[Federal Register Volume 85, Number 166 (Wednesday, August 26, 2020)]
[Notices]
[Pages 52611-52613]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-18444]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Review and Revision of the Screening Framework Guidance for
Providers of Synthetic Double-Stranded DNA
AGENCY: Office of the Secretary, Assistant Secretary for Preparedness
and Response (ASPR), Department of Health and Human Services.
ACTION: Notice.
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SUMMARY: Synthetic biology is a multidisciplinary field of research
that involves the design, modification, and creation of biological
systems and holds broad promise to advance both basic and applied
research in areas ranging from materials science to molecular medicine.
However, synthetic nucleic acids and associated technologies may also
pose risks if misused. To reduce the risk that individuals with ill
intent may exploit the application of nucleic acid synthesis technology
to obtain genetic material derived from or encoding Select Agents and
Toxins and, as applicable, agents on the Export Administration
Regulations' (EAR's) Commerce Control List (CCL), the U.S. Government
issued guidance in 2010 providing a framework for screening synthetic
double-stranded DNA (dsDNA). This document, the Screening Framework
Guidance for Providers of Synthetic Double-Stranded DNA (Guidance),
sets forth recommended baseline standards for the gene and genome
synthesis industry and other providers of synthetic dsDNA products,
regarding the screening of orders, so they are filled in compliance
with U.S. regulations prohibiting the possession, use, and transfer of
specific pathogens and biological toxins. The other goals of the
Guidance are to encourage best practices in addressing biosecurity
concerns associated with the potential misuse of these products to
inflict harm or bypass existing regulatory controls and to minimize any
negative impacts on the conduct of research and business operations.
Rapid and continued advances in nucleic acid synthesis technologies and
synthetic biology applications necessitate periodic reevaluation of
associated risks and mitigation measures. We invite public comments on
whether and, if so, how the Guidance should be modified to address new
and emerging challenges posed by advances in this area.
Please submit all comments related to this request for information
(RFI) through the web form on the Screening Framework Guidance for
Providers of Synthetic Double-Stranded DNA website at https://www.phe.gov/syndna/update2020.
DATES: Responses to this RFI must be received no later than 12 p.m.
(ET) on October 25, 2020.
FOR FURTHER INFORMATION CONTACT: Dr. C. Matthew Sharkey; Division of
Policy; Office of Strategy, Policy, Planning, and Requirements; Office
of the Assistant Secretary for Preparedness and Response; U.S.
Department of Health and Human Services; phone: 202-401-1448; email:
Matthew.Sharkey@hhs.gov; website: https://www.phe.gov/syndna/update2020.
SUPPLEMENTARY INFORMATION:
Disclaimer and Important Notes: The U.S. Government is seeking
feedback from life sciences stakeholders, including from the
commercial, health care, academic, and non-profit sectors; federal and
state, local, tribal, and territorial (SLTT) law enforcement
organizations; SLTT governments; and others, including the members of
the public. The focus of this RFI is to help inform whether updates or
modifications of the Guidance are needed and, if so, what updates or
modifications are desired. The U.S. Government will review and consider
all responses to this RFI. The U.S. Government will not provide
reimbursement for costs incurred in responding to this RFI. Respondents
are advised that the U.S. Government is under no obligation to
acknowledge receipt of the information received or to provide feedback
to respondents with respect to any information submitted under this
RFI. Responses to this RFI do not bind the U.S. Government to any
further actions related to this topic. Respondents are welcome to
answer all or any subset of the questions and are strongly advised to
not include any information in their responses that might be considered
attributable, business sensitive, proprietary, or otherwise
confidential, as comments may be made available for public review.
Categories and Questions
Scope of the Guidance
Nucleic acid synthesis technologies are fundamental for biomedical
research and allow for the generation and modification of some viruses,
bacteria, and toxins. Such technologies serve as tools to advance
important research to understand such agents better as well as in
developing medical countermeasures. Additionally, dsDNA synthesis could
pose biosecurity risks, including enabling individuals with ill intent
or who are not authorized to possess Select Agents and Toxins (or, for
international orders, items listed on the CCL) to obtain them using
materials ordered from providers of synthetic dsDNA. The Guidance sets
forth recommended baseline standards for the gene and genome synthesis
industry and other providers of synthetic dsDNA, regarding the
screening of orders, to ensure they are filled in compliance with
Select Agent Regulations (SAR) and CCL and to encourage best practices
in addressing biosecurity concerns associated with the potential misuse
of their products to bypass existing regulatory controls. The U.S.
Government--after receiving feedback from the scientific community and
synthetic biology industry stakeholders--developed the Guidance to
align with providers' existing protocols, to be implemented without
unnecessary cost, and to be globally extensible for U.S.-based
providers operating abroad and for international providers. The
Guidance recommends synthetic dsDNA providers perform customer
screening, sequence screening, and follow-up screening to verify the
legitimacy of the customer, the principal user, and the end-use of the
sequence. The following questions address how the Guidance could be
modified to identify nucleic acid sequences that pose biosecurity risks
for follow-up screening, if deemed necessary. Please include
explanations, examples, or potential benefits and drawbacks in your
responses.
Should the focus of the Guidance extend beyond the Select Agents
and Toxins list and CCL?
Are there potential benefits and/or downsides to screening for
sequences not on the Select Agents and Toxins list or CCL?
Should the scope of the Guidance be broadened beyond synthetic
dsDNA? If so, how? Should the scope of the Guidance be broadened to
other synthetic nucleic acids? If so, what synthetic sequences? Or,
should the scope of the Guidance be broadened beyond providers of
synthetic dsDNA? If so, to whom? Why?
Should the scope of the Guidance be narrowed, either in terms of
types of sequences screened or the audience of the Guidance? Why or why
not?
Sequence Screening
The Guidance currently suggests follow-up screening for synthetic
dsDNA orders, with the greatest percent identity (Best Match), over
each 200 nucleic acid segment, and the corresponding amino acid
sequence, to regulated Select Agents and Toxins and, as applicable, the
CCL. The following questions seek to
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understand whether the Guidance should be modified from a technical
perspective.
Should the Guidance be further clarified or otherwise updated to
identify embedded ``sequences of concern'' within larger-length orders?
If so, how?
Are there approaches other than the Best Match, using the Basic
Local Alignment Search Tool (BLAST) or other local sequence alignment
tools, to check against the National Institutes of Health's (HIH's)
GenBank database that should be considered? What are the benefits and/
or downsides of those approaches compared with the current Guidance?
Are there other approaches (e.g., predictive bioinformatics tools)
that could be utilized to identify sequences of concern for follow-up
screening?
Are there other considerations that would be appropriate (e.g.,
batch size) in decisions about whether to conduct follow-up screening,
such as oligonucleotide orders in quantities that indicate they are
intended for use in assembling a pathogen genome directly?
Biosecurity Measures
The Guidance recommends that dsDNA orders be screened for sequences
derived from or encoding Select Agents and Toxins and, for
international customers, dsDNA derived from or encoding items on the
CCL. The U.S. Government recognizes that there may be concerns that
synthetic dsDNA sequences not unique to Select Agents and Toxins or CCL
agents may also pose a biosecurity risk. The U.S. Government also
recognizes that many providers have already instituted measures to
address these potential concerns. The ongoing development of best
practices in this area is commendable and encouraged, particularly
considering continued advances in DNA sequencing and synthesis
technologies and the accelerated rate of sequence submissions to public
databases such as the NIH's GenBank. However, owing to the complexity
of determining if pathogenicity and other material properties pose a
biosecurity risk and to the fact that many such agents are not
currently encompassed by regulations in the United States, generating a
comprehensive list of such agents to screen against was not feasible
when the Guidance was released in 2010. The following questions pertain
to how the biosecurity risks arising from the potential misuse of
genetic sequences should be assessed.
Is maintenance and use of broader list-based approach(es) now
feasible? If so, how might this approach be realized? If not, what are
major roadblocks to implementing this approach? Since the release of
the original Guidance, have providers or other entities developed
customized database approaches, or approaches that evaluate the
biological risk associated with non-Select Agent and Toxin sequences
or, for international orders, sequences not associated with items on
the CCL? If so, how effective have they been, and have there been any
negative impacts?
Are there other security or screening approaches (e.g., risk
assessments, virulence factor databases) that would be able to
determine potential biosecurity risks arising from the use of nucleic
acid synthesis technologies? What are the potential opportunities and
limitations of these approaches?
Given that nucleic acid sequences not encompassed by SAR and the
CCL may pose biosecurity risks, are there alternative approaches to the
screening mechanism that could be established? If such approaches have
been established, how effective have they been, and have there been any
negative impacts?
Customer Screening
The Guidance suggests that if either customer screening or sequence
screening raises any concerns, providers should perform follow-up
screening of the customer. The purpose of follow-up screening is to
verify the legitimacy of the customer and the principal user, to
confirm that the customer and principal user placing an order are
acting within their authority, and to verify the legitimacy of the end-
use. If follow-up screening does not resolve concerns about the order
or there is reason to believe a customer may intentionally or
inadvertently violate U.S. laws, providers are encouraged to contact
designated entities within the U.S. Government for further information
and assistance. The following questions address how the Guidance could
be modified to improve follow-up screening of customers.
What, if any, mechanisms for pre-screening customers or categories
of customers for certain types of orders, if any, should be considered
to make secondary screening for providers of synthetic oligonucleotides
more efficient?
Are there additional types of end-user screenings or follow-up
mechanisms that should be considered to mitigate the risk that
synthetic genetic materials containing sequences assessed to pose
biosecurity risks are transferred to a second party who does not have a
legitimate purpose to receive them?
Minimizing Burden of the Guidance
The Guidance sets forth recommended baseline standards for the gene
and genome synthesis industry and other providers of synthetic dsDNA
products. Although voluntary, it places upon dsDNA providers the
responsibility for screening sequences, customers, and end-users. In
considering updates to the Guidance, the U.S. Government seeks
approaches that minimize undue negative impacts of customer and
sequence screening on the synthetic biology industry and the life
sciences research community. The following questions are meant to
elicit insights into how these responsibilities may have impacted
synthetic dsDNA providers and customers.
Does implementation of the current Guidance unduly burden providers
of synthetic dsDNA? If so, how could it be modified without
compromising effectiveness?
Have customers experienced delays in receiving orders of synthetic
dsDNA due to screening?
Have there been any undue burdens, financial, logistical, or
otherwise since implementing the Guidance? If so, has it increased,
especially as other costs associated with dsDNA synthesis have
decreased?
What challenges, if any, do the recommendation to retain records of
customer orders, ``hits,'' and/or follow-up screening for at least
eight years present for your organization?
How might potential changes to the Guidance to expand the scope or
methodologies affect the burden for providers of dsDNA and customers
(including delays to scientific progress caused by extended review)?
Is your organization concerned about legal liability challenges
between customers and providers?
Technologies Subject to the Guidance
The Guidance currently addresses only synthetic dsDNA and it was
developed based on providers' existing protocols and technologies at
that time. The life sciences field is rapidly advancing through
improved bioinformatics tools, new technologies, and new discoveries.
The following questions pertain to how the Guidance could be modified
to address the new biosecurity risks that may be posed by advances in
the life sciences.
Do other oligonucleotide types and other synthetic biological
technologies, currently not covered by the Guidance, pose similar
biosecurity risks as synthetic dsDNA (e.g., Ribonucleic Acid [RNA],
single-stranded DNA, or other oligonucleotides)?
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Are there other appropriate security measures that should be
established to address the potential threats arising from the use of
nucleic acid synthesis, given new and emerging technologies in the life
sciences?
Are there new biosecurity risks posed by the introduction of new
generations of benchtop DNA synthesizers capable of synthesizing and
assembling dsDNA, RNA, single-stranded DNA, or oligonucleotides in-
house that should be addressed by the Guidance?
As synthetic biology becomes an increasingly digital enterprise
with large databases, digital tools, robotics, and artificial
intelligence, what new risks are presented to providers and consumers
of synthetic oligonucleotides?
If new risks are evident, how should these risks be addressed,
keeping in mind the potential impacts on providers, customers, and
scientific progress?
Additional Considerations
The U.S. Government is committed to mitigating the potential
biosecurity risks associated with synthetic DNA and its applications,
while minimizing undue impacts on providers, customers, and scientific
progress.
Are there other mechanisms that the U.S. Government should consider
for screening sequences, customers, or end-uses that may help mitigate
the biosecurity risks associated with synthetic nucleotides and their
applications, while minimizing undue impacts on providers, customers,
and scientific progress?
(Authority: Section 301 of the Public Health Service Act, 42 U.S.C.
241; Section 605 of the Pandemic and All-Hazards Preparedness and
Advancing Innovation Act of 2019, Pub. L. 116-22.)
Robert P. Kadlec,
Assistant Secretary for Preparedness and Response.
[FR Doc. 2020-18444 Filed 8-25-20; 8:45 am]
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