[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: 
[email protected]; 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]
BILLING CODE 4150-37-P