Update on Policy Change Proposal to End Institutional Biosafety
Committee Review of rDNA Vaccine Clinical Trials
Mary E. Enama, Nancy Jones, Barney S. Graham, H. Clifford Lane
National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda, MD)
Figure 2. Recombinant DNA Research History: Representative and Key Events Timeline
Abstract
Background: The HIV vaccine regimen showing partial efficacy in the RV 144 study included a canarypoxvectored vaccine (ALVAC). The ongoing HIV vaccine efficacy trial, HVTN 505, involves two gene-based vaccines
developed by VRC/NIAID/NIH: plasmid DNA and adenoviral-vectored vaccines. The “NIH Guidelines for Research
Involving Recombinant DNA Molecules,” established in 1976, have evolved over time. Current NIH policy is that
every clinical trial of rDNA vaccines must have IBC reviews. The primary role of the IBC is to assess risk to public
health and the environment.
Methods: The NIAID Barriers to Clinical Research project identified repetitive IBC review of gene-based vaccines
as a barrier. For example, in the last 10 years >100 local IBC reviews have been conducted for the VRC HIV
vaccines. IBC reviews for ALVAC vaccines remain a requirement for NIH funding despite completion of a Phase III
clinical trial, >20 years of human experience with ALVAC vaccines and widespread community-based use of USDAapproved canarypox-vectored veterinary vaccines, which have not indicated a risk to public health or the
environment.
Results: An NIAID policy change proposal has been considered by a Recombinant DNA Advisory Committee (RAC)
working group. Policy change options have been discussed at the September 2011, December 2011 and March 2012
RAC meetings. The RAC proposal will be published in the Federal Register for public comments.
Conclusions: Repetitive IBC reviews of rDNA vaccine clinical trials divert time and attention of IBC expertise from
truly novel agents and incur a cost to NIH with no added safety benefit. NIAID proposes that IBC review is no longer
needed for clinical trials of non-transmissible rDNA vaccines because there are no unique biosafety concerns for this
class of vaccines based on their recombinant DNA nature. The IBC specific roles are not applicable for rDNA vaccine
protocols and are fulfilled through other regulatory oversight including the FDA.
NIH Office of Biotechnology Activities (OBA) FAQs: http://oba.od.nih.gov/rdna/rdna_faq_list.html
Vaccine trials meeting exemption criteria in Appendix M-VI-A are expected to follow other
requirements in the NIH Guidelines as an NIH Terms of Award.
This includes having each vaccine clinical trial reviewed and approved by the site’s
Institutional Biosafety Committee (IBC) before the site begins enrollments.
IBCs were established under the NIH Guidelines to provide local review and oversight of NIHfunded research with recombinant DNA. The IBC evaluates the following:
• Containment level
• Adequate facilities
• Sufficient expertise
Figure 1. NIAID Alternative Policy Option Proposal for NIH Guidelines Covering Recombinant Gene-Based Vaccine Clinical Trials
The policy change proposal was developed through the Barriers to Clinical Research Project and approved by the NIAID Executive Committee (Feb 2011)
With >30 years of recombinant DNA research,>20 years clinical trials experience with non-transmissible gene-based
constructs, and >7 years of commercial sales of veterinary vaccine constructs of this type, IBC review of each clinical
trial to ensure the safety of the institutional environment is no longer needed.
1971
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Stanford experiment (Berg, et al) with E. coli phage λ
Restriction enzymes used to create rDNA plasmid
Stanford/UCSF (Cohen/Boyer) apply for rDNA patent. RAC created at NIH
Asilomar Conference: voluntary moratorium rDNA research
Cambridge, MA halts all rDNA research for 3 months; NIH Guidelines issued
Early methods to sequence DNA (Gilbert/Sanger)
Stanford/UCSF rDNA patent awarded
Human insulin (Genentech) 1st FDA-approved drug made by rDNA methods
FDA asserts jurisdiction over gene transfer; NIH Guidelines vaccine exemption
rAd5 preclinical studies (FL Graham, et al)
June 1989: WHO Meeting on viral/bacterial vectored vaccines
1st clinical trial of ALVAC (rabies: Cadoz/Plotkin; Lancet 1992)
Nov 1992: “Splicing Life” presidential commission
June 1995: 1st DNA vaccine clinical trial (HIV: MacGregor/Weiner)
FDA issues “Points to Consider” on DNA vaccines
NIH Guidelines vaccine exemption reinterpreted
DNA vaccine shown to induce CTL in clinical trial (malaria: Wang/Hoffman)
Merck begins rAd5 HIV clinical trial evaluation
Oct 2001: 1st VRC HIV DNA vaccine clinical trial begins (VRC 001)
RV 144 (USMHRP) ALVAC/AIDSVAX HIV vaccine Thai Phase 3 trial begins
1st veterinary ALVAC vaccine USDA approved (WNV: Merial); 1st VRC rAd5 trial
1st veterinary plasmid DNA vaccine USDA approved (WNV: Fort Dodge)
NIH OBA posts new FAQs on rDNA vaccines and need for IBC review
FDA issues Guidance on DNA vaccines. STEP trial of Merck rAd5 halted
Partial efficacy ALVAC/AIDSVAX announced; HVTN 505 VRC DNA-rAd5 begins
RAC Working Group formed to consider policy change re IBC reviews
June 2012: influenza DNA vaccine clinical trial in children (VRC 702) begins
Estimate: >30,000 study participants in clinical trials (across all sponsors)
of non-replicating, gene-based vaccines, internationally, over >20 years
Alternative Policy Option for NIH Guidelines Covering February
Recombinant Gene-Based Vaccine Clinical Trials 2011
Case Study in NIAID Proposal Document
The three vaccine constructs in this case study
were manufactured using recombinant DNA
technology designed to yield vaccine products
that are non-replicating and non-integrating.
They are composed of closed, circular, DNA
plasmids or adenoviral vectors that encode for
HIV protein sequences.
These three products exemplify stages in the
vaccine developmental pathway, from single
agent through combination regimens. Two of
the vaccines are in the HVTN 505 Phase 2b
efficacy study prime-boost regimen.
As of the Aug 2010 date used in the proposal’s
case study there had been at least 100 local IBC
reviews conducted (Table 1) and the platform
technology used for manufacturing the VRC
vaccines had been used to produce more than 15
VRC investigational vaccine products that
progressed to human clinical trials.
*Table 1: IBC Reviews of Human Clinical Trials of 3 VRC Vaccines
IND Number
Vaccine(s)
BB-IND 10681
VRC-HIVDNA009-00-VP
BB-IND 11661
VRC-HIVADV014-00-VP
BB-IND 11750
VRC-HIVDNA016-00-VP
BB-IND 11894
VRC-HIVDNA009-00-VP
VRC-HIVADV014-00-VP
BB-IND12326
VRC-HIVDNA016-00-VP
VRC-HIVADV014-00-VP
BB-IND 13971
VRC-HIVDNA016-00-VP
VRC-HIVADV014-00-VP
6 INDs
3 Investigational Vaccine
Protocol
Agency
# of Study
Sites
VRC 004
HVTN 052
RV 156
VRC 006
HVTN 054
VRC 015
VRC 007
HVTN 057
VRC 009
RV 156A
HVTN 068
HVTN 069
VRC 008
VRC 010
VRC 011
HVTN 204
IAVI-V001
RV-172
VRC
HVTN
USMHRP
VRC
HVTN
VRC
VRC
HVTN
VRC
USMHRP
HVTN
HVTN
VRC
VRC
VRC
HVTN
IAVI
USMHRP
1
15
1
1
4
1
1
15
1
1
9
8
1
1
1
13
3
3
HVTN 505
HVTN
20
19 Protocols
4 Agencies
100 IBC
Reviews
*Table 1 does not include INDs with therapeutic indications or studies not initiated; data are as of Aug 2010
SUMMARY
• Regulatory policies should evolve to reflect current scientific knowledge and to be
proportionate to the risks.
• Amendment of the current NIH policy requiring IBC review of gene-based vaccines will
allow the limited resources of IBCs to be devoted to truly novel and potentially
transmissible agents that need the time, attention and expertise of the IBC to protect the
personnel and institutional environment.
• The proposed policy change that will be published by the Recombinant DNA Advisory
Committee (RAC) Working Group in the Federal Register will likely be different from the
NIAID proposal. Vaccine researchers will have the opportunity to submit comments
when the RAC proposal is published in the Federal Register (projected for Fall 2012).