[Federal Register Volume 78, Number 92 (Monday, May 13, 2013)]
[Notices]
[Pages 27977-27980]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-11222]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Office of Biotechnology Activities; Recombinant DNA Research: 
Proposed Actions Under the NIH Guidelines for Research Involving 
Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)

SUMMARY: The NIH Office of Biotechnology Activities (NIH OBA) proposes 
to revise the NIH Guidelines for Research Involving Recombinant or 
Synthetic Nucleic Acid Molecules (NIH Guidelines) to streamline review 
of certain human gene transfer trials that present a low biosafety 
risk. Specifically, the NIH OBA proposes to remove the requirement that 
institutional biosafety committees (IBCs) review and approve certain 
human gene transfer clinical trials that use plasmids and certain 
attenuated, non-integrating viral vectors, provided the clinical trial 
follows an initial study in humans that was previously approved by an 
IBC registered with the OBA. This initial trial will have established 
the safety of the proposed dose of the gene transfer product (vector 
and transgene) in a comparable population (adults or children). The 
initial study should have been conducted in the same country as the 
proposed study to control for potential variability in infectious 
disease backgrounds of the participants.
    An initial IBC review is important to evaluate the safety of the 
product and to set standards for administration; however, for well-
characterized vectors, in the absence of any unexpected toxicities in 
the initial study, subsequent biosafety assessments may not provide any 
additional information. While a single IBC review does not pose an 
undue burden, as the gene transfer field advances and more Phase II and 
Phase III multisite trials are developed, the time, effort and expense 
associated with multiple IBC reviews can be significant without adding 
commensurate value in the form of additional recommendations to protect 
the health and safety of the subject, health care worker, and 
community.
    IBCs play a critical role in the evaluation of new products and 
their review can inform other oversight bodies, such as Institutional 
Review Boards. However, given the competing demands on IBCs, this 
change will provide IBCs with the option of focusing their efforts on 
those clinical trials where review will be most productive. While IBCs 
will no longer be required to review all clinical trials using the same 
product, each institution can implement its own policies regarding the 
need to review such trials and the information that a principal 
investigator (PI) should submit regarding the safety of the previous 
trial. For example, an institution may designate the Biological Safety 
Officer and the IBC Chair to review data from the initial trial and 
determine whether a subsequent trial using the same agent meets the 
exemption criteria outlined herein. The institution may also set its 
own policies regarding the need for the PI to inform the IBC about 
enrollment, any relevant new biosafety findings, and completion of the 
trial.
    This policy will only exempt human gene transfer clinical trials 
from IBC review under Section III-C-1. It does not apply to basic, 
nonclinical research. In addition, it does not create an exemption from 
registration of the trial with the NIH OBA or the Recombinant DNA 
Advisory Committee (RAC) review and reporting requirements. By 
continuing to require registration and reporting on these trials, the 
NIH OBA will be able to continue to monitor adverse events or incident 
reports of accidental exposures by health care workers delivering these 
agents and, if necessary, provide information regarding these events to 
investigators, IBCs, and the public. The NIH OBA will also be able to 
assess whether this change in policy has any adverse impact on the 
biosafety of gene transfer trials.

DATES: All comments should be submitted by June 12, 2013.

ADDRESSES: Comments may be submitted to the NIH OBA by email at 
[email protected]; by fax to 301-496-9839; or by mail to the NIH Office of 
Biotechnology Activities, National Institutes of Health, 6705 Rockledge 
Drive, Suite 750, Bethesda, MD 20892-7985. All written comments 
received in response to this notice will be available for public 
inspection in the NIH Office of Biotechnology Activities, 6705 
Rockledge Drive, Suite 750, Bethesda, Maryland, weekdays between the 
hours of 8:30 a.m. and 5:00 p.m.

FOR FURTHER INFORMATION CONTACT: If you have questions, or require 
additional information about these proposed changes, please contact the 
NIH OBA by email at [email protected] or telephone at 301-496-9838. 
Comments

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can be submitted to the same email address or by fax to 301-496-9839 or 
mail to the NIH Office of Biotechnology Activities, National Institutes 
of Health, 6705 Rockledge Drive, Suite 750, Bethesda, MD 20892-7985. 
Background information may be obtained by contacting the NIH OBA by 
email at [email protected].

SUPPLEMENTARY INFORMATION: Human gene transfer is a maturing field. 
There are currently over 1,200 gene transfer trials registered since 
1988 with the OBA. While the majority of trials are still small safety 
studies, increasingly Phase II and III multisite trials are being 
initiated. IBCs play a critical role in the evaluation of human gene 
transfer trials. IBCs identify and manage biosafety issues raised by 
gene transfer agents, including safety issues that may arise due to the 
nature of the vector. The IBC assesses the risks of horizontal and 
vertical viral vector transmission and provides guidance on the safe 
handling and administration of the product in a context that considers 
the local clinical environment. The IBC also examines the preclinical 
data that support the safety of the vector as delivered. Finally, the 
IBC reviews the informed consent to ensure that the risks that arise 
from the biological nature of the vector are clearly stated.
    Investigators have noted that repeated reviews by multiple IBCs of 
a multisite Phase II or III trial have often not resulted in new 
recommendations and such reviews can impose a cost on the research, 
including the cost of establishing IBCs at sites without pre-existing 
IBCs and the time required to complete multiple reviews. The NIH OBA 
recognizes that the biosafety profiles of many vectors are well 
characterized, and while the transgene may have an impact on the safety 
profile, an IBC may be able to identify most of the issues through the 
review of the initial trial. In addition, members of the RAC, some of 
whom have served on IBCs, also note that providing IBCs some discretion 
in whether to review certain low risk clinical trials is desirable.
    In order to identify the type(s) of trials that might qualify for 
an exemption from further IBC review, the NIH OBA considered the types 
of vectors that have been frequently used in gene transfer protocols 
over a number of years. The NIH OBA concluded, with the advice of the 
RAC, that gene transfer products that employ plasmids or attenuated 
Risk Group (RG) 2 viruses that are not designed to integrate into the 
host genome are of sufficiently low biosafety risk to be considered for 
this exemption. The vectors OBA proposes to make eligible for this 
exemption are derived from the following viruses: Adenoviruses, 
serotypes 2 and 5; herpes simplex viruses 1 (HSV-1); adeno-associated 
viruses (AAV); and poxviruses, except for vaccinia. While AAV vectors 
do integrate, given the safety record to date with AAV vectors and the 
fact that they are more likely to remain episomal, including them in 
this exemption is appropriate. Research with vaccinia vectors was not 
considered eligible for the exemption because of the adverse events 
that were documented when vaccinia was used as a vaccine against 
smallpox and reports of skin pustules developing in some research 
participants receiving intravenous administration of vaccinia vectors 
in gene transfer protocols. Continued oversight by an IBC to ensure 
proper handling and administration of vaccinia vectors seems prudent. 
Clinical research with integrating vectors, including transposons, is 
not eligible for this exemption due to the need for long-term follow-
up; therefore IBC oversight is again appropriate.
    A list of viruses eligible for this exemption will be presented in 
a new section of Appendix B (Appendix B-V-2) that will be titled 
Viruses used as Vectors for Human Gene Transfer that Present Low 
Biosafety Risk and are Eligible for Exemption from IBC Review under 
Section III-C-1. This list can be updated by the NIH OBA, in 
consultation with the RAC chair and one or more RAC members as needed. 
(See Minor Actions in the NIH Guidelines Section IV-C-1-b-(2).) As 
experience grows with other vectors, they may also become eligible for 
this exemption and will be added to Appendix B-V-2.
    Almost all viral vectors used in gene transfer are attenuated 
compared to the wild-type virus. To be exempt from IBC review, there 
must be data that the vector is attenuated compared to the wild type 
virus; this data should be provided from both animal models and the 
previous clinical trial. Attenuation may be achieved by gene deletions 
or irreversible mutations in genes required for cell-to-cell 
transmission or virulence.
    In order to be exempt from IBC review, in addition to using one of 
the specified vectors, an initial clinical trial must have been 
conducted using the same gene transfer product. This initial trial may 
not be a single subject protocol or what is sometimes referred to as a 
``compassionate use trial.'' An initial safety trial, or Phase I trial, 
may be used to support the exemption of a Phase II trial while an 
initial safety trial, Phase I, or a Phase II trial may be used to 
support the exemption of a Phase III trial. The design of the proposed 
trial should be comparable to the previous clinical study that is being 
used to justify an exemption from IBC review. This ensures that the 
safety data from the initial trial is applicable to the subsequent 
trials. Specifically, the dose(s) of the gene transfer agent to be used 
in the Phase II or III trial must be equal to or less than the dose 
administered in the safety trial and the delivery route must be 
identical, e.g., a trial using intramuscular delivery would not support 
exemption of a trial using intravenous administration, as the 
biodistribution of the product may be quite different. Chemotherapy, 
radiation, and other immune modulatory agents can also potentially 
alter the biodistribution and/or shedding of the vectors due to effects 
on the immune system. Consequently, if concomitant chemotherapy or 
radiotherapy will be administered with the gene transfer agent, the co-
administration of these agents must have been tested in the initial 
safety trial.
    Also the population enrolled in the initial trial must be 
comparable to the population in the proposed trial. The NIH OBA 
recognizes that there are many clinical factors that affect the safety 
of a product in a certain population, including co-morbidities and type 
of disease. However, in order to have an exemption that can be 
uniformly applied across IBCs, the proposed exemption focuses on two 
factors: The age of the subject and the infectious disease background. 
In drug development, it is recognized that children are not simply 
small adults. Children's immune systems are different and the 
pharmacokinetics of viral vectors in pediatric patients may be altered; 
therefore, an initial safety study must be conducted in a pediatric 
population before exempting subsequent studies in pediatric 
populations.
    Another issue is whether the safety profile of a product will 
differ if the population has significantly different background 
exposure to infectious diseases, as many of the vectors proposed to be 
included in this exemption are viral vectors. Even within the U.S. 
there can be differences in the prevalence of certain infectious 
diseases; however, it is likely that those differences may be more 
pronounced between different countries, as certain infectious diseases 
are endemic in some countries but rarely observed in others. That is 
not to say that the infectious disease background is always 
significantly different across countries

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(for example one would not expect significant differences between the 
U.S. and Canada), but in order to make this criterion easily 
interpretable by the IBC, the clinical protocol that will be the basis 
for exempting review of subsequent protocol(s) must have been conducted 
in the same country. This will also ensure that an IBC in the country 
in which the trial will be conducted has carried out a review of the 
product.
    The main impetus for this proposed policy change is to facilitate 
multisite trials that follow an initial Phase I safety trial or a Phase 
II study by removing the requirement for multiple IBC reviews for a 
well-characterized agent. When a trial is only conducted at a single 
site, the burden of a single IBC review should not be significant or 
unduly delay the research. Therefore, the original intent was to limit 
this exemption to trials that would be conducted at more than one site, 
including at sites that might not already have an IBC. However, it is 
possible that one might conduct an initial safety study at a single 
site and conduct the next study with an identical design at a single 
site, perhaps because the available population in which to study the 
disease is limited. Given that there is no scientific rationale for 
limiting the IBC review exemption only to subsequent multisite trials, 
and since an IBC can still choose to review the trial, the NIH OBA 
concludes that the exemption should apply to all studies that meet the 
above criteria, be they single or multisite trials.
    The NIH OBA has used the terms Phase II and Phase III in this 
notice to describe the type of trial that would be exempt under this 
new policy. These terms are used because they are typically the way 
studies are classified as they progress through the FDA regulatory 
process. However, the NIH OBA recognizes that such labels are not all 
inclusive and there may be Phase I/II trials that follow an initial 
safety study. Therefore, rather than limiting the exemption to just 
Phase II or Phase III trials, the policy focuses instead on having data 
from at least one comparable trial. The NIH OBA also recognizes that 
the initial study may be a small safety study of ten to 20 subjects, 
which is not unusual in gene transfer trials, and that such trials do 
not definitively establish the safety of the product. Indeed, safety 
data continue to emerge throughout the life cycle of a drug or biologic 
agent, including after licensing. Nonetheless, given the experience 
with the vectors eligible for an exemption, it is anticipated that the 
types of safety issues of most concern to an IBC will likely emerge 
during the review of the documentation submitted in support of the 
initial clinical trial and the clinical experience from the initial 
trial. Again, IBCs have the institutional prerogative to require 
registration of trials and can decide to review certain trials if new 
data emerges.
    The determination of whether a trial meets this exemption from IBC 
review should be made by the local IBCs. The initial trial, whether 
done at one or more sites, requires IBC review. For the subsequent 
trials using the same agent, if they will be conducted only at sites 
that receive NIH funding for recombinant or synthetic nucleic acid 
research, then these sites should already have an IBC registered with 
the NIH OBA. If the sponsor or a site investigator concludes that their 
trial meets the exemption criteria, this should be confirmed by at 
least one IBC at one of the trial sites. Institutions with IBCs should 
establish a policy for how to handle protocols that are eligible for 
exemption. An IBC may require that the PI at that site or the sponsor 
register and provide an abbreviated summary of the data from the first 
trial to confirm that the trial indeed meets the exemption criteria. An 
institution may also decide to rely on a decision by another IBC that 
the protocol is eligible to be exempt. The NIH OBA has proposed 
exemption criteria that are objective to facilitate uniform decisions 
across IBCs. However, the NIH OBA is available to provide guidance and 
clarification upon request.
    In some cases, a non-NIH-funded trial will be conducted both at 
sites that receive NIH funding for recombinant or synthetic nucleic 
acid research--and therefore have IBCs--and at non-NIH-funded sites 
that do not have IBCs. In this situation, the NIH OBA expects the 
individual responsible for the conduct of the trial to confirm with an 
established IBC at one of the institutions that their trial does not 
require IBC review before initiating the trial at a site that does not 
have an IBC. It is also possible that the trial could be funded by NIH, 
or by an NIH-funded Institution, but the trial will be conducted only 
at non-NIH-funded sites that do not have IBCs, for example clinics or 
community hospitals that do not receive NIH funding for recombinant or 
synthetic nucleic acid research. In this situation, because it is 
subject to the NIH Guidelines, the trial must be reviewed by an IBC at 
each trial site, even if the site does not receive funding from NIH for 
recombinant or synthetic nucleic acid research. However, there would 
not necessarily be IBCs established at the planned trial sites to make 
a determination regarding whether the trial meets the exemption 
criteria. It would not make sense to set up an IBC solely to determine 
if a trial is exempt from IBC review. The PI or sponsor should consult 
with the NIH OBA regarding whether the trial is exempt from review.
    To implement this exemption, the following proposed changes will be 
made to Section III-C and to Appendices M-I-C-1, M-I-C-2, and B. The 
current Section III-C-1 states:

    Section III-C-1. Experiments Involving the Deliberate Transfer 
of Recombinant or Synthetic Nucleic Acid Molecules, or DNA or RNA 
Derived from Recombinant or Synthetic Nucleic Acid Molecules, into 
One or More Human Research Participants
    Human gene transfer is the deliberate transfer into human 
research participants of either:
    1. Recombinant nucleic acid molecules, or DNA or RNA derived 
from recombinant nucleic acid molecules, or
    2. Synthetic nucleic acid molecules, or DNA or RNA derived from 
synthetic nucleic acid molecules, that meet any one of the following 
criteria:
    a. Contain more than 100 nucleotides; or
    b. Possess biological properties that enable integration into 
the genome (e.g., cis elements involved in integration); or
    c. Have the potential to replicate in a cell; or
    d. Can be translated or transcribed.
    No research participant shall be enrolled (see definition of 
enrollment in Section I-E-7) until the RAC review process has been 
completed (see Appendix M-I-B, RAC Review Requirements).
    In its evaluation of human gene transfer proposals, the RAC will 
consider whether a proposed human gene transfer experiment presents 
characteristics that warrant public RAC review and discussion (See 
Appendix M-I-B-2). The process of public RAC review and discussion 
is intended to foster the safe and ethical conduct of human gene 
transfer experiments. Public review and discussion of a human gene 
transfer experiment (and access to relevant information) also serves 
to inform the public about the technical aspects of the proposal, 
meaning and significance of the research, and any significant 
safety, social, and ethical implications of the research.
    Public RAC review and discussion of a human gene transfer 
experiment may be: (1) Initiated by the NIH Director; or (2) 
initiated by the NIH OBA Director following a recommendation to NIH 
OBA by: (a) Three or more RAC members; or (b) a Federal agency other 
than NIH. After a human gene transfer experiment is reviewed by the 
RAC at a regularly scheduled meeting, NIH OBA will send a letter, 
unless NIH OBA determines that there are exceptional circumstances, 
within 10 working days to the NIH Director, the Principal 
Investigator, the sponsoring institution, and other DHHS components, 
as appropriate, summarizing the RAC recommendations.

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    For a clinical trial site that is added after the RAC review 
process, no research participant shall be enrolled (see definition 
of enrollment in Section I-E-7) at the clinical trial site until the 
following documentation has been submitted to NIH OBA: (1) 
Institutional Biosafety Committee approval (from the clinical trial 
site); (2) Institutional Review Board approval; (3) Institutional 
Review Board-approved informed consent document; (4) curriculum 
vitae of the Principal Investigator(s) (no more than two pages in 
biographical sketch format); and (5) NIH grant number(s) if 
applicable.

    The fifth paragraph of Section III-C-1 will be amended to add ``if 
required'' at the end of the statement regarding IBC approval in order 
to recognize that some trials will not need IBC review. In addition, a 
new final paragraph outlining the exemption will be added. The new 
proposed language is as follows:

    For a clinical trial site that is added after the RAC review 
process, no research participant shall be enrolled (see definition 
of enrollment in Section I-E-7) at the clinical trial site until the 
following documentation has been submitted to the NIH OBA: (1) 
Institutional Biosafety Committee approval (from the clinical trial 
site), if required; (2) Institutional Review Board approval; (3) 
Institutional Review Board-approved informed consent document; (4) 
curriculum vitae of the Principal Investigator(s) (no more than two 
pages in biographical sketch format); and (5) NIH grant number(s) if 
applicable.
    Institutional Biosafety Committee review and approval will not 
be required for gene transfer protocols that meet all of the 
following criteria:
    (1) A previous clinical trial using this investigational gene 
transfer agent (vector and transgene) enrolled more than one subject 
and was reviewed by an Institutional IBC and is now complete.
    (2) The investigational gene transfer agent uses a plasmid or 
viral vector derived from a virus listed in Appendix B-V-2 that is: 
(a) Not designed to integrate, and (b) attenuated compared to the 
wild-type virus or is not known to have ever caused disease in 
humans.
    (3) The previous clinical trial:
    a. Was conducted in the same country as the proposed trial;
    b. Enrolled a comparable population in terms of age (i.e. adult 
and/or pediatric); and
    c. Tested a dose equal to or less than the dose proposed for the 
new trial, using the same administration route and, if concomitant 
interventions (e.g. radiation and/or chemotherapy) are proposed, 
they have been used in a prior trial with the same agent.

    Appendix M-I-C-1 currently states:

Appendix M-I-C-1: Initiation of the Clinical Investigation

    No later than 20 working days after enrollment (see definition 
of enrollment in Section I-E-7) of the first research participant in 
a human gene transfer experiment, the Principal Investigator(s) 
shall submit the following documentation to NIH OBA: (1) A copy of 
the informed consent document approved by the Institutional Review 
Board (IRB); (2) a copy of the protocol approved by the 
Institutional Biosafety Committee (IBC) and IRB; (3) a copy of the 
final IBC approval from the clinical trial site; (4) a copy of the 
final IRB approval; (5) a brief written report that includes the 
following information: (a) How the investigator(s) responded to each 
of the RAC's recommendations on the protocol (if applicable); and 
(b) any modifications to the protocol as required by FDA; (6) 
applicable NIH grant number(s); (7) the FDA Investigational New Drug 
Application (IND) number; and (8) the date of the initiation of the 
trial. The purpose of requesting the FDA IND number is for 
facilitating interagency collaboration in the Federal oversight of 
human gene transfer research.

    Appendix M I-C-1 would be amended to again recognize that IBC 
approval may not be needed for every trial. The proposed Appendix M-I-
C-1 is as follows:

Appendix M-I-C-1: Initiation of the Clinical Investigation

    No later than 20 working days after enrollment (see definition 
of enrollment in Section I-E-7) of the first research participant in 
a human gene transfer experiment, the Principal Investigator(s) 
shall submit the following documentation to the NIH OBA: (1) A copy 
of the informed consent document approved by the Institutional 
Review Board (IRB); (2) a copy of the protocol approved by the 
Institutional Biosafety Committee (IBC) and/or IRB; (3) a copy of 
the final IBC approval from the clinical trial site, if required; 
(4) a copy of the final IRB approval; (5) a brief written report 
that includes the following information: (a) How the investigator(s) 
responded to each of the RAC's recommendations on the protocol (if 
applicable), and (b) any modifications to the protocol as required 
by FDA; (6) applicable NIH grant number(s); (7) the FDA 
Investigational New Drug Application (IND) number; and (8) the date 
of the initiation of the trial. The purpose of requesting the FDA 
IND number is for facilitating interagency collaboration in the 
federal oversight of human gene transfer research.

    Appendix M-I-C-2 will likewise be revised to recognize that not all 
clinical trials will require IBC review. Appendix M-I-C-2 now states:

Appendix M-I-C-2: Additional Clinical Trial Sites

    No research participant shall be enrolled (see definition of 
enrollment in Section I-E-7) at a clinical trial site until the 
following documentation has been submitted to NIH OBA: (1) 
Institutional Biosafety Committee approval (from the clinical trial 
site); (2) Institutional Review Board approval; (3) Institutional 
Review Board-approved informed consent document; (4) curriculum 
vitae of the Principal Investigator(s) (no more than two pages in 
biographical sketch format); and (5) NIH grant number(s) if 
applicable.

    The proposed Appendix M-I-C-2 is:

Appendix M-I-C-2: Additional Clinical Trial Sites

    No research participant shall be enrolled (see definition of 
enrollment in Section I-E-7) at a clinical trial site until the 
following documentation has been submitted to the NIH OBA: (1) 
Institutional Biosafety Committee approval (from the clinical trial 
site), if required; (2) Institutional Review Board approval; (3) 
Institutional Review Board-approved informed consent document; (4) 
curriculum vitae of the Principal Investigator(s) (no more than two 
pages in biographical sketch format); and (5) NIH grant number(s) if 
applicable.

    A new section will be added to Appendix B.

Appendix B-V-2. Viruses Used in Vectors for Human Gene Transfer That 
Present Low Biosafety Risk and Are Eligible for Exemption From IBC 
Review Under Section III-C-1

--Adenovirus, serotypes 2 and 5
--AAV, all serotypes
--Herpes Simplex virus 1
--Pox Viruses, with the exception of vaccinia

    Dated: May 6, 2013.
Lawrence A. Tabak,
Deputy Director, National Institutes of Health.
[FR Doc. 2013-11222 Filed 5-10-13; 8:45 am]
BILLING CODE 4140-01-P