The American Society for Microbiology (ASM) is submitting the following comments on the revisions to the list of select agents and toxins that are under consideration, which were published by the Centers for Disease Control and Prevention (CDC) in the August 23, 2002 Federal Register. The Federal Register notice of intent to issue regulations states that the Secretary of the Department of Health and Human Services (DHHS) directed the CDC to convene an interagency work group to review the current list of biological agents and toxins and revise the list as necessary. In June, 2002, CDC convened an interagency working group to review the current list of select agents and toxins and develop recommendations regarding possible changes to the list. According to the notice, CDC has reviewed those recommendations and the August 23 notice of intent seeks to solicit comments from the public on potential changes to the current list of select agents and toxins. The ASM wishes to remind the CDC that the Public Health Safety and Bioterrorism Preparedness and Response Act of 2002, PL 107-188, mandates in Section 351A (B) (ii) that the DHHS consult with "scientific experts representing appropriate professional groups" in determining whether to include an agent or toxin on the list of biological agents and toxins that have the potential to pose a severe threat to public health and safety. The ASM recommends that in the future the DHHS/CDC follow the consultation process mandated in the law for revising the select agent and toxin list to ensure that the list is based on the best scientific advice.
Appropriate changes to the current list of select agents and toxins
A number of the changes to the current list of select agents and toxins in the August 23 proposed notice represent appropriate updates based upon new taxonomic classification and nomenclature. For example, the name change of Equine morbillivirus to Nipah and Hendra complex viruses and the proposed change for the Tick-borne encephalitis complex (flavi) viruses are scientifically appropriate. Similarly, there is no longer a need to reference the Burkholderia species as Pseudomonas as Burkholderia is the accepted scientific name. Rickettsia are bacteria and thus removing the header is scientifically valid.
Section 351A (B) of Title II of PL 107-188 establishes criteria for determining whether to include an agent or toxin on the select agent and toxin list, including consideration of the effect on human health of exposure to the agent or toxin, the degree of contagiousness of the agent or toxin and the methods by which the agent or toxin is transferred to humans, the availability and effectiveness of pharmacotherapies and immunizations to treat and prevent any illness resulting from infection by the agent or toxin and any other criteria , including the needs of children and other vulnerable populations that the Secretary of DHHS considers appropriate. The proposed deletion of Yellow fever virus and Aflatoxins seems appropriate. The addition of Herpes B virus and of Monkeypox virus seems appropriate. Consideration should be given to adding Camelpox to the list given that recent publications on camelpox have raised concerns about its potential use as a biological weapon.
We recommend making the following change in the listing of Variola major (smallpox) to read Variola major and variola minor associated viruses including alastrim.
The elimination of the LD50 criteria and their replacement with specific amounts is a critical change that eliminates ambiguities. This change is strongly supported
Areas of concern in the select agent and toxin list under consideration
The retention of Coccidioides immitis and the addition of C. posadasii should receive further consideration based on the criteria for including an agent or toxin on the list and their demonstrated potential for causing widespread harm to public health. The rationale for the original inclusion of Coccidioides was never clear to the microbiological community. These fungi do not present a significant risk for use as a biological weapon. C. immits is a common source of infections in the southwestern United States. Both C. immitis and C. posadsii should be considered for removal from the list of select agents.
The acceptability of the list depends on defining appropriate exemptions but exemptions are not generally given in the August 23 Federal Register notice. There is also no clear process or mechanism for exempting agents from the list. CDC states that exemptions will be addressed in the interim final rule. Thus, it is difficult to evaluate the appropriateness of the revised list of select agents and toxins given that most exemptions are not provided. The absence of clarity on this issue is important since it is related to the scope of the regulations and the levels of biosecurity that will be required.
The exemption for medical uses is ambiguous and does not relate to the guidance document currently being used by the contractor for the select agent notification process. The current notification form requires notification for investigational products. CDC indicates that exemptions will be considered later. The proposed select agent and toxin list states, "The medical uses of toxins for patient treatment are exempt." PL 107-188 directs DHHS to exempt products that are, bear, or contain a select agent and are licensed or approved under several specified federal laws, unless the Secretary determines that additional regulation is necessary for a specific product to ensure protection of the public health and safety. The House report accompanying the bill states that Congress intends that the DHHS will exempt by regulation categories of products and will act to regulate a specific product, or a particular application of a specific product, only when existing regulation under federal laws is inadequate. PL107-188 grants the DHHS discretionary authority to exempt, on a case by case basis, investigational products when they are used in investigational or clinical trials authorized under federal laws and recognizes the time sensitivity of such trials by mandating a prompt determination by DHHS of an exemption request. It is important that CDC address and clarify the exemptions for products, off label uses of products, and investigational products used in clinical trials.
While changing Botulinum toxins to Botulinum neurotoxins seems like a reasonable technical change, the change of Clostridium botulinum to Botulinum neurotoxin producing strains of Clostridium seems to be a backwards way of exempting those strains of Clostridium botulinum that do not produce neurotoxins. If this is the purpose then C. boulinum should be retained and an exemption should be included for those strains that do not produce neurotoxin.
Changing Shigatoxin to shiga like toxins raises the issue of ambiguity which should be avoided in regulations. This could mean that analagous proteins that are not toxic but that resemble shigatoxin inadvertently become regulated. An exemption will be needed to clarify that analagous proteins that are not toxic are not select agents.
Genetic elements section presents significant areas of concern
It would be better to replace "full length nucleic acids of any of the select agent viruses" with "nucleotide sequences encoding the complete genome for any of the viruses designated as select agents except as may be specifically exempted." This eliminates the issue of defining a full length nucleic acid of any of the select agent viruses and the issue that if one nucleotide was left out it would not be full length and thus not regulated. The 100 nucleotide sequence from Variola is appropriate but this criterion for a select agent should also be applied to monkey pox and perhaps other viruses as well.
The sufficient to cause disease phrase is ambiguous. If this phrase is retained, there is no need for the next section on toxins.Toxins can cause disease. Thus if there is a section dealing with any factor that can cause disease there is no need for a separate one dealing with the subset of toxins.
The last section deals with all genetically modified select agents. Thus, any strains that are made avirulent are specifically covered, as are naturally occurring avirulent strains. If these are later considered exempt when the final interim rule is promulgated this will be a source of confusion. It would be better to simply say up front that all strains of the select agents, including any that have been genetically modified, are covered unless specifically exempted. It is important that a process or mechanism be established for additional exemptions for otherwise covered agents and avirulent strains, whether genetically modified or naturally occurring.
The last section on additional restrictions would better be handled as a footnote. Since all genetic modification of select agents is regulated under this Federal Register notice any transfer of drug resistance also is regulated. What this last section should say is that it should be noted that any genetic modification must not create an antibiotic resistant organism that would resist drugs used to treat the disease caused by that organism. But if such restrictions are to be included there may be others, not the least of which is the BWC prohibition on creating biological weapons. Thus, there should be a restriction to prohibit any genetic or physical modification of any of the select agents (or any agent for that matter) to produce a biological weapon.
The Public Health Safety and Bioterrorism Preparedness and Response Act recognizes that the list of select agents and toxins will be in need of regular updating (Section 351A (a)(2)) to take account of advancing scientific knowledge. The ASM recommends that the review and update of the list be done in consultation with scientists with the appropriate expertise from CDC and those identified by the American Society for Microbiology. The list of select agents and toxins should represent a broad consensus by the scientific community about which infectious agents should be covered.
The ASM appreciates the opportunity to comment on the revisions to the select agent and toxin list and offers its assistance to the CDC as it develops the regulations for the select agents and toxins.