1 nih recombinant dna advisory committee (rac) and gene transfer research jacqueline corrigan-curay,...
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NIH Recombinant DNA Advisory NIH Recombinant DNA Advisory Committee (RAC) Committee (RAC)
and and Gene Transfer Research Gene Transfer Research
Jacqueline Corrigan-Curay, J.D., M.D.Jacqueline Corrigan-Curay, J.D., M.D.Office of Biotechnology ActivitiesOffice of Biotechnology Activities
Office of Science PolicyOffice of Science PolicyJune 4, 2013June 4, 2013
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 directions
Overview Overview
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NIH Framework for Oversight ofNIH Framework for Oversight of Recombinant and Synthetic Nucleic Acid (NA) Recombinant and Synthetic Nucleic Acid (NA)
Research Research
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The RAC Today 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
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The RAC Today 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
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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 directions
Overview Overview
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What is Gene Therapy?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
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Gene Transfer VectorsGene Transfer Vectors1990 - 20121990 - 2012
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Gene Transfer VectorsGene Transfer Vectors2012 2012
Special Features of Gene TherapySpecial 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
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Number of Protocols Registered with NIHNumber of Protocols Registered with NIH from 1991 to 2012from 1991 to 2012
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N=1194
Rev: 08-16-12err
GeneGene Therapy: A Snapshot by PhaseTherapy: A Snapshot by Phase
122005 - 2012
Rev: 08-16-12err
GeneGene Therapy: A Snapshot by ApplicationTherapy: A Snapshot by Application
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e.g. arthritis,diabetes, pain,overactive bladder,ED, peanut allergy
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 directions
Overview Overview
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Goals of Individual Protocol ReviewGoals 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
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Goals of Individual Protocol ReviewGoals 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
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Rev: 08-16-12err
Protocols Selected for In-Depth Review Protocols Selected for In-Depth Review Compared to All SubmissionsCompared to All Submissions
172005 - 2012
Decreasing Emphasis on Individual Decreasing Emphasis on Individual Protocol ReviewProtocol Review
19921992 20022002 20122012
% selected forpublic review% not selected
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OBA
Summary of Human Gene Transfer Summary of Human Gene Transfer Protocol Review Process Protocol Review Process
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Full RACReview at Quarterly Meeting
OBA
≥ 5 VotesFor Review
Initial RAC
Member review
< 5 Votes
PI Informed
No Public
Review
No more than 15 days8 Weeks
Prior to RAC meeting
Protocol Submission
Protocol Summary/Protocol
IRB
Dissemination of RAC Dissemination of RAC RecommendationsRecommendations
CompanySponsor (if applicable)
NIH IC
FDA
OHRP
RAC
IBC
PI
OBA Web site(minutes, video)
Dissemination of RAC Recommendations Dissemination of RAC Recommendations
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Special Attributes of the RAC 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
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RAC and FDA have Complementary Roles RAC and FDA have Complementary Roles
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RAC review is a 360o 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
RAC’s Role in Review of ProtocolsRAC’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
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Protocol Review Continues to Provide Protocol Review Continues to Provide Important FeedbackImportant 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%
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Public Interest Remains HighPublic 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
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Improving Informed Consent Improving Informed Consent
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Promoting Patient Understanding: Promoting Patient Understanding: Informational BrochureInformational 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
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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 directions
Overview Overview
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Outputs from Individual Protocol Reviews Outputs from Individual Protocol Reviews Are Integral to Other ActivitiesAre Integral to Other Activities
Review of Review of Novel ProtocolsNovel Protocols
Safety SymposiumsSafety SymposiumsPolicy ConferencesPolicy Conferences
Adverse Events
AnnualReports
Amend-
ments
Webcasts
Slides
Public discussion
Changes in protocol design
Patient protections
New research avenues
29INPUTS OUTPUTS
Emphasis Shifting to OtherEmphasis Shifting to Other Clinical Activities 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
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Individual PublicProtocol Review
Gene Transfer Safety Gene Transfer Safety Assessment Board (GTSAB)Assessment Board (GTSAB)
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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
Analysis of Analysis of Aggregate Data from Protocols Aggregate Data from Protocols Promotes Patient Safety Promotes Patient Safety
Safety data often discussed in advance of publications
Informs the conduct of current trials and design of new trials
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Public summaries of significant adverse events that are possibly related to the gene transfer are available to investigators on a quarterly basis
RAC Activities Lead to New Resources for RAC Activities Lead to New Resources for Researchers and the Public Researchers and the Public
Genetic Modification Clinical Research Information System (GeMCRIS)
Scientific Symposium
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Genetic Modification Clinical Research Genetic Modification Clinical Research Information System (GeMCRIS)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
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Genetic Modification Clinical Research Genetic Modification Clinical Research Information System (GeMCRIS)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
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Case Study: RAC Analysis of an Case Study: RAC Analysis of an Unexpected DeathUnexpected Death
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Rapid Access to Aggregate DataRapid Access to Aggregate DataGeMCRIS Public Web Interface GeMCRIS Public Web Interface
Vector Descriptor =• “Adeno-Associated”
53 Total hits returned
Using both terms:“Adeno-Associated”
&“ocular” as route
returns:
1 Hit
Rapid Access to Aggregate DataRapid Access to Aggregate DataGeMCRIS Public Web Interface GeMCRIS Public Web Interface
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Protocol Information
Protocol Amendments
Adverse Events: GeMCRISAdverse Events: GeMCRISCustom Queries for Data AnalysisCustom Queries for Data Analysis
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National Symposium on Adverse EventNational 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
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Outcome of RAC Analysis: Outcome of RAC Analysis: Immediate Cause of Death Identified 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.
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Impact of RAC Discussions:Impact of RAC Discussions:Publications in Leading Scientific JournalsPublications in Leading Scientific Journals
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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
Impact of RAC Discussions:Impact of RAC Discussions:Change in Labeling Change in Labeling
TNF-inhibitors and the risk of histoplasmosis
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Scientific, Safety, and Policy SymposiaScientific, 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
2012 Retroviral and Lentiviral Vectors for Long-Term Gene Correction
2011 Gene-Modified T Cells: Challenges in Clinical Trial Design
2010 Public Health and Biosafety Practices for Research with 1918 H1N1 Influenza Virus 2007 Immune Responses to AAV Vectors
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Scientific, Safety, and Policy SymposiaScientific, Safety, and Policy Symposia
2005 Gene Transfer for X-SCID
2004 Safety Considerations in Recombinant DNA Research with Pathogenic Viruses
2001 IBCs in a Changing Research Landscape
2001 Adeno-Associated Virus in Gene Transfer Clinical Trials
2000 Cardiovascular Gene Transfer Clinical Research
1999 Prenatal Gene Transfer: Scientific, Medical and Ethical 1998 Lentiviral Vectors for Gene Delivery
Optimizing the Safety of Optimizing the Safety of Human Gene Transfer ResearchHuman Gene Transfer Research
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Optimizing the Safety of Optimizing the Safety of Human Gene Transfer ResearchHuman Gene Transfer Research
T cell Immunotherapy – Optimizing Trial Design, Sept. 10-11, 2013
Continued follow-up on important areas of research
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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 directions
Overview Overview
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RAC’s Continued RelevanceRAC’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
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Looking ForwardLooking 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
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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
QUESTIONSQUESTIONS
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Emphasis Shifting from Emphasis Shifting from Individual Protocol ReviewIndividual Protocol Review
Insertional mutagenesisX-SCID trial
19921992 20022002 20122012
% selected forpublic review% not selected
54Revised in October 2013
Number of Protocols Selected for Number of Protocols Selected for RAC Public Review by Year RAC Public Review by Year