1. 1 NIH Recombinant DNA Advisory Committee (RAC) and Gene Transfer Research Jacqueline Corrigan-Curay, J.D., M.D. Office of Biotechnology Activities Office of Science Policy June 4, 2013

2.  NIH framework for oversight of recombinant and synthetic nucleic acid research  Current roles of the RAC  Gene therapy – a snapshot  RAC review of individual protocols  Individual protocol review and other clinical activities  Future directionsOverview 2

3.  Federal biosafety guidelines  NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) Compliance is a term and condition of NIH funding Many other government agencies and private institutions require that their funded research be conducted in accordance with the NIH Guidelines Model for other countries  National advisory body  NIH Recombinant DNA Advisory Committee  Local review of risks and implementation of NIH Guidelines  Institutional Biosafety Committees NIH Framework for Oversight of Recombinant and Synthetic Nucleic Acid (NA) Research 3

4. The RAC Today  Federal scientific advisory committee of 20 members with broad expertise in clinical and basic research as well as bioethics and a public member  Meets quarterly in open forum with significant webcast audience  Provides an enduring public forum for discussion and analysis of biosafety, clinical and ethical policy issues that arise from recombinant and synthetic nucleic acid research 4

5. The RAC Today  Review of individual gene therapy protocols  Ongoing analysis of data across > 1200 protocols  Development of scientific symposium  Advice and guidance on biosafety, resulting in numerous updates to the NIH Guidelines in response to changes in the science 5

6.  NIH framework for oversight of recombinant and synthetic nucleic acid research  Current roles of the RAC  Gene therapy – a snapshot  RAC review of individual protocols  Individual protocol review and other clinical activities  Future directionsOverview 6

7. What is Gene Therapy?  Under the NIH Guidelines gene therapy, or gene transfer, involves the transfer of recombinant or synthetic nucleic acids to humans  Involves the transfer of genetic constructs to humans, and  The delivery vehicle for these constructs are plasmids or viral/bacterial vectors 7

8. 8 Gene Transfer Vectors 1990 - 2012

9. 9 Gene Transfer Vectors 2012

10. Special Features of Gene Therapy  Gene therapy is not a “one gene, one effect,” but intervenes in the complex system of gene regulation that is still not completely understood.  Only area of research in which we create novel organisms and constructs and routinely release them from the lab via human administration  Products draw from multiple fields, including microbiology, immunology, and stem cells  Common drug parameters, such as pharmacokinetics, biodistribution, and even dose are not easily determined  Many protocols target the immune system, seeking to not only overcome natural checks on immune system regulation, but to create new immune system cells that can proliferate in vivo 10

11. Number of Protocols Registered with NIH from 1991 to 2012 from 1991 to 2012 11 N=1194

12. Rev: 08-16-12err Gene Therapy: A Snapshot by Phase 12 2005 - 2012

13. Rev: 08-16-12err Gene Therapy: A Snapshot by Application 13 e.g. arthritis, diabetes, pain, overactive bladder, ED, peanut allergy

14.  NIH framework for oversight of recombinant and synthetic nucleic acid research  Current roles of the RAC  Gene therapy – a snapshot  RAC review of individual protocols  Individual protocol review and other clinical activities  Future directionsOverview 14

15. Goals of Individual Protocol Review  Optimize clinical trial design and increase the safety for subjects, and as necessary biosafety protections for researchers, health care workers, close contacts of research subjects  Enhance the efficiency of gene therapy research by allowing scientists to build on a common foundation of new knowledge emanating from a timely, transparent analytic process  This pre-competitive arena has fostered the growth of gene therapy 15

16. Goals of Individual Protocol Review  Inform the deliberations of the FDA, the Office of Human Research Protections, IRBs, IBCs, and other oversight bodies  Identify the scientific issues that would benefit from in-depth discussion at a national meeting 16

17. Rev: 08-16-12err Protocols Selected for In-Depth Review Compared to All Submissions 17 2005 - 2012

18. Decreasing Emphasis on Individual Protocol Review 19922002 2012 % selected for public review % not selected 18

19. OBA Summary of Human Gene Transfer Protocol Review Process 19 Full RAC Review at Quarterly Meeting OBA ≥ 5 Votes For Review Initial RAC Member review < 5 Votes PI Informed No Public Review No more than 15 days 8 Weeks Prior to RAC meeting Protocol Submission Protocol Summary/ Protocol

20. IRB Dissemination of RAC Recommendations Company Sponsor (if applicable) NIH IC FDA OHRP RAC IBC PI OBA Web site (minutes, video) Dissemination of RAC Recommendations 20

21. Special Attributes of the RAC  Provides a unique open and transparent forum to tackle ongoing scientific and safety issues with the research community and public  Draws on a body of knowledge derived from the review of > 1200 protocols and associated safety data to: allow the field to advance and grow with the benefit of this shared learning enhance the safety and efficiency of the research  Is a dynamic process that takes into account emerging data on an ongoing basis 21

22. RAC and FDA have Complementary Roles 22  RAC review is a 360 o review of early phase trials, not limited to a primary assessment of safety  How does this trial fit in with the future development plan for the agent?  Will the study as designed answer the key questions needed to move to the next level, including a biological proof of principle?  Are there biosafety considerations for the agent?  What are the key ethical issues raised by the protocol?  What can the investigator learn from previous applications?  Operates in a transparent, open environment

23. RAC’s Role in Review of Protocols  RAC is not an approval body, makes recommendations to the NIH to improve the scientific design and safety of protocols  Under the NIH Guidelines, the PI must address the recommendations by the time the protocol begins enrollment  This creates a transparent record on why key protocol design decisions are made 23

24. Protocol Review Continues to Provide Important Feedback  The majority of protocols that are publicly reviewed receive 7 or more recommendations that results in valuable modifications in the protocol  For protocols reviewed at public meetings from 2006-2010, the majority of recommendations from the RAC were accepted by the investigator who changed the protocol or performed additional studies Preclinical 56% Clinical 72% Ethical 74% 24

25. Public Interest Remains High  Over the past two years, OBA website material regarding RAC meetings and symposia have been accessed nearly 10,000 times  OBA receives about 70 requests per year for additional information about RAC related activities 25

26. Improving Informed Consent 26

27. Promoting Patient Understanding: Informational Brochure  Helps potential participants understand fundamental concepts in gene transfer research  Suggests questions participants should pose to their physicians and to research staff in order to make a fully informed decision about participation 27

28.  NIH framework for oversight of recombinant and synthetic nucleic acid research  Current roles of the RAC  Gene therapy – a snapshot  RAC Review of individual protocols  Individual protocol review integral to other clinical activities  Future directionsOverview 28

29. Outputs from Individual Protocol Reviews Are Integral to Other Activities Review of Novel Protocols Safety Symposiums Policy Conferences Adverse Events Annual Reports Amend- ments Webcasts Slides Public discussion Changes in protocol design Patient protections New research avenues 29 INPUTSOUTPUTS

30. Emphasis Shifting to Other Clinical Activities  Over time the need to focus on individual public protocol reviews has declined while opportunities have expanded to mine data from >1200 protocols to examine trends and provide analysis of novel approaches Clinical Safety data analysis Policy and Safety Symposiums 30 Individual Public Protocol Review

31. Gene Transfer Safety Assessment Board (GTSAB) 31  A working group of the clinical members of the RAC who meet quarterly to review all serious adverse events that are possibly related, as well as summaries of over 400 amendments and annual reports filed on active protocols  Akin to a “national DSMB,” responding in real time to emerging information  GTSAB meetings are attended by FDA staff

32. Analysis of Aggregate Data from Protocols Promotes Patient Safety  Safety data often discussed in advance of publications  Informs the conduct of current trials and design of new trials 32 Public summaries of significant adverse events that are possibly related to the gene transfer are available to investigators on a quarterly basis

33. RAC Activities Lead to New Resources for Researchers and the Public  Genetic Modification Clinical Research Information System (GeMCRIS)  Scientific Symposium 33

34. Genetic Modification Clinical Research Information System (GeMCRIS)  Public facing side promotes access to information and understanding about human gene transfer clinical research beyond what is available in Clinical Trials.gov  Vector data, abstracts, links to RAC reviews, updates on design  Developed in collaboration with FDA 34

35. Genetic Modification Clinical Research Information System (GeMCRIS)  NIH and FDA access to full protocol information, including summaries of amendments, annual reports and safety data  Investigators can file their adverse events directly into GeMCRIS  In 2012, 21% of adverse events were reported directly into GeMCRIS by investigators  Over 10,000 searchable serious adverse event reports available to authorized staff of NIH and FDA 35

36. Case Study: RAC Analysis of an Unexpected Death 36

37. Rapid Access to Aggregate Data GeMCRIS Public Web Interface Vector Descriptor = “Adeno-Associated” 53 Total hits returned Using both terms: “Adeno-Associated” & “ocular” as route returns : 1 Hit

38. Rapid Access to Aggregate Data GeMCRIS Public Web Interface 38 Protocol Information Protocol Amendments

39. Adverse Events: GeMCRIS Custom Queries for Data Analysis 39

40. National Symposium on Adverse Event  September 17, 2007  NIH hosts public meeting with RAC, FDA, sponsor, hospital health care team, and outside experts to examine scientific and clinical data and review informed consent and subject recruitment procedures 40

41. Outcome of RAC Analysis: Immediate Cause of Death Identified  RAC meeting revealed that this subject’s death was primarily a result of an opportunistic infection (disseminated histoplasmosis) with subsequent bleeding complications, and multi-organ failure.  NIH used GeMCRIS to confirm this was a unique case and no similar cases using the same gene transfer vector had occurred.  RAC involvement facilitated the release of medical information and serum samples.  RAC was seen by the family as impartial, scientific body which would objectively review the data. 41

42. Impact of RAC Discussions: Publications in Leading Scientific Journals 42 Gene therapy might not have caused patient’s death Nature, Sept. 2007 NIH: Gene therapy didn’t cause death The Scientist, December 2007 Gene Transfer and Unlikely Contributor in Patient’s Death Science, December 2007 Systemic TNF Antagonist Levels

43. Impact of RAC Discussions: Change in Labeling TNF-inhibitors and the risk of histoplasmosis 43

44. 44 Scientific, Safety, and Policy Symposia 2013 Gene Therapy: Charting a Future course 2012 Gene Transfer and Rare Diseases 2011 RNA Oligonucleotides: Emerging Clinical Applications 2010 Sham Neurosurgical Procedures in Clinical Trials for Neurodegenerative Diseases 2010 Retroviral and Lentiviral Vectors for Long-Term Gene Correction 2010 Gene-Modified T Cells: Challenges in Clinical Trial Design 2008 Public Health and Biosafety Practices for Research with 1918 H1N1 Influenza Virus 2007 Immune Responses to AAV Vectors

45. 45 Scientific, Safety, and Policy Symposia 2005Gene Transfer for X-SCID 2004Safety Considerations in Recombinant DNA Research with Pathogenic Viruses 2001 IBCs in a Changing Research Landscape 2001Adeno-Associated Virus in Gene Transfer Clinical Trials 2000 Cardiovascular Gene Transfer Clinical Research 1999 Prenatal Gene Transfer: Scientific, Medical and Ethical 1998Lentiviral Vectors for Gene Delivery

46. Optimizing the Safety of Human Gene Transfer Research 46

47. Optimizing the Safety of Human Gene Transfer Research  T cell Immunotherapy – Optimizing Trial Design, Sept. 10-11, 2013  Continued follow-up on important areas of research 47

48.  NIH framework for oversight of recombinant and synthetic nucleic acid research  Current roles of the RAC  Gene therapy – a snapshot  RAC review of individual protocols  Individual protocol review and other clinical activities  Future directionsOverview 48

49. RAC’s Continued Relevance  Many lines of recombinant and synthetic nucleic acid research continue to raise safety, ethical, and scientific issues that benefit from transparent discussion and analysis  Human gene therapy  Emerging applications using genetically modified stem cells  Novel vectors, e.g. polio-rhino virus vectors, replication competent retroviruses, measles, Sendai and vesicular stomatitis virus 49

50. Looking Forward  Continue to advance the clinical and basic applications of recombinant and synthetic nucleic acid research by providing a transparent forum that builds upon the knowledge base of over 20 years of data  Individual protocol review limited to small number of novel protocols that may present unique safety, ethical or social issues  Continued aggregation and analysis of data submitted in real time will allow for the detection of trends that can inform the field 50

51. AAAS Scientific Freedom and Responsibility Award To Recombinant DNA Advisory Committee of the National Institutes of Health 2004 For providing outstanding leadership and enabling society to proceed with recombinant DNA research and genetic therapy in a responsible manner thereby enhancing the opportunities presented by modern genetic advances. 51

52. QUESTIONS 52

53. 53

54. Emphasis Shifting from Individual Protocol Review Insertional mutagenesis X-SCID trial 19922002 2012 % selected for public review % not selected 54 Revised in October 2013

55. Number of Protocols Selected for RAC Public Review by Year