comment • Public participation continues to be a hallmark of rDNA oversight

13. 1982 • President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research • “Splicing Life: Social and Ethical Issues of Genetic Engineering with Human Beings”

14. Revised NIH GuidelinesApril 1984 • IBCs become responsible for review of human gene transfer research • New responsibility pursuant to recommendations of RAC Working Group for Development of Response to President’s Commission Report on Ethical and Social Issues • Subsequently, RAC Working Group on Human Gene Therapy embarks on “Points to Consider”

15. Revised NIH GuidelinesMay 1986 • Adoption of “Points to Consider” guidance document for gene therapy protocols • IBC approval prior to submission to NIH • Points for IBC consideration and review • Characteristics of the biological system • Pre-clinical risk assessment studies • Public health

16. 1989/90 • 1989: NIH Director approves 1st human gene transfer protocol • 1990: “Points to Consider” added to NIH Guidelines as Appendix M • Requirements for submitting human gene transfer protocols to NIH for review and approval • Emphasis on gene transfer not therapy

17. Revised NIH Guidelines July 1994 • Adoption of Appendices P (plants) and Q (animals) • Containment guidance for IBC’s • Augments IBC membership

18. Revised NIH Guidelines October 2000 • Amended requirements for submission of gene transfer protocols • Protocols require RAC review prior to IBC approval • Rationale • Research participants are assured that prior to their enrollment in a gene transfer clinical trial that is either novel or raises significant ethical or safety concerns, their local IRB and IBC, and PI are apprised of the results of public RAC review and discussion.

19. Revised NIH GuidelinesOctober 2000 • IBC functions specified for review and approval of gene transfer protocols • Ensure PI addresses all aspects of Appendix M • Ensure new enrollment requirements are met • Ensure appropriate consideration by PI and IBC of results of public RAC review • Ensure final IBC approval is granted after RAC review process • Ensure compliance with surveillance and reporting requirements

20. Why is Biosafety Review of Recombinant DNA Needed Today? • Hasn’t history proven the technology to be safe? • Why have a technology-based approach to oversight instead of one that is based on the risks of individual products? • Are there really any residual scientific or public concerns?

21. Hasn’t History Proven the Technology to be Safe? • Many of the catastrophic dangers originally feared never materialized • The oversight system changed to respond to this new understanding • The RAC no longer reviews and approves most basic science protocols • Local review is still important to ensure biological safety (medical, occupational, environmental) and responsible scientific practice

22. Why a Technology-Based Approach to Oversight (Instead of Product Based)? • The NIH review system encompasses technology and product, as they are intertwined • The products of recombinant techniques can have unpredictable characteristics that are unlike the source or host organisms • This unpredictability warrants a local case-by-case assessment

23. Are there Really Any Residual Concerns? • The public here and abroad is still concerned about many aspects of this technology • Our oversight system has provided scientifically-based surveillance of this research that has reassured the public and permitted the science to move forward safely • Human gene transfer continues to raise many safety, ethical, and scientific issues in need of public discussion and analysis

24. NIH Guidelines for Research Involving Recombinant DNA Molecules • A scientifically-responsive document that will continue to evolve • Have undergone multiple revisions since 1976 • Latest version - April 2002 http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html

25. Content of the NIH Guidelines • Section I – Scope • Section II – Safety Considerations • Section III – Types of Experiments Covered • Section IV – Roles and Responsibilities • Appendices

26. NIH Guidelines – Section I • Scope • Specifies practices for constructing and handling • Recombinant DNA molecules • Organisms and viruses containing recombinant DNA molecules • Definition • Constructed outside living cells by joining natural or synthetic DNA segments to DNA molecules that can replicate in a living cell • Molecules resulting from the replication of those described above

27. The NIH Guidelines Apply to… • Recombinant DNA research that is • Funded by the NIH • Performed at or sponsored by an institution that receives any NIH funding for recombinant DNA research • Rationale: For biosafety to be meaningful, it has to be observed by all investigators at an institution

28. Are the NIH Guidelines Optional? • “Guidelines” does not mean “optional” • They are a term and condition of NIH funding for recombinant DNA research

29. Are the NIH Guidelines optional? • What are potential consequences of noncompliance with the NIH Guidelines? • suspension, limitation, or termination of NIH funds for recombinant DNA research at the institution, or • a requirement for prior NIH approval of any or all recombinant DNA projects at the institution.

30. Prescription versus Flexibility • Some matters are left to institutional discretion • Flexibility is a two-sided coin • Accommodates institutional diversity and heterogeneity • Can create uncertainty about expectations

31. NIH Guidelines – Section II • Safety Considerations • Risk assessments: (Appendix B) RG 1 RG 2 RG 3 RG 4

32. BSL1 BSL2 BSL3 BSL4 NIH Guidelines – Section II • Containment • Physical (Appendix G) • Practices • Equipment/facilities • Biological (Appendix I) • Survival • Transmission • Safety Considerations

33. NIH Guidelines - Section III Levels of Review

34. Key Portions of the NIH Guidelines for Animal Research • Section III-D-4 Experiments Involving Whole Animals – IBC Approval Before Initiation • Experiments in which: • the animal’s genome has been altered by stable introduction of rDNA into germline, or • rDNA modified microorganisms are tested on whole animals • BL2 or BL2-N or greater containment

35. Key Portions of the NIH Guidelines for Animal Research • Section III-D-5 Experiments Involving Whole Plants – IBC Approval Before Initiation • Experiments in which: • Plants genetically engineered by rDNA methods, or • Plants are used with recombinant DNA-modified insects • Generally BL2-P through BL4-P, depending on risk

36. Key Portions of the NIH Guidelines for Animal Research • Section III-E-3 Experiments Involving the Generation of Transgenic Rodents – IBC Notice at Initiation • Experiments in which: • Rodent’s genome has been altered by stable introduction of rDNA into germline • BL1 containment is appropriate

37. Key Portions of the NIH Guidelines for Animal Research • Section III-F (and Appendix C-VI) - Exempt Experiments • The purchase or transfer of rodents for experiments that require BL-1 containment • Further manipulations of these animals with recombinant DNA are not necessarily exempt from the NIH Guidelines

38. NIH Guidelines – Section IV • Roles and Responsibilities • Institution • Institutional Biosafety Committee (IBC) • Biological Safety Officer (BSO) • Principal Investigator (PI) • NIH

39. Institutional Responsibilities under the NIH Guidelines • The Institution shall: • Establish and implement policies for the safe conduct of recombinant DNA research • Establish an Institutional Biosafety Committee • Assist and ensure compliance with the NIH Guidelines by investigators • Ensure appropriate training for IBC members and staff, PIs, laboratory staff • Determine necessity for health surveillance of personnel • Report any significant problems or violations to OBA within 30 days

40. PI Responsibilities under the NIH Guidelines • The Principal Investigator shall (among other things): • Initiate or modify no recombinant DNA research which requires IBC approval until approval is granted • Determine whether experiments are covered under III-E and notify the IBC as appropriate • Be adequately trained in good microbiological techniques • Adhere to IBC emergency plans for spills and personnel contamination • Report any significant problems or violations to OBA within 30 days

41. NIH Responsibilities under the NIH Guidelines • NIH OBA (on behalf of the NIH Director) • Managing the RAC • Conducting and supporting training of IBCs, BSOs, investigators, laboratory staff • Convening Scientific Symposia and Gene Therapy Policy Conferences • Review of: • Human gene transfer protocols • Certain basic recombinant DNA experiments • “Minor actions” • Changes not requiring approval by the NIH Director

42. NIH Responsibilities under the NIH Guidelines • Basic recombinant DNA experiments reviewed by NIH OBA • Deliberate transfer of drug resistance trait to microorganisms not known to acquire the trait naturally, if it could compromise disease control • Cloning of toxin molecules with LD50 <100 ng/Kg bodyweight • DNA from restricted agents transferred to nonpathogenic prokaryotes or lower eukaryotes • DNA from nonpathogenic prokaryotes or lower eukaryotes transferred to restricted agents • Use of infectious or defective restricted poxviruses in presence of helper virus

43. NIH Guidelines - Appendices • Appendix A – Exemptions: Natural Exchangers • Appendix B – Classification of Etiologic Agents • Appendix C – Exemptions under IIIF • Appendix D – Major Actions • Appendix E – Certified Host-Vector Systems • Appendix F – Biosynthesis of Toxic Molecules • Appendix G – Physical Containment • Appendix H – Shipment • Appendix I – Biological Containment

44. Organization of the NIH Guidelines • Appendix J – Biotechnology Research Subcommittee • Appendix K – Large Scale Physical Containment • Appendix L – Gene Therapy Policy Conferences • Appendix M – Points to Consider in Human Gene Transfer Research • Appendix P – Physical and Biological Containment: Plants • Appendix Q – Physical and Biological Containment: Animals

45. Key Portions of the NIH Guidelines for Animal Research • Appendix G • Specifies details of containment and confinement for standard laboratorypractices • Defines Biosafety Level 1 through Biosafety Level 4 • Appropriate for animals that are worked with in a laboratory setting

46. Key Portions of the NIH Guidelines for Animal Research • Appendix Q • Applies when research animals are of a size or have growth requirements that preclude laboratory containment • For example, cattle, swine, sheep, goats, horses, poultry, etc.

47. Key Portions of the NIH Guidelines for Animal Research • Appendix Q (cont’d) • Addresses containment and confinement practices in animal facilities (BL1-N to BL4-N) • Applies to animals: • In which genome is altered by stable introduction of rDNA; or • On which rDNA-modified microorganisms are being tested

48. Key Portions of the NIH Guidelines for Animal Research • Primates - Appendix G or Q? • Depends on the conditions under which the primates are being housed and used in experimentation • Primates used in high-level, laboratory containment conditions; Appendix G applies • In other settings, primates may be worked with in settings akin to those described in Appendix Q • Professional judgment is key - OBA can help!

49. Key Portions of the NIH Guidelines for Animal Research • Appendix M • Applies to human gene transfer experiments • Includes many considerations related to preclinical studies with animals • Expedited safety reporting requirements amended to include specifically the reporting of animal data “that suggest a significant risk for human research participants.”

50. Good Judgment is Key! • “The NIH Guidelines will never be complete or final since all conceivable experiments involving recombinant DNA cannot be foreseen. Therefore, it is the responsibility of the institution and those associated with it to adhere to the intent of the NIH Guidelines as well as to the specifics.” • Good judgment is key • OBA can help