Federal Register / Vol. 85, No. 200 / Thursday, October 15, 2020 / Proposed Rules 65311

401, 403, 404, 407, 414, 416, 3001–3011, No. R2021–1 on the Postal Regulatory Authority: 5 U.S.C. 552(a); 13 U.S.C. 301– 3201–3219, 3403–3406, 3621, 3622, 3626, Commission’s website at www.prc.gov. 307; 18 U.S.C. 1692–1737; 39 U.S.C. 101, 3632, 3633, and 5001. The Postal Service’s proposed rule 401, 403, 404, 414, 416, 3001–3011, 3201– ■ 2. Revise the following sections of includes: Changes to prices, mail 3219, 3403–3406, 3621, 3622, 3626, 3632, 3633, and 5001. Mailing Standards of the United States classification updates, and product ■ Postal Service, International Mail simplification efforts. 2. Revise the following sections of Manual (IMM), as follows: New prices Mailing Standards of the United States Seamless Acceptance Incentive will be listed in the updated Notice 123, Postal Service, Domestic Mail Manual Price List. Currently, mailers who present (DMM), as follows: qualifying full-service mailings receive Mailing Standards of the United States Joshua J. Hofer, an incentive discount of $.003 per piece Postal Service, Domestic Mail Manual Attorney, Federal Compliance. for USPS Marketing Mail and First-Class (DMM) [FR Doc. 2020–22886 Filed 10–13–20; 8:45 am] Mail and $0.001 for Bound Printed BILLING CODE 7710–12–P Matter flats and Periodicals. * * * * * The Postal Service is proposing an Notice 123 (Price List) incentive discount for mailers who mail POSTAL SERVICE through the Seamless Acceptance [Revise prices as applicable.] program, in addition to the full-service * * * * * 39 CFR Part 111 incentive discount. We will publish an appropriate Beginning on the day of their first amendment to 39 CFR part 111 to reflect New Mailing Standards for Domestic mailing, following onboarding to the these changes. Mailing Services Products program the mailer or mail service Joshua J. Hofer, TM provider, as applicable, will receive an AGENCY: Postal Service . Attorney, Federal Compliance. incentive discount in addition to the ACTION: Proposed rule. full-service incentive discount. The [FR Doc. 2020–22887 Filed 10–13–20; 8:45 am] BILLING CODE P SUMMARY: On October 9, 2020, the Postal mailer would be allowed to combine the Service (USPS®) filed a notice of Seamless and full-service incentive mailing services price adjustments with discounts. The Seamless incentive the Postal Regulatory Commission discount would be based on a mailer’s DEPARTMENT OF HEALTH AND (PRC), effective January 24, 2021. This customer registration ID (CRID). A HUMAN SERVICES Seamless mailer is defined by their proposed rule contains the revisions to 42 CFR Part 110 Mailing Standards of the United States status in PostalOne!. Moving to Postal Service, Domestic Mail Manual Seamless is defined as the status [Docket No. 2020–0003] ® changing from ‘‘None’’ or ‘‘Seamless (DMM ) that we would adopt to RIN 0906–AB22 implement the changes coincident with Parallel’’ to ‘‘Seamless Acceptance’’. the price adjustments. The proposal would leave the full- Countermeasures Injury service discount exactly as it is now and DATES: Submit comments on or before Compensation Program: Smallpox provide a $.001 per piece incentive November 16, 2020. Countermeasures Injury Table discount for Seamless. The maximum ADDRESSES: Mail or deliver written incentive discount per piece is $0.004 AGENCY: Health Resources and Services comments to the Manager, Product for USPS Marketing Mail and First-Class Administration (HRSA), HHS. Classification, U.S. Postal Service, 475 Mail and $0.002 for Bound Printed ACTION: Notice of proposed rulemaking. L’Enfant Plaza SW, Room 4446, Matter flats and Periodicals. Washington, DC 20260–5015. If sending Although exempt from the notice and SUMMARY: The Department of Health and comments by email, include the name comment requirements of the Human Services (HHS) proposes adding and address of the commenter and send Administrative Procedure Act (5 U.S.C. a Smallpox Countermeasures Injury to [email protected], with a 553(b), (c)) regarding proposed Table (Table) for designated covered subject line of ‘‘January 2021 Domestic rulemaking by 39 U.S.C. 410(a), the smallpox countermeasures identified in Mailing Services Proposal.’’ Faxed Postal Service invites public comments a declaration. The proposed Smallpox comments are not accepted. on the following proposed revisions to Countermeasures Injury Table includes All submitted comments and Mailing Standards of the United States a list of smallpox countermeasures, attachments are part of the public record Postal Service, Domestic Mail Manual proposed time intervals for the first and subject to disclosure. Do not (DMM), incorporated by reference in the symptom or manifestation of onset of enclose any material in your comments Code of Federal Regulations. See 39 CFR injury, and Qualifications and Aids to that you consider to be confidential or 111.1. Interpretation, which set forth the inappropriate for public disclosure. We will publish an appropriate definitions and requirements necessary You may inspect and photocopy all amendment to 39 CFR part 111 to reflect to establish the Table injuries. written comments, by appointment these changes if our proposal is DATES: ® Written comments and related only, at USPS Headquarters Library, adopted. material to this proposed rule must be 475 L’Enfant Plaza SW, 11th Floor List of Subjects in 39 CFR Part 111 received to the online docket via North, Washington, DC 20260. These www.regulations.gov, or to the mail records are available for review on Administrative practice and address listed in the ADDRESSES section Monday through Friday, 9 a.m.–4 p.m., procedure, Postal Service. below, on or before December 14, 2020. Accordingly, 39 CFR part 111 is by calling 202–268–2906. ADDRESSES: proposed to be amended as follows: You may submit comments FOR FURTHER INFORMATION CONTACT: on this proposed rule identified by HHS Jacqueline Erwin at (202) 268–2158, or PART 111—[AMENDED] Docket No. HRSA–2020–0003, by any Dale Kennedy at (202) 268–6592. one of the following methods: SUPPLEMENTARY INFORMATION: Proposed ■ 1. The authority citation for 39 CFR 1. Federal eRulemaking Portal prices will be available under Docket part 111 continues to read as follows: (preferred): www.regulations.gov.

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Follow the website instructions for identifying serious physical injuries injury or death, an individual must submitting comments. presumed to be directly caused by the submit a timely Request for Benefits 2. Mail: You may mail written administration or use of covered with the required information. comments to the following address only: countermeasures identified in PREP Act The Secretary published the interim Health Resources and Services declarations issued by the Secretary. final rule implementing the Program on Administration, Department of Health The Secretary may only add injuries to October 15, 2010.4 The final rule, and Human Services, Attention: HRSA a Table if it is determined based on published on October 7, 2011, explains Regulations Officer, 5600 Fishers Lane, ‘‘compelling, reliable, valid, medical the Program’s policies, procedures, and Room 13N82, Rockville, MD 20857. and scientific evidence’’ that the requirements. Title 42 of the Code of Mail must be postmarked by the administration or use of the covered Federal Regulations (CFR) § 110.20(a) comment submission deadline. countermeasure directly causes such states that individuals must establish Because of staffing and resource covered injuries.1 Such a Table informs that a covered injury occurred to be limitations, and to ensure that no the public about serious physical eligible for benefits under the Program. comments are misplaced, the Program injuries supported by medical and A covered injury is a death or a serious cannot accept comments by facsimile scientific evidence known to be directly injury determined to have occurred as a (FAX) transmission. When commenting caused by covered countermeasures. direct result of the administration or use by any of the above methods, please The purpose of a PREP Act of a covered countermeasure. The refer to file code: #0906–AB22. declaration is to identify a disease, Secretary has determined that the list health condition, or threat to health that FOR FURTHER INFORMATION CONTACT: includes: (1) An injury meeting the is currently, or may in the future Please visit the Countermeasures Injury requirements of covered constitute, a public health emergency. Compensation Program’s website, countermeasures placed on an injury In addition, the Secretary, through a http://www.hrsa.gov/cicp/, or contact table, unless the Secretary determines declaration, may recommend and Tamara Overby, Acting Director, there is another more likely cause; or (2) encourage the development, Division of Injury Compensation an injury (or health complications) that manufacturing, distribution, dispensing, Programs, Healthcare Systems Bureau, is the direct result of the administration administration, or use of one or more HRSA, 5600 Fishers Lane, Room or use of a covered countermeasure. covered countermeasures to treat, 08N146B, Rockville, MD 20857. Phone This includes serious aggravation of a prevent, or diagnose the disease, calls can be directed to (855) 266–2427. pre-existing condition caused by a condition, or threat specified in the 5 This is a toll-free number. covered countermeasure. declaration.2 Serious injury means serious physical SUPPLEMENTARY INFORMATION: This notice of proposed rulemaking injury. Serious injuries may, in certain I. Public Participation (NPRM) concerns only the circumstances, be considered physical compensation program authorized by or biochemical alterations leading to HHS urges all interested parties to the PREP Act, not the liability physical changes and serious functional examine this regulatory proposal protections set forth therein. abnormalities at the cellular or tissue carefully and share your views, Specifically, the PREP Act authorizes level in any bodily function. As a including data, to support your the Secretary to establish and general matter, only injuries that positions. We must consider all written administer the Countermeasures Injury warranted hospitalization (whether or comments received during the comment Compensation Program (CICP or the not the person was actually period before issuing a final rule. Program) to provide timely, uniform, hospitalized) or injuries that led to a Subject to consideration of the and adequate compensation to certain significant loss of function or disability comments received, the Secretary of individuals who develop serious (whether or not hospitalization was Health and Human Services (the physical injuries or to certain survivors warranted) will be considered serious Secretary) intends to publish a final of individuals who die as a direct result injuries.6 regulation. of the use or administration of a covered The Secretary proposes adding a If you are a person with a disability countermeasure identified in a Smallpox Countermeasures Injury Table and/or a user of assistive technology declaration.3 The Secretary delegated to subpart K of 42 CFR part 110 for who has difficulty accessing this responsibility for establishing and designated covered smallpox document, please see the website: administering the Program to HRSA. countermeasures identified in https://www.hrsa.gov/about/508- The PREP Act authorizes the declarations. The proposed Smallpox resources.html to obtain this Secretary to publish regulations to Countermeasures Injury Table includes information in an accessible format. establish and administratively a list of smallpox countermeasures, Please visit http://www.HHS.gov/ implement the Program. Specifically, proposed time intervals for the first regulations for more information on the PREP Act authorizes the Secretary to symptom or manifestation of onset of HHS rulemaking and opportunities to determine Program eligibility, the injury, and Qualifications and Aids to comment on proposed and existing process to apply for benefits, the Interpretation, which set forth the rules. methods of payments and amounts of definitions and requirements necessary compensation, and the process for II. Background and Purpose to establish the Table injuries. further review of ‘‘Requests for The Table proposed in this NPRM is The Public Readiness and Emergency Benefits’’ submitted by, or on behalf of, limited to covered smallpox Preparedness Act (PREP Act) of 2005, requesters. To be considered for countermeasures. To date, the CICP enacted as Division C of the Department compensation for any serious physical published a Pandemic Influenza of Defense, Emergency Supplemental Countermeasures Injury Table.7 Since Appropriations to Address Hurricanes 1 Section 319F–4(b)(5)(A) of the Public Health the PREP Act mandates the in the Gulf of Mexico, and Pandemic Service Act, as amended (42 U.S.C. 247d– 6e(b)(5)(A)). Influenza Act, 2006 (Public Law 109– 4 2 Section 319F–3(b) of the PHS Act (42 U.S.C 75 FR 63656–63688; 42 CFR part 110. 148), directs the Secretary to establish, 247d–6d(b)). 5 42 CFR 110.3(g). through regulation, a Covered 3 Section 319F–4(a) of the PHS Act (42 U.S.C. 6 42 CFR 110.3(z). Countermeasures Injury Table (Table) 247d–6e(a)). 7 80 FR 47411, August 7, 2015.

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establishment of a Table identifying Act of 2005 (PREP Act), with an determines is: (1) A priority to diagnose, covered injuries that may be presumed effective date of January 24, 2008. The mitigate, prevent harm or treat any to be directly caused by the PREP Act authorizes the establishment biological, chemical, radiological, or administration or use of a covered and administration of the CICP. The nuclear agent identified as a material countermeasure, the CICP may establish CICP’s implementing regulation, at 42 threat by the Secretary of Homeland future Tables for other countermeasures CFR part 110, is based on the SVICP’s Security, or to diagnose, mitigate, relating to threats to health that pose or regulation and provides similar benefits. prevent harm or treat a condition that constitute potential public health On December 9, 2015, the PREP Act may result in adverse health emergencies. The PREP Act authorized Declaration for smallpox consequences or death and may be the Secretary to create Tables for each countermeasures was amended and caused by administering a drug, covered countermeasure identified in a republished (80 FR 76546–76553), biological product, or device against declaration if there is compelling, extending the effective time period to such an agent; (2) is a necessary reliable, valid, medical and scientific December 31, 2022, and deleting countermeasure to protect public health evidence that the countermeasure obsolete language referring to SEPPA. as determined by the Secretary of Health directly causes a covered injury. 14 Definition of Covered Countermeasure and Human Services; and (3) is Declarations have been issued with approved or cleared under the FD&C respect to countermeasures against A ‘‘covered countermeasure’’ is Act 15 or will likely be approved, pandemic influenza A viruses, anthrax, defined in the PREP Act and includes cleared, or licensed within 10 years after botulism, smallpox, acute radiation three categories.8 The first category, the Department’s determination that syndrome, Ebola, Zika, COVID–19, and consisting of ‘‘qualified pandemic or procurement of the countermeasure is nerve agents and certain insecticides epidemic product[s],’’ is defined in appropriate or is authorized for (organophosphorus and/or carbamate). section 319F–3(i)(7) of the PHS Act.9 A emergency use under sections 564 of the In the future, the Secretary may publish qualified pandemic or epidemic product FD&C Act.16 tables in the Federal Register through means a drug or device, as defined in The final category consists of drugs,17 separate amendments to 42 CFR part the Federal Food, Drug, and Cosmetic biologics,18 or devices 19 authorized for 110 addressing additional covered Act (FD&C Act), or a biological product, emergency use in accordance with countermeasures. as defined in the PHS Act 10 that is: (i) section 564, 564A, or 564B of the FD&C The CICP’s Smallpox Manufactured, used, designed, Act. Countermeasures Injury Table is distinct developed, modified, licensed, or To be eligible for the liability from the Smallpox Vaccine Injury Table procured to diagnose, mitigate, prevent, protections of the PREP Act or to receive authorized under the Smallpox treat, or cure a pandemic or epidemic or benefits under the compensation Emergency Personnel Protection Act of to limit the harm such pandemic or provisions of the PREP Act, a covered 2003 (SEPPA) (42 U.S.C. 239 et seq.). epidemic might otherwise cause; (ii) countermeasure must meet one of these The SEPPA, enacted on April 30, 2003, manufactured, used, designed, three categories and must be described authorized the Secretary to establish the developed, modified, licensed, or in a declaration. Smallpox Vaccine Injury Compensation procured to diagnose, mitigate, prevent, Program (SVICP). The SVICP provided treat, or cure a serious or life- Covered Smallpox Countermeasures benefits to certain persons who threatening disease or condition caused The Secretary issued two PREP Act sustained a covered injury as the direct by such a drug, biological product, or declarations concerning smallpox result of the administration of the device; (iii) or a product or technology countermeasures, pursuant to section smallpox vaccine or other covered intended to enhance the use or effect of 319F–3(b) of the PHS Act.20 On countermeasure, and to certain such a drug, biological product, or December 9, 2015, the Secretary individuals who sustained a covered device.11 To qualify as a pandemic or amended the smallpox countermeasures injury as the direct result of accidental epidemic product, a drug, biologic, or declaration issued on October 10, vaccinia inoculation (and/or death device must be: (1) Approved or cleared 2008 21, pursuant to section 319F–3 of benefits to certain survivors of these under the Federal Food, Drug, and the PHS Act 22 to: (1) Include individuals). The SVICP’s implementing Cosmetic Act (FD&C Act) or licensed countermeasures authorized for use regulation was codified at 42 CFR part under the PHS Act; (2) the subject of under section 564A and/or 102, and included a Smallpox Vaccine research for possible use and subject to prepositioned under section 564B of the Injury Table. The SEPPA’s Declaration an exemption under sections 505(i) or FD&C Act; 23 (2) clarify the description Regarding Administration of Smallpox 520(g) of the FD&C Act; or (3) of covered countermeasures; (3) extend Countermeasures, expired on January authorized for emergency use in the effective time period of the 23, 2008, and was not renewed. Vaccine accordance with section 564, 564A, or declaration; (4) reformat the declaration; recipients and accidental vaccinia 564B of the FD&C Act. contacts had 1 and 2 years, respectively, The second category includes 14 42 U.S.C. 247d–6d(i)(1)(B),(c)(1)(B). to file a request for program benefits. ‘‘security countermeasures.’’ A security 15 21 U.S.C. 301 et seq. The SVICP ended on January 23, 2010, countermeasure, as defined in section 16 21 U.S.C. 360bbb–3, 360bbb–3a, 360bbb–3b. and its outmoded regulations were 319F–2(c)(1)(B) of the PHS Act, is a drug 17 As defined in section 201(g)(1) of the FD&C Act rescinded on November 14, 2016. See 81 or device 12, as defined in the FD&C Act, (21 U.S.C. 321(g)(1)). 18 FR 62817–62818. or a biologic product, as defined in the As defined in section 351(i) of the PHS Act (42 PHS Act,13 that the Secretary U.S.C. 262(i)). Relying instead on later-enacted 19 As defined in section 201(h) of the FD&C Act legislation, based on a credible risk that (21 U.S.C. 321(h)). the threat of exposure to variola virus, 8 Section 319F–3(i)(1) of the PHS Act (42 U.S.C. 20 See 73 FR 61869, October 10, 2008, as amended the causative agent of smallpox, 247d–6d(i)(1)). by 80 FR 76546, December 9, 2015.; 42 U.S.C. 9 constitutes a public health emergency, 42 U.S.C. 247d–6d(i)(7). 247d–6d(b). 10 21 U.S.C. 321(g)(1), (h); 42 U.S.C. 262(i). 21 73 FR 61869 (October 10, 2008); https:// the Secretary issued a Declaration (73 11 Section 319F–3(i)(7)(A)(ii) of the PHS Act (42 www.gpo.gov/fdsys/pkg/FR-2008-10-17/pdf/E8- FR 61869–61871) covering smallpox U.S.C. 247d–6d(i)(7)(A)(ii)). 24737.pdf. countermeasures under the Public 12 21 U.S.C. 321(g)(1), (h);42 U.S.C. 262(i). 22 42 U.S.C. 247d–6d. Readiness and Emergency Preparedness 13 21 U.S.C. 321(g)(1), (h);42 U.S.C. 262(i). 23 21 U.S.C. 360bbb–3a and 360bbb–3b.

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(5) modify or clarify terms of the Table presumption for a particular and serious functional abnormalities at declaration; and, (6) republish the countermeasure at this time. This is to the cellular or tissue level in any bodily declaration in its entirety, as reflect that consideration was given function may, in certain circumstances, amended.24 regarding the possibility of Table be considered serious physical Covered countermeasures under the injuries for these covered injuries.’’ According to the preamble to declaration are ‘‘any vaccine, including countermeasures. Claims related to any the CICP Administrative all components and constituent injuries alleged to be caused by these Implementation interim final rule, 42 materials used in the administration of countermeasures will be considered on CFR part 110, serious physical injuries these vaccines, and all devices and their a case-by-case basis. also include ‘‘instances in which there constituent components used in the may be no measurable anatomic or III. Discussion of Proposed Rule administration of these vaccines; any structural change in the affected tissue antiviral; any other drug; any biologic; This NPRM proposes to amend the or organ, but there is an abnormal or any diagnostic or other device to Program’s implementing regulation 29 functional change. For example, many identify, prevent or treat smallpox or and, if adopted, would establish a table psychiatric conditions are caused by orthopoxvirus or adverse events from of injuries resulting from the abnormal neurotransmitter levels in key such countermeasures.’’ 25 Moreover, administration or use of smallpox portions of the central nervous system. these covered countermeasures ‘‘must covered countermeasures. Certain It is possible that certain serious be ‘qualified pandemic or epidemic conditions that are currently not being psychiatric conditions will qualify as products,’ or ‘security countermeasures,’ proposed for inclusion on the Table also serious physical injuries if the or drugs, biological products, or devices are discussed in this NPRM. psychiatric conditions are a authorized for investigational or General Requirement of Serious manifestation of a physical biochemical emergency use as those terms are Physical Injuries or Deaths abnormality in neurotransmitter level or defined in the PREP Act, the FD&C Act, type caused by a covered and the PHS Act.’’ 26 The covered By statute, only serious physical countermeasure. One way of countermeasures subject to this injuries or deaths directly resulting from determining that an abnormal physical declaration that will be included on the the use or administration of a covered change in neurotransmitter level is proposed Table include smallpox countermeasure may be compensable causing the injury would be a clinical vaccines, vaccinia immunoglobulin, under the Program regardless of whether challenge that demonstrates a positive cidofovir, tecovirimat, brincidofovir, the injury is a Table injury or a non- clinical response to a medication that is and smallpox infection diagnostic Table injury. Because the requirement of designed to restore the balance of testing. a serious physical injury applies to all appropriate neurotransmitters necessary Requests for Benefits filed with the for normal function in an injured General Information Program, the Secretary considered this countermeasure recipient.’’ 31 The Secretary proposes a Table for requirement while drafting the proposed Minor injuries do not meet the injuries directly resulting from the use Table included in this NPRM. definition of a serious physical injury. or administration of covered smallpox In general, only injuries or serious For example, covered injuries do not countermeasures identified in the aggravation of injuries that warranted include common and expected skin above-referenced declaration. The hospitalization (whether or not the reactions (such as localized swelling or proposed Table lists serious physical person was actually hospitalized) or that warmth that is not of sufficient severity injuries demonstrated by compelling, led to a significant loss of function or to warrant hospitalization and does not reliable, valid, medical and scientific disability will be considered serious lead to significant loss of function or evidence to be directly caused by the physical injuries.30 It is recognized that disability). Expected minor reactions, administration or use of the covered the term ‘‘disability’’ can be defined in such as headaches and body aches that countermeasures (hereafter referred to many ways, and there are several commonly occur with other types of as ‘‘evidence standard’’).27 Only injuries definitions used by the federal vaccinations, are not considered serious. supported by this evidence standard are government specific to various programs However, if a minor injury leads to a proposed for inclusion on the Table. and services. To provide further clarity serious physical injury, and the minor For each covered countermeasure, the as to the type of disability that would injury was directly caused by a covered proposed Table will include the covered qualify as a serious injury for the countermeasure, the Program may injuries and/or conditions directly Program, under this NPRM, the term compensate the individual for the caused by such countermeasure and the ‘‘disability’’ is defined as ‘‘a physical or serious physical injury. The injury’s applicable time intervals for the first mental impairment that substantially causal link to the countermeasure must symptom or manifestation of onset of limits one or more major life activities be based on compelling, reliable, valid, injuries. The Program’s statute directs of an individual.’’ This definition medical and scientific evidence. that covered injuries presumed to be corresponds with the first listed Therefore, the Program will consider caused by the administration or use of definition of disability in the Americans such claims on a case-by-case basis. a covered countermeasure must be with Disabilities Act, 42 U.S.C. Serious Aggravation of Pre-Existing included on a Table.28 The Secretary 12102(1)(A). This definition was chosen Conditions also proposes to indicate on the Table because it is consistent with the if no injuries or conditions qualify for a Program’s existing authorities and adds Injuries covered under the Program further guidance by using a widely may include serious aggravations of pre- 24 80 FR 76546 (December 9, 2015); https:// accepted definition familiar to the existing conditions if such aggravations www.gpo.gov/fdsys/pkg/FR-2015-12-09/pdf/2015- general public. were caused by a covered 31092.pdf. In addition, pursuant to 42 CFR countermeasure (e.g., any disorder that 25 80 FR 76546, 76552 (December 9, 2015). is proven to the satisfaction of the 26 110.3(z), ‘‘physical biochemical 80 FR 76546, 76552 (December 9, 2015). Secretary to have been made 27 Section 319F–4(b)(5)(A) of the PHS Act (42 alterations leading to physical changes U.S.C. 247d–6e(b)(5)(A)). significantly more severe as the direct 28 Section 319F–4(b)(5)(A) of the PHS Act (42 29 42 CFR part 110. U.S.C. 247d–6e(b)(5)(A)). 30 42 CFR 110.3(z). 31 75 FR 63656, 63661.

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result of the administration or use of the of causation by submitting medical non-Table injuries on a case-by-case covered countermeasure). The serious documentation demonstrating the basis. aggravation of the pre-existing condition covered injury occurred, that it began Injuries Sustained as a Result of the must be supported by compelling, within the time interval specified on the Smallpox Virus reliable, valid, medical and scientific Table after administration or use of a evidence and show a direct causal link covered countermeasure and all other An individual will not have suffered between the aggravation or worsening of applicable Table requirements and a covered injury if a covered the pre-existing condition and the definitions are met. Nevertheless, it may countermeasure is ineffective in countermeasure. The Program will be rebutted if, based on review of the diagnosing, preventing, or treating the consider claims involving serious relevant medical and scientific underlying condition or disease for aggravations of pre-existing conditions evidence, the Secretary determines the which the countermeasure was on a case-by-case basis. Table injury was more likely caused by administered or used, and the other factors and not directly caused by individual sustains an injury caused by Table Time Intervals the countermeasure. the condition or disease and not by the For each covered injury, the proposed covered countermeasure. An injury Table describes the time interval Non-Table Injuries sustained as the direct result of a between the administration or use of the Compensation may be available for disease, health condition or threat to covered countermeasure and the first individuals who: (1) Develop an injury health, for which the Secretary symptom or manifestation of onset of not included on the Table, (2) develop recommended the administration or use injury after the administration or use of an injury that is included on the Table of a covered countermeasure in a the countermeasure. In addition to but the injury began outside the allotted declaration, is not a covered injury. The meeting the requirements of the Table time interval provided by the Table, or injury is not covered because it resulted injury, the symptom or manifestation of (3) develop an injury that does not from the disease itself and not from the onset of injury must have occurred satisfy the definition or requirements administration or use of a covered within the Table time interval. The time included in the Qualifications and Aids countermeasure. For more information, intervals are based on compelling, to Interpretation that accompanies the see 42 CFR 110.20(d). reliable, valid medical and scientific Table with respect to such injury. In Amendments to the Proposed Table of evidence in which nearly all of the cases these cases, the injured countermeasure Injuries of injury are known to be actually recipient does not receive the The Secretary has the discretion to caused by the covered countermeasure. presumption of causation for a Table amend or modify the Table at any time As is the case for non-Table injuries, injury and must demonstrate that the while the Program remains operational. Table injuries not meeting the Table use or administration of the covered For example, the Secretary may amend time intervals may be compensated, on countermeasure directly caused the the Table by adding or removing a case-by-case basis, based on adequate injury. The regulation administratively injuries, modifying the governing time demonstration of compelling, reliable, implementing the Program includes intervals, and/or revising the Table valid, medical and scientific evidence more information about the definitions and requirements. New supporting that the countermeasure had requirements for such an injury.33 For studies and evolving medical and a causal role. example, a temporal association scientific evidence will be reviewed by between the administration or use of a Table Definitions and Requirements the Secretary to determine causal covered countermeasure and onset of The proposed Table also includes relationships between covered the injury (e.g., the injury occurs a Qualifications and Aids to countermeasures and injuries or deaths. certain time after the administration or Interpretation, which set forth the Changes to the Table will be use of the countermeasure) alone is not definitions and requirements necessary implemented as amendments to 42 CFR sufficient to show that an injury is the to establish the Table injuries. For this part 110 and will be published in the direct result of a covered reason, the Table definitions and Federal Register. countermeasure.34 Proof of a causal requirements are part of the Table. To association for the non-Table injury The Table in Effect at the Time a Claim receive compensation for a Table injury, must be based on compelling, reliable, is Filed the individual must meet the time valid, medical and scientific evidence. interval, Table definition, and any other The Table in effect when the Request Table requirements, in addition to the Sequelae (Health Complications) of for Benefits form is filed should be used, other Program requirements. Table and Non-Table Injuries unless another Table is published after the claim is filed that provides greater Presumption Created for Table Injuries A requester may be entitled to benefit to the requester. If a new Table For purposes of this Program, a benefits if the Program determines that or an amendment to an existing Table rebuttable presumption exists that a the sequelae (health complications), would benefit a requester, as described Table injury was directly caused by the including death, resulted from a Table in the following section, the requester administration or use of a covered injury. This is also applicable to a may have an additional opportunity to countermeasure if the first symptom or requester who develops sequelae from a file a Request for Benefits. manifestation of onset of an injury listed non-Table injury, but only if the non- Table injury is shown to be directly Filing Deadlines and Table Additions or on the Table occurred within the Amendments timeframe indicated, and the Table’s caused by a covered countermeasure definitions and requirements are based on compelling, reliable, valid, In accordance with 42 CFR 110.42(f), satisfied. By statute, this presumption medical and scientific evidence. The in the event that the Secretary issues a only applies to Table injuries.32 An Program will consider compensation for new Covered Countermeasures Injury individual may obtain this presumption sequelae that develop from Table and Table or amends a previously published Table, requesters may have an extended 32 Section 319F–4(b)(5)(A) of the PHS Act (42 33 42 CFR 110.20(c). filing deadline based on the effective U.S.C. 247d–6e(b)(5)(A)). 34 42 CFR 110.20(c). date of the Table amendment. An

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extended filing deadline will apply only amendment would not enable such Smallpox Background if the Table amendment enables individuals to establish a Table injury, Smallpox is a highly contagious requesters to establish an injury when they would be subject to the standard they could not establish one previously. disease that may cause fever, a severe filing deadline described in 42 CFR rash, and a high death rate. The variola If the Table proposed in this NPRM is 110.42(a) (e.g., 1 year from the date of adopted, any person who meets the virus causes smallpox disease. Variola administration or use of the covered is a large orthopoxvirus within the Table requirements for a newly listed countermeasure). injury after receiving the smallpox Poxviridae family. Other poxviruses that vaccine would have 1 year from the Eligible requesters have 1 year from infect humans include molluscum effective date of the Table’s adoption to the date of administration or use of a contagiosum, vaccinia (the virus used in 35 file a Request for Benefits. This filing covered countermeasure to file a smallpox vaccine), and monkeypox. deadline applies regardless of whether Request for Benefits. Also, if an injury The variola virus usually enters the the requester previously filed a Request is added to a countermeasure injury body through the respiratory system. for Benefits with the Program. table, then the requester has 1 year from The virus can also enter through the Individuals may seek compensation the effective date of publication of the skin and, rarely, through the eyes, or for one or more injuries stemming from table revision to file a Request for crosses the placenta.36 It then rapidly a single administration of a covered Benefits for that injury. enters the regional lymph nodes. On the countermeasure. However, if It is important to note that the third or fourth day after infection, the individuals previously received additional filing deadline described in virus is circulating in the blood even compensation for an injury through the 42 CFR 110.42(f) is only available to though the infected person may not Program, they may not re-file a claim for persons whose Request for Benefits show symptoms. The virus then spreads compensation if the same injury is later meet the requirements of: (1) A new further into the spleen, bone marrow, added to a Table. Not being able to re- Table or an amendment(s) to a Table; (2) and other lymph nodes. Increased virus file such claims avoids giving the Table time interval(s); (3) Table levels within lymph tissue leads to individuals the opportunity to receive definitions; and (4) any other Table secondary viremia (elevated virus levels additional compensation for the same requirements. In this case, such persons in the bloodstream), which causes fever serious physical injury. However, this and the characteristic smallpox rash. may be eligible for the presumption of does not preclude filing a Request for During the 8th to 12th day after causation. Persons who sustained Benefits for an injury or aggravation of infection, secondary viremia occurs injuries not included on the Table, or an injury, resulting from the subsequent leading to severe illness.37 those who do not meet all of the administration or use of the same type During the first week after the rash of covered countermeasure. It also does requirements for such a Table injury but may prove causation of the injury starts, patients are most infectious when not preclude subsequent Requests for sores in the mouth open and release Benefits for an injury, or an aggravation through other means, will not be afforded an additional 1-year filing large amounts of virus into the saliva. of a pre-existing condition, resulting The ability to pass the infection to deadline based on the Table from the administration or use of a others has been estimated as being amendment. Because the Table different covered countermeasure or a highest from 3 to 6 days after the onset amendment would not enable such different injury from the same of fever.38 The period of infectiousness individuals to establish a Table injury, countermeasure. lasts until all the lesions have scabbed they would be subject to the standard Eligible requesters have one year from over and the scabs have fallen off. the date of administration or use of a filing deadline described in 42 CFR Although, viral particles can be detected covered countermeasure to file a 110.42(a) (e.g., 1 year from the date of in scabs, scabs are considered relatively Request for Benefits. Also, if an injury administration or use of the covered non-infectious, since the viral particles is added to a countermeasure injury countermeasure). are bound in the scab.39 Once the table, then a requester has 1 year from Smallpox Countermeasures Injury Table smallpox infection resolves, the person the effective date of publication of the cannot infect others. table revision to file a Request for The proposed Table lists serious Naturally occurring smallpox virus Benefits for that injury. covered injuries directly caused by It is important to note that the has been eliminated. The absence of covered smallpox countermeasures. additional filing deadline described in endemic smallpox led to the halt of Although the occurrence of many of the 42 CFR 110.42(f) is only available to routine vaccination in the United States persons whose Request for Benefits injuries included on the Table is rare, in 1972.40 In 1980, the World Health relates to a new or amended Table the Secretary is including such injuries Organization declared that the smallpox injury and otherwise meets the on the Table to ensure that people who requirements of: (1) The new Table or are otherwise eligible for benefits and/ 35 Zack S. Moore, Jane F. Seward and J. Michael the amendment(s) to a Table, (2) the or compensation under the Program will Lane, ‘‘Smallpox.’’ Lancet 367; 9508: (2006): 425. 36 Table time interval(s), (3) Table receive the Table’s presumption of Frank Fenner et al. ‘‘Smallpox and its causation. The Table presumption can eradication.’’ World Health Organization, Geneva: definitions, and (4) any other Table (1988): 182. requirements. In this case, such persons be rebutted if the Secretary determines, 37 Fenner et al. ‘‘Smallpox and its eradication.’’ may be eligible for the presumption of based on a review of the relevant 188. causation. Persons who sustained evidence, that an injury meeting the 38 Hiroshi Nishiura and Martin Eichner, Table requirements was more likely ‘‘Infectiousness of smallpox relative to disease age: injuries not included on the new or Estimates based on transmission network and amended Table, or those who do not caused by other factors and not directly incubation period.’’ Epidemiology and Infection meet all of the requirements for such a caused by the smallpox countermeasure. 135, no. 7 (2007): 1147. Table injury but may prove causation of Claims involving injuries that do not 39 Fenner et al. ‘‘Smallpox and its eradication.’’ the injury through other means, will not meet the requirements of the Table may 188. qualify as non-Table injuries and will be 40 Richard B. Kennedy, Inna Ovsyannikova and be afforded an additional 1-year filing Gregory A. Poland, ‘‘Smallpox vaccines for deadline based on the Table reviewed on a case-by-case basis by the biodefense.’’ Vaccine 5; 27 Supplement 4 amendment. Because the Table Program. (November 2009): D73.

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vaccine was essential for the successful Smallpox vaccines are either does not imply that any specific set of global eradication of smallpox virus. replication-competent or replication- qualifications has been met, but instead Even though smallpox no longer deficient. The replication-competent represents the initiation of a series of occurs in nature because of the vaccines are administered via the preliminary interactions between the administration of the smallpox vaccine, intradermal scarification method and FDA and a product sponsor to discuss concern exists that the smallpox virus the virus in the vaccine reproduces potential suitability for EUA could be used as a biological weapon. within the vaccine recipient. This consideration.44 All of the known samples of variola method uses a bifurcated needle that Dryvax, a type of smallpox vaccine, is virus in the world are kept in two punctures the skin multiple times while no longer manufactured or used. It has designated laboratories. However, it is placing a drop of live-attenuated been replaced by Smallpox (Vaccinia) unknown if other samples of the virus vaccinia virus vaccine in the wound Vaccine Live, which was derived from exist outside those in these two created by the needle. This method Dryvax. Smallpox (Vaccinia) Vaccine laboratories. This creates the potential creates a vaccination site. There is a risk Live may cause myocarditis and of an accidental or intentional release of of transferring the vaccinia virus from pericarditis, conditions involving the virus back into the environment and the vaccination site to other parts of the inflammation and swelling of the heart the need for the ability to provide mass individual’s body or to others. This type and surrounding tissues. Most of these vaccination against smallpox. The use of of vaccine also has an increased risk of cases are mild, resolve on their own, smallpox as a biological weapon is a adverse side effects in individuals with and do not have symptoms, but some concern for several reasons. First, much immunodeficiencies or skin disorders. can be very serious. Based on clinical of the population is susceptible to A second type of vaccine involves the studies, myocarditis and/or pericarditis infection because smallpox vaccination use of replication-deficient vaccinia occur in 1 in 175 adults who get this programs have stopped, and thus, the virus. This vaccine contains a live- vaccine for the first time.45 general population is not routinely attenuated virus; and is administered In the Smallpox (Vaccinia) Vaccine given the smallpox vaccine. In addition, subcutaneously; however, the viral Live clinical trial, 7 of the 2,983 first- the virus is infectious via the respiratory agent does not reproduce in human time vaccine recipients were suspected system, requires only a small amount of cells. This reduces the risk of of having myocarditis and/or the virus to cause infection, and is transferring the vaccine to other parts of pericarditis. Three of the 868 first-time transmissible from person to person. the body or to others. Individuals with recipients used the smallpox vaccine Furthermore, the disease has a long certain skin disorders or who are HIV- (Dryvax). No cases of myocarditis and/ asymptomatic incubation period and a infected were included in clinical or pericarditis were reported among high rate of morbidity and mortality. studies, the frequencies of solicited participants who had been previously Also, very few treatments exist, and local and systemic adverse reactions vaccinated with a smallpox vaccine. In experience has shown that the presence among these adults were generally Smallpox (Vaccinia) Vaccine Live of smallpox virus creates havoc and similar to those observed in healthy (replication-competent) clinical trials, panic.41 The ability of individuals to adults. among vaccinees naı¨ve to vaccinia, 8 The current Food and Drug travel rapidly over great distances by air cases of suspected myocarditis and Administration (FDA) approved increases the risk of rapid dissemination pericarditis were identified across both smallpox vaccines contain live vaccinia of the disease. Additionally, the impact treatment groups, for a total incidence viruses that protect against smallpox of smallpox on the general population rate of 6.9 per 1,000 vaccinees (8 of disease. They do not contain variola would be greater today because the 1,162). The rate for the Smallpox virus, the causative agent of smallpox. prevalence of immunosuppressed (Vaccinia) Vaccine Live (replication- The U.S. Government has three different individuals is higher. This includes competent) treatment group were smallpox vaccines available in the U.S. people living with Human similar: 5.7 (95 percent CI: 1.9–13.3) per Strategic National Stockpile (SNS): Immunodeficiency Virus (HIV) and 1,000 vaccinees (5 of 873 vaccinees) and Smallpox (Vaccinia) Vaccine Live ® individuals taking certain medications for the Dryvax group 10.4 (95 percent (replication-competent), Smallpox and that suppress their immune systems to CI: 2.1–30.0) per 1,000 vaccinees (3 of Monkeypox Vaccine, Live, Non- ameliorate specific medical 289 vaccinees). No cases of myocarditis replicating (replication-deficient), and conditions.42 and/or pericarditis were identified in APSV (Aventis Pasteur Smallpox 1,819 previously vaccinated subjects.46 Smallpox Vaccines Vaccine) (replication-competent). Commonly observed side effects Smallpox (Vaccinia) Vaccine Live and After confirmation of one or more included itching, sore arm, fever, Smallpox and Monkeypox Vaccine, human smallpox cases, the primary headache, body ache, mild rash, and Live, Non-replicating are licensed by the 47 strategy for controlling the spread of fatigue. FDA, whereas APSV, which is an disease involves the use of the smallpox investigational vaccine and is not vaccine in combination with other Recommendations and Reports 64(2): (Feb 20, licensed by the FDA, would be made surveillance and containment activities. 2015): 11. available under an Investigational New 44 U.S. Department of Health and Human As demonstrated during the eradication Drug (IND) or under Emergency Use Services, Food and Drug Administration, campaign, the immune response Authorization (EUA). Although an EUA ‘‘Emergency Use Authorization of Medical Products generated by smallpox vaccination is and Related Authorities, Guidance for Industry and cannot be issued until an emergency one of the most effective tools for Other Stakeholders,’’ January 2017; https:// determination and declarations are in www.fda.gov/media/97321/download. halting the transmission of smallpox. place, a product sponsor can submit and 45 ‘‘ACAM2000 (smallpox vaccine): Questions the FDA can review product data as pre- and answers.’’ United States Food and Drug 41 Tara O’ Toole, Michael Mair and Thomas V. Administration, (March 23, 2018): 2. Inglesby, ‘‘Shining light on dark winter.’’ Clinical EUA submissions before a formal EUA 46 ACAM2000, Smallpox (vaccinia) vaccine, live. 43 Infectious Disease 34(7) (April 1, 2002): 972. request.’’ Such a pre-EUA submission Package Insert, Emergent Product Development. 42 Louisa E. Chapman, Gina T. Mootrey and Linda Revised 03/2018, https://www.fda.gov/media/ J. Neff, ‘‘Vaccination against smallpox in the post 43 Brett W. Petersen et al. ‘‘Clinical guidelines for 75792/download. eradication era.’’ Clinical Infectious Disease 15;46 smallpox vaccine use in a post-event vaccination 47 Petersen et al. ‘‘Clinical guidelines for Supplement 3: (March 2008): S155. program.’’ Morbidity and Mortality Weekly Report: smallpox.’’ 7.

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Another smallpox vaccine available and eczema vaccinatum.49 APSV would Smallpox Vaccine in Pregnancy Registry for use is Smallpox and Monkeypox be used if there is a shortage of showed that women vaccinated during Vaccine, Live, Non-replicating. This Smallpox (Vaccinia) Vaccine, Live and pregnancy with replication-competent vaccine uses a modified Vaccinia of Smallpox and Monkeypox Vaccine, vaccine did not have higher-than- Ankara virus in its composition. Live, Non-replicating. expected rates of pregnancy loss, Smallpox and Monkeypox Vaccine, Smallpox vaccination for pre- preterm birth, or birth defects compared Live, Non-replicating is administered exposure prophylaxis using replication- with pregnant women not receiving the via subcutaneous injection. The vaccine competent vaccine is contraindicated in smallpox vaccine. Most of the women in virus is replication-deficient; therefore, people with severe immunodeficiency the registry (77 percent) were vaccinated Smallpox and Monkeypox Vaccine, (such as individuals undergoing bone near the time of conception, before Live, Non-replicating does not present a marrow transplantation or those with results of a standard pregnancy test risk of secondary transmission. This primary or acquired immunodeficiency would have been positive. No cases of vaccine requires two doses, 28 days requiring isolation). A vaccine fetal vaccinia were identified. A apart. Clinical trials evaluating the containing replication competent virus retrospective cohort study employing safety of Smallpox and Monkeypox should be used with caution in the information from Department of Defense Vaccine, Live, Non-replicating found following groups: (1) Anyone who is databases examined outcomes among that among the smallpox vaccine-naı¨ve allergic to the vaccine or any of its 31,420 infants born to active-duty subjects, serious adverse events (SAEs) components; (2) anyone younger than military women during 2003–2004. were reported for 1.5 percent of 12 months of age; (3) people who have, There were 7,735 infants born to women Smallpox and Monkeypox Vaccine, or have had, certain skin conditions who had previously been vaccinated Live, Non-replicating (replication- (especially eczema or atopic dermatitis); against smallpox. An additional 672 deficient) recipients and 1.1 percent of (4) people who have been diagnosed as infants were delivered by women who placebo recipients. Among the smallpox having a heart condition, or having had been vaccinated for smallpox in the vaccine-experienced subjects enrolled three or more known major cardiac risk first trimester of pregnancy. Analysis in studies without a placebo factors; (5) women who are pregnant or revealed that maternal smallpox comparator, SAEs were reported for 2.3 planning to become pregnant within 4 vaccination during pregnancy was not percent of Smallpox and Monkeypox weeks after vaccination; (6) persons associated with preterm or extreme Vaccine, Live, Non-replicating with congenital or acquired immune preterm delivery.53 Maternal smallpox (replication-deficient) recipients. Across deficiency disorders (e.g., HIV/AIDS, vaccination during the first trimester all studies, a causal relationship to leukemia, lymphoma); and (7) persons was not significantly associated with Smallpox and Monkeypox Vaccine, using corticosteroid eye drops. Within overall birth defects.54 Live born infants Live, Non-replicating (replication- these identified groups, the risk of who experience a covered injury as the deficient) could not be excluded for four vaccination must be weighed against the direct result of a covered SAEs, all non-fatal, which included risk of potential smallpox virus countermeasure administered to or used 50 Crohn’s disease, sarcoidosis, extraocular exposure. by a pregnant woman, such as a muscle paresis and throat tightness.48 Smallpox vaccination using smallpox vaccine, are eligible for APSV, sometimes called ‘‘WetVax’’ replication-deficient vaccine has no compensation from the CICP.55 was manufactured from 1956 to 1957. It absolute contraindication for Serious adverse reactions to smallpox 56 is a replication-competent vaccine. It administration, it should be noted, vaccination can occur. It has been has been maintained in cold storage however, that this vaccine has not been estimated that during mass vaccinations studied in individuals less than 18 years campaigns with replication-competent since it was produced. It was 51 manufactured from the same vaccinia old. Warning and precautions for this vaccines, 1 to 2 deaths and hundreds of virus strain as Dryvax. It contains live product include: Severe allergic complications severe enough to require vaccinia virus without preservatives or reactions; altered immunocompetence hospitalization occurred for every 1 antibiotics. Testing of samples indicate (‘‘Immunocompromised persons, million people vaccinated. Estimates that it is safe to use from a bioburden including those receiving from the medical and scientific (presence of bacteria within the sample) immunosuppressive therapy, may have literature indicate that if the current a diminished immune response.’’) and perspective. The vaccine is population of the United States was limitations of vaccine effectiveness.52 administered in a single dose with a vaccinated with the replication- In a smallpox bioterrorism emergency, competent smallpox vaccine, hundreds bifurcated needle and the appropriate pregnant women at high risk of number of punctures at the vaccination of deaths and thousands of exposure may be advised to be hospitalizations could occur.57 Statistics site. The preferred site of vaccination is vaccinated, since the risk of death and on the upper arm over the deltoid from the 1960s and 1970s documented serious illness from smallpox in that the rate of serious complications after muscle. Once appropriately diluted, situation would likely outweigh risks to each vial contains approximately 500 receipt of the smallpox vaccine. These the fetus from fetal vaccinia caused by rates may be higher today as more doses of vaccine. It has a similar side replication-competent vaccines. A study effect profile as Dryvax and a safety of 376 women enrolled in the National 53 Margaret Ryan and Jane F. Seward, Pregnancy, profile similar to Dryvax and Smallpox birth, and infant health outcomes from the national (Vaccinia) Vaccine Live. It is thought to 49 Petersen et al. ‘‘Clinical guidelines for smallpox vaccine in pregnancy registry, 2003–2006. be 95 percent effective when used as smallpox.’’ 10. Clinical Infectious Disease 2008:46 (Suppl 30): pre-exposure prophylaxis. The most 50 ACAM2000, Smallpox (vaccinia) vaccine, live. S222. frequently encountered serious Package Insert, Emergent Product Development. 54 Margaret Ryan, et al. Evaluation of preterm 51 births and birth defects in liveborn infants of US complications of APSV include: JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Non-replicating. Package Insert, Bavarian military women who received smallpox vaccine. encephalitis, progressive vaccinia (PV), Nordic A/S. Aug 2019. https://www.fda.gov/media/ Birth Defect Research (Part A): Clinical and 131078/download. Molecular Teratology 82:2008, 533–539. 48 JYNNEOS (Smallpox and Monkeypox Vaccine, 52 JYNNEOS (Smallpox and Monkeypox Vaccine, 55 42 CFR 110.3(n)(3). Live, Non-replicating. Package Insert, Bavarian Live, Non-replicating. Package Insert, Bavarian 56 Petersen et al. ‘‘Clinical guidelines for Nordic A/S. Aug 2019. https://www.fda.gov/media/ Nordic A/S. Aug 2019. https://www.fda.gov/media/ smallpox.’’ 131078/download. 131078/download. 57 Kennedy et al. ‘‘Smallpox Vaccines,’’ D75.

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individuals are immunocompromised, Injuries Associated With Both Smallpox vaccines are currently immunosuppressed or Replication-Competent and Replication- prepared using various techniques that immunodeficient. However, the Deficient Smallpox Vaccines result in the final products containing a licensure of a vaccine with an improved limited quantity of foreign protein that A. Anaphylaxis safety profile is expected to decrease can induce immediate hypersensitivity serious complications resulting from Anaphylaxis is a single discrete event reactions in some persons with severe smallpox vaccination. Earlier studies that presents as a severe and potentially protein mediated allergies. It is primarily sought information only life threatening multi-organ reaction, established that smallpox vaccines can regarding what was already known to particularly affecting the skin, cause anaphylaxis similar to that seen in occur because of the administration of respiratory tract, cardiovascular system, other vaccines.62 63 the smallpox vaccine. It is possible that and the gastrointestinal tract. In an A 1994 IOM Report supports the previously unrecognized adverse anaphylactic reaction, an immediate causal association between vaccines and reactions will become more evident reaction generally occurs within a biologic gradient of host responses, with improved surveillance. minutes after exposure, and in most ranging from true anaphylaxis to milder cases, the individual develops signs and Minor adverse events following forms of hypersensitivity reactions. symptoms within 4 hours after exposure smallpox vaccination occur.58 These Biological gradient refers to the to the antigen (substance causing the include tenderness and erythema observation of a spectrum of responses reaction). The immediate reaction leads (redness) at the injection site and other from mild to severe. In the case of to a combination of skin rash, mucus localized reactions. With replication- hypersensitivity reactions, the reported membrane swelling, leakage of fluid competent vaccines, minor reactions spectrum after the vaccine runs from from the blood into surrounding tissues, also include allergic reactions to tape mild skin manifestations to chest and restriction of the air passages in the adhesives and ‘‘robust takes.’’ ‘‘Robust throat tightness and cardiovascular lungs with tissue swelling, and takes’’ are local reactions that are larger events to full blown anaphylaxis. The gastrointestinal symptoms that can lead than expected and generally greater than to shock, organ damage, and death if not IOM also stated that the onset of 7.5 centimeters (cm), and are promptly treated. Death, if it occurs, anaphylaxis generally occurs within a accompanied by some or all of the 64 usually results from airway obstruction few hours of exposure. Consistent following signs and symptoms: caused by laryngeal edema (throat with the time interval for the first Erythema, induration (firmness of the swelling) or bronchospasm and may be manifestation of anaphylaxis after skin extending beyond the vaccination associated with cardiovascular vaccines covered by the National site), tenderness and warmth in the collapse.59 Vaccine Injury Compensation Program absence of secondary cellulitis (a Anaphylaxis may occur following and the CICP’s Pandemic Influenza bacterial infection of the skin). Robust exposure to allergens from a variety of Countermeasure Injury Table, the takes are not generally considered a sources including food, aeroallergens, Secretary proposes an onset interval for Table injury. In addition to localized insect venom, drugs, and the first symptom or manifestation of 0– reactions, systemic reactions such as immunizations. Most treated cases 4 hours for anaphylaxis to be covered ° fever of at least 100 F, body aches, resolve without additional under the proposed Table. muscle pain, and local enlargement of complications. Anaphylaxis can be due Based on the nature and timing of the lymph nodes can occur and have to an exaggerated acute systemic anaphylaxis, and the medical and been associated with replication- hypersensitivity reaction. It is not an scientific literature, the Program’s competent vaccines. initial episode of a chronic condition, evidence standard has been met, and The vaccinia virus in the replication- such as chronic hives. anaphylaxis is proposed for inclusion competent smallpox vaccines is live and Anaphylaxis following immunization on the Table because it is a serious can be transmitted to other parts of the is a rare occurrence with estimates in physical injury that may be directly body of the vaccine recipient. For the range of 1–10 per 1 million doses caused by the administration or use of purposes of this NPRM, the term distributed, depending on the vaccine either the replication-competent or ‘‘vaccination’’ refers to the studied.60 In 2003, the Institute of replication-deficient smallpox vaccine. administration and receipt of the Medicine (IOM) reported that evidence In rare cases of acute anaphylaxis, vaccinia virus through the smallpox favors acceptance of a causal initial symptoms of the immediate vaccine and not through contact, relationship between certain vaccines reaction may present up to 12 hours whereas, the term ‘‘inoculation’’ refers and anaphylaxis based on case reports after exposure. A slow evolving late to transmission of, and subsequent and case series. The IOM reported that phase hypersensitivity reaction is infection with, the vaccinia virus causality could be inferred with possible, with an onset that usually through a means other than smallpox reasonable certainty based on one or begins 4–8 hours after the immediate vaccination. Autoinoculation occurs more case reports because of the unique reaction ends. The medical literature when vaccine recipients touch their nature and timing of anaphylaxis contains reports of late phase onset up vaccination site before it has healed and following vaccine administration and then touch another part of their body. provided there is an absence of in infancy.’’ The National Academies Press, (2003): 61 Accidental or inadvertent, person-to- alternative causes. 31. person inoculation occurs when a 62 Joanne Cono, Christine G. Casey and David M. person or the vaccine recipient touches 59 The Brighton Collaboration Anaphylaxis Bell, ‘‘Smallpox vaccination and adverse reactions. a vaccination site before it has healed Working Group, ‘‘Anaphylaxis: Case Definition and Guidance for clinicians.’’ Morbidity and Mortality Guidelines for Data Collection, Analysis, and Weekly Report, 52(RR04) (February 21, 2003): 2. and then touches another person. Presentation of Immunization Safety Data,’’ 63 Werner J. Pichler et al. ‘‘Drug hypersensitivity The proposed Table lists the Vaccine, Aug. 2007; 5676. reactions: pathomechanism and clinical following injuries for the smallpox 60 Jens U. Ruggeberg et al. ‘‘Anaphylaxis: case symptoms.’’ Medical Clinics of North America 94, vaccines. definition and guidelines for data collection, (July 2010): 646. analysis, and presentation of immunization safety 64 Institute of Medicine, ‘‘Adverse events data.’’ Vaccine. (August 2007): 5676. associated with childhood vaccines evidence 58 ACAM2000, Smallpox (vaccinia) vaccine, live. 61 Institute of Medicine, ‘‘Immunization safety bearing on causality.’’ The National Academies Package Insert, Emergent Product Development. review vaccination and sudden unexpected death Press, (1994): 22.

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to 72 hours later.65 The late phase Injuries Associated With Only cells resulting in a localized lesion.75 reaction results from a different Replication-Competent Smallpox This can result in a typical local skin immunologic mechanism of action. The Vaccines reaction in a naı¨ve (first-time) vaccine recipient composed of a papule, which late phase reaction is part of a biphasic A. Skin Reactions reaction. It is possible for the first develops 3 to 4 days post-vaccination. immediate hypersensitivity reaction to Certain skin reactions are associated The papule then goes on to mature into be relatively mild, unrecognized, or not with the administration of replication- a vesicle and a pustule over the next 4 observed. There may be unusual cases competent smallpox vaccines. These to 5 days. The vaccine lesion is in which the immediate reaction is include: (1) Significant local skin generally at its maximum size by day 8 reaction, (2) Stevens-Johnson syndrome/ post-vaccination. The primary lesion is delayed and/or cases that the immediate toxic epidermal necrolysis (SJS/TEN), surrounded by erythema and reaction is not recognized, with the first (3) inadvertent autoinoculation, (4) inflammation, and regional apparent manifestation occurring in the eczema vaccinatum, (5) generalized lymphadenopathy is generally present. late phase. These unusual cases do not vaccinia, and (6) progressive vaccinia, The scab formed by the healing pustule meet the requirements to be considered previously termed ‘‘vaccinia separates by day 21 post-vaccination. table injuries, and will be evaluated on necrosum.’’ 67 Widespread skin The cutaneous reaction in individuals a case-by-case basis based on the reactions are larger than a simple skin being revaccinated may be reduced in Program’s evidence standard. reaction and include two groups. The severity or entirely absent. In previously B. Vasovagal Syncope first group includes significant skin immunized individuals who fail to reactions (such as SJS/TENS) and other develop a skin response with the second Vasovagal syncope is a temporary loss nonspecific post-vaccination rashes immunization, no additional smallpox of consciousness (fainting) and postural with lesions that are thought to be free immunizations are required.76 tone, which includes a reflex drop in of the vaccinia virus. The second group Cono et al. found that approximately blood pressure and may be triggered by includes adverse reactions thought to be 10 percent of first time vaccinees will go an event associated with pain or caused by replicating vaccinia virus on to develop a large vaccination reaction, defined as a reaction greater anxiety. This reaction is known to occur recovered from skin lesions, which can than 10 cm in diameter at the site of the when a vaccine is administered with a be associated with risk for inoculation. This is a normal variant needle which pierces the skin. Some autoinoculation or contact transmission.68 69 70 71 72 73 within the population.77 people may experience jerking In an examination of the data movements after losing consciousness, 1. Significant Local Skin Reaction generated in the most recent mass which generally are not seizures. A significant local skin reaction is, for smallpox vaccination program In its 2012 report, Adverse Effects of purposes of the Table, an unexpected completed in the U.S. with HHS and the Vaccines, the IOM concluded, based on and extreme response to the inoculation U.S. Department of Defense (DoD) in mechanistic evidence (mechanism of of the vaccinated person. The expected 2003 and 2004, using replication- action), that the evidence convincingly onset of this injury is the initial skin competent vaccine, significant local supports a causal relationship between lesion at the smallpox vaccination or skin reactions leading to hospitalization 78 the injection of a vaccine and vasovagal inoculation site. The replication- were not identified. Of the nearly syncope. Vasovagal syncope after competent smallpox vaccine is 770,000 individuals (both first time and revaccinated) vaccinated during this vaccination is usually not associated administered through a multiple program, there were no reported cases of with serious injuries; however, some puncture technique known as local skin reaction requiring cases of vasovagal syncope will result in scarification. The dose of vaccine is placed on a needle, which is then hospitalization. The improved pre- serious injury related to physical trauma screening of smallpox vaccine recipients from an associated fall or other related penetrated multiple times into the skin, commonly, in the upper arm.74 Other is thought to have reduced the accidents. incidence of significant local skin sites for vaccine administration may be 79 Based on a review of the medical and selected utilizing this same technique. reactions. In the 2003 Grabenstein and scientific literature, the Program’s The vaccinia virus in the vaccine Winkenwerder study, the data indicates evidence standard has been met, and replicates and causes damage in the vasovagal syncope may be a serious that 16 of 450,000 military patients vaccinated were hospitalized due to the physical injury that may be directly 67 Aysegul Nalca and Elizabeth E. Zumbrun, caused by the administration or use of ‘‘ACAM2000: The new smallpox vaccine for United uncertainty of the communicability of any injected smallpox vaccine.66 Since States strategic national stockpile,’’ Drug Design, their skin conditions after receiving the Development and Therapy 4. (2010): 76. replication-competent smallpox most cases of vasovagal syncope occur 68 Cono et al. ‘‘Smallpox vaccination and adverse within 1 hour of vaccination, syncope is reaction.’’ 2. 75 Xiaolin Tan et al. ‘‘Failure of the smallpox 69 proposed to be added to the Table with Cono et al. ‘‘Smallpox vaccination and adverse vaccine to develop a skin lesion in vaccinia virus- an onset interval for the first symptom reactions.’’ 3. naı¨ve individuals is related to differences in 70 Lane and Goldstein, ‘‘Adverse Events.’’ 191– or manifestation of 0–1 hour after antibody profiles before vaccination, not after.’’ 192. Clinical and Vaccine Immunology 19(3) (March vaccination with the injected smallpox 71 Kent A. Sepkowitz, ‘‘How contagious is 2012): 418. vaccine. vaccinia?’’ New England Journal of Medicine 348(5) 76 ACAM2000, Smallpox (vaccinia) vaccine, live. (January 30, 2003): 443–445. Package Insert, Emergent Product Development. 72 Vincent A. Fulginiti et al. ‘‘Smallpox 77 Cono et al. ‘‘Smallpox vaccination and adverse vaccination: a review, part II. Adverse events.’’ reaction.’’ 5. Clinical Infectious Disease 37 (July 15, 2003): 252. 78 Gregory A. Poland, John D. Grabenstein and 73 Ellen R. Wertheimer et al. ‘‘Contract John M. Neff, ‘‘The US smallpox vaccination 65 Ruggeberg et al. ‘‘Anaphylaxis: case definition transmission of vaccinia virus from smallpox program: a review of a large modern era smallpox and guidelines.’’ 5677. vaccinees in the United States, 2003–2011.’’ vaccination implementation program.’’ Vaccine 23 66 Institute of Medicine, Adverse effects of Vaccine 30. (2012): 986. (February 4, 2005): 2079. vaccines: Evidence and causality. (Washington, DC 74 Richard B. Kennedy et al. Vaccines. 79 Poland et al. ‘‘The US smallpox vaccination The National Academies Press, 2012): 18. (Philadelphia: Elsevier-Saunders, 2013): 730. program.’’ 2081.

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vaccine. After additional evaluation, directly caused by the use of the 1–2 people per million, per year. SJS/ each patient was returned to duty. The replication-competent smallpox TEN is most commonly triggered by authors also describe 36 cases of vaccine. As explained above, the medication, but it is also seen in suspected mild generalized vaccinia; expected time interval between individuals experiencing infections each of these patients were treated and exposure and onset of injury for the first with Mycoplasma pneumoniae and released. Of these 36 patients, nine were symptom or manifestation is 1–21 cytomegalovirus. In many cases, no hospitalized. These hospitalizations days.84 cause of SJS/TEN is ever identified.90 were attributed to providers who were A Table injury in a recipient requires Although rare, generalized seeing smallpox vaccinated patients for sufficient evidence in the medical hypersensitivity reactions have been the first time being overly cautious. records of the occurrence of a significant documented with the use of live Each of these patients were treated and local skin reaction at the vaccination or attenuated vaccines, such as the returned to duty. A single service inoculation site. The presence of a scar replication-competent smallpox member developed erythema resulting from the significant local skin vaccine, as the body reacts to the multiforme major after receiving reaction would not be considered a presence of an identified foreign multiple vaccines. This was seen as a Table injury unless the scar is of protein.91 92 93 possible reaction to the replication- sufficient severity to warrant SJS/TEN frequently begins with flu- competent smallpox vaccine.80 hospitalization or lead to a significant like symptoms. Shortly thereafter, the A revaccination program that loss of function or disability. skin begins to blister and peel creating painful open areas on the skin, mouth, occurred in Israel in 2002 and 2003 2. SJS/TEN provided replication-competent airways, and potentially the urinary smallpox vaccinations to 21,000 first SJS and TEN, are acute tract and genitals. In SJS/TEN, mucosal responders and utilized a different hypersensitivity reactions that affect involvement generally predominates. vaccine strain than the one used in the skin, mucus membranes, and sometimes Mucosal lesions generally occur at more U.S. Many of the vaccine recipients internal organs (systemic toxicity). As than one location and manifest as experienced local swelling and pain. mentioned in the previous section, the painful lesions in sites, such as the However, only one individual was terms Erythema Multiforme (EM) and mouth or eyes. Skin rash or lesions in hospitalized with a diagnosis of SJS have been historically linked to TEN SJS/TEN usually consist of red raised cellulitis at the injection site.81 and are often confused by clinicians areas, blisters, and ulcerations. Open The severity of adverse reactions even today. It is now recognized that areas created by SJS/TEN can lead to EM is a different disease from SJS and fluid loss and make the person following vaccination can vary based 102 upon factors such as the immune status TEN. Although SJS and TEN were susceptible to infection. Because of the of the individual and a positive or once thought to be separate conditions, damage that occurs to the skin and negative history of past exposure to the they are now considered part of a mucus membranes, SJS/TEN is smallpox vaccine. Typically, those with continuum. SJS is on the less severe end considered a life threatening condition. a potentially higher level of immunity, of the spectrum and TEN represents the Serious complications of SJS/TEN more severe end.85 SJS/TEN is the most because of previous exposure to the include pneumonia, sepsis, shock, commonly used term to refer to the vaccine, may develop a reduced multiple organ failure, and death. spectrum of conditions that include SJS, response to revaccination. Vaccination Approximately 10 percent of SJS/TEN overlap, and TEN. The site lesions generally resolve with the individuals with SJS/TEN will die from difference between SJS, SJS/TEN 94 separation of the overlaying scab within the condition. For those who survive overlap, and TEN is defined by the 21 days post-vaccination.82 This 21-day SJS/TEN, the potential long-term degree of skin detachment. SJS is period is the expected timeframe of a complications include skin color defined as skin involvement of less than normal immune response and the time changes, skin and mucosal dryness, 10 percent. TEN is defined as skin in which reactions associated with the excessive sweating, hair loss, impaired involvement of greater than 30 percent. vaccine should have occurred and been taste, difficulty urinating, and genital SJS/TEN is defined as overlap of 10–30 resolved.83 abnormalities. Some individuals percent skin involvement.86 For the Skin reactions that occur because of develop chronic dry eye leading to purposes of the Table, the term SJS/TEN receiving the replication-competent photophobia (light sensitivity) and will be used to refer to the SJS and TEN 95 smallpox vaccine are generally self- vision impairment. disease spectrum, consistent with its limiting and resolve without A 1968 survey identified 48 cases of use in recent scientific articles.87 88 89 intervention. Minor scarring or minor EM among 572 patients identified with SJS/TEN is a rare condition that affects local reactions do not constitute a Table injury. A robust take does not constitute 90 National Institutes of Health, U.S. National 84 Kennedy et al. ‘‘Smallpox and vaccinia.’’ 730. Library of Medicine, ‘‘Stevens-Johnson a Table injury. 85 National Institutes of Health, U.S. National syndrome.’’1. Based on a review of the medical and Library of Medicine, ‘‘Steven-Johnsons syndrome/ 91 Adena E. Rosenblatt and Sarah L. Stein, scientific literature, the Program’s toxic epidermal necrolysis.’’ (September 10, 2019): ‘‘Cutaneous reactions to vaccines.’’ Clinics in evidence standard has been met, and 1–2. Dermatology 33(3). (2015): 327. significant local skin reactions are 86 Marianne Lerch et al. ‘‘Current Perspectives on 92 J. Michael Lane et al. ‘‘Deaths attributed to Stevens-Johnson syndrome and Toxic Epidermal smallpox vaccinations, 1959 to 1966, and 1968.’’ serious physical injuries that may be Necrolysis.’’ Clinical Reviews in Allergy & Journal of the American Medical Association 212(3) Immunology. Feb 2018;54(1):147–176. (April 20, 1970): 441. 80 John D. Grabenstein and William 87 Roni P. Dodiuk-Gad et al. ‘‘Stevens-Johnson 93 Ashish Chopra et al. ‘‘Stevens-Johnson Winkenwerder, ‘‘US Military smallpox vaccination syndrome and Toxic Epidermal Necrolysis: An syndrome after immunization with smallpox, program experience.’’ Journal of the American Update.’’ American Journal of Clinical anthrax and tetanus vaccines.’’ Mayo Clinic Medical Association 289(24) (June 25, 2003): 3280. Dermatology. Dec 2015:16(6):475–493. Proceedings 79(9) (September 2004): 1193. 81 Emilia Anis et al. ‘‘Smallpox revaccination of 88 National Institutes of Health, U.S. National 94 National Institutes of Health, U.S. National 21,000 first responders in Israel: lessons learned.’’ Library of Medicine, ‘‘Stevens-Johnson syndrome.’’ Library of Medicine, ‘‘Stevens-Johnson syndrome.’’ International Journal of Infectious Disease 13 1. 1. (August 6, 2009): 406. 89 Lerch et al. ‘‘Current Perspectives on Stevens- 95 National Institutes of Health, U.S. National 82 Lane et al. ‘‘Adverse Events.’’ 190. Johnson syndrome and Toxic Epidermal Library of Medicine, ‘‘Stevens-Johnson syndrome.’’ 83 Kennedy et al. ‘‘Smallpox and vaccinia.’’ 730. Necrolysis.’’ 147–176. 1.

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adverse reactions to the replication- 3. Inadvertent Autoinoculation (IA) information regarding the rate of competent smallpox vaccine; however, (Self-Inoculation) hospitalization.112 it was noted that this may actually be an Unintentional transfer of replication- In the 2002–2003 Israeli replication- under representation of the actual total competent vaccinia virus, which competent smallpox immunization number of SJS cases.96 At the time of the includes transfer from the vaccination effort to revaccinate 21,000 first study, EM and SJS were considered site to elsewhere on the vaccine responders, there were 221 identified synonyms for the same condition or recipient’s body, is called inadvertent cases of IA. This represents a 1 percent conditions on the same spectrum of autoinoculation (IA) or self-inoculation. incident rate within this group of vaccine recipients. The study did not disease. The United States Armed IA is the most common adverse event provide details regarding the extent of Forces vaccinated 450,293 of its associated with the smallpox vaccine.106 the IA, and although some individuals members from December 2002, to May Smallpox vaccine recipients or contacts can transfer replication- were hospitalized as a result of 2003, and reported one case of severe receiving vaccines, the article does not 97 competent vaccinia virus to their hands EM, defined as SJS, during this period. make clear if these hospitalizations were or fomites (inanimate objects that carry 113 Based on a review of the medical and infection), which become a source for the result of IA or other causes. Based on a review of the medical and scientific literature, the Program’s infection elsewhere on the body. The scientific literature, the Program’s evidence standard has been met, and Program does not cover injuries caused evidence standard has been met, and IA SJS/TEN is a serious physical injury that by the transfer of the vaccinia virus to is a serious physical injury that may be may be directly caused by the use of the individuals who are not primary directly caused by the use of the replication-competent smallpox vaccine recipients. Other than ocular replication-competent smallpox vaccine.98 For SJS/TEN to be a Table (eyes), the most common sites are the vaccine. Therefore, IA is proposed to be injury, both skin and mucus membrane face, nose, mouth, lips, genitalia, and added to the Table with an onset rash or lesions must be present. Two or 107 anus. Lesions at IA sites progress interval for the first symptom or more mucosal sites must be involved through the same stages (e.g., papular, manifestation of onset of 1–21 days for and the distribution of the rash must be vesicular, pustular, crusting, and scab) the first symptom or manifestation to 99 100 widespread. The proposed onset as the vaccination site. When IA occurs occur after vaccination since the live interval for the first symptom or greater than 5 days post-vaccination, the vaccinia virus can be transferred from manifestation is 4–28 days after developing immune response might the vaccination site to another location vaccination. The earliest time of onset, reduce the lesions and their progression. on the vaccine recipient’s body at any 4 days post-vaccination, is consistent Persons at highest risk for IA are time during this period. By day 21 post- with other conditions that cause SJS/ children ages 1–4 years and those with vaccination, the vaccination site should TEN.101 102 The 28-day mark represents disruption of the epidermis, such as be healed, and the scab should have 108 the point at which any immune abrasions and burns. become dislodged and fallen Ocular vaccinia infections result from response in the form of SJS/TEN would off.114 115 116 117 For the purpose of this the transfer of vaccinia from the vaccine have occurred.103 104 105 regulation, the inadvertent or site or other lesion containing vaccinia intentional inoculation of other persons to or near the eye. Infections can be 96 by the vaccine recipient is not J Michael Lane et al. ‘‘Complications of clinically mild to severe and can lead to smallpox vaccination, 1968* National Surveillance considered a covered injury. Only 109 110 in the United States.’’ The New England Journal of vision loss. individuals who were administered the Medicine 281 (22) (November 27, 1969): 1205. IA was a frequently reported smallpox vaccine will be eligible for 97 Chopra et al. ‘‘Stevens-Johnson syndrome.’’ complication of early smallpox benefits.118 1196. vaccination programs. Proper adherence 98 Rosenblatt et al. ‘‘Cutaneous Reactions to to aseptic technique with dressing 4. Generalized Vaccinia Vaccinations,’’ 327. changes, hand washing, and the use of Generalized vaccinia (GV) is caused 99 Chopra et al. ‘‘Stevens-Johnson Syndrome after hand sanitizers with greater than 60 by the systemic spread of replication- Immunization with Smallpox, Anthrax, and percent alcohol content help to reduce Tetanus Vaccines.’’ 1195. competent vaccinia from the site of the frequency of IA, but it still remains 100 Heng et al. ‘‘Epidermal necrolysis: 60 years of vaccination with the smallpox errors and advances.’’ 1252. a complication of replication-competent vaccine.119 It presents as a disseminated 101 Dodiuk-Gad et al. ‘‘Stevens-Johnson syndrome smallpox vaccines. Treatment is based vesicular or pustular rash and is usually and Toxic Epidermal Necrolysis: An Update.’’ 475, on the number of transfer sites or the benign and self-limited among 477. size of the resulting lesions.111 immunocompetent hosts. GV may be 102 Maja Mockenhaupt, Cecile Viboud, Ariane During the 2002–2004 HHS and DoD accompanied by fever and can produce Dunant, Luigi Naldi, Sima Halevy, Jan Nico Bouwes smallpox vaccination program, 101 of skin lesions anywhere on the body. GV Bavinck, Alexis Sidoroff, Jurgen Schneck, Jean- the 770,000 individuals vaccinated Claude Roujeau and Antoine Flahault. Stevens- can also appear as a regional form Johnson syndrome and Toxic Epidermal Necrolysis: reported cases of IA. This number characterized by extensive vesiculation Assessment of Medication Risks with Emphasis on represents both ocular and non-ocular Recently Marketed Drugs. The Euro SCAR Study. forms of IA. The study did not provide 112 Poland et al. ‘‘The US smallpox vaccination Journal of Investigative Dermatology. January 2008; program: a review.’’ 2079. 128(1):35–44. 106 Kennedy et al. ‘‘Smallpox and vaccinia.’’ 738. 113 Anis et al. ‘‘Smallpox revaccination of 103 Dodiuk-Gad et al. ‘‘Stevens-Johnson syndrome 107 Lane et al. ‘‘Adverse Events.’’ 191. 21,000.’’ 406. and Toxic Epidermal Necrolysis: An Update.’’477. 108 Kennedy et al. ‘‘Smallpox and vaccinia.’’ 741. 114 Cono et al. ‘‘Smallpox Vaccination and 104 B. Sassolas, C. Haddad, M. Mockenhaupt, A. 109 Frederick Ruben and J. Michael Lane, ‘‘Ocular Adverse Reactions.’’ 3. Dunant, Y. Liss, K. Bork, UF Haustein, D. Vieluf, vaccinia: an epidemiologic analysis of 348 cases.’’ 115 Lane et al. ‘‘Adverse Events.’’ 191. JC Roujeau and H. Le Louet. ‘‘ALDEN, an Algorithm Archives of Ophthalmology 84 (July 1970): 47. 116 Kennedy et al. ‘‘Smallpox and vaccinia.’’ 738. for Assessment of Drug Causality in Stevens- 110 Danielle M. Tack et al. ‘‘Unintentional transfer 117 Wertheimer et al. ‘‘Contract transmission of Johnson syndrome and Toxic Epidermal Necrolysis: of vaccinia virus associated with smallpox vaccinia virus.’’ 985. Comparison with Case-Control Analysis’’ Nature. vaccines.’’ Human Vaccines & Immunotherapeutics 118 See sections 319F–4(b)(4), (e)(2), and (e)(5) of July 2010;88(1): 60–68. 9:7 (July 2013): 1491. the PHS Act (42 U.S.C. 247d–6e(b)(4), (e)(2), and 105 Cono et al. ‘‘Smallpox Vaccination and 111 Fulginiti et al. ‘‘Smallpox vaccination: a (e)(5)). Adverse Reactions.’’ 3. review, Part II.’’ 256. 119 Kennedy et al. ‘‘Smallpox and vaccinia.’’ 738.

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around the vaccination site or as an not possible to predict completely who medical literature, but is not completely eruption localized to a single body may develop GV, but Smallpox understood.131 region (e.g., arm or leg). The skin lesions (Vaccinia) Vaccine Live is EV may occur as the result of of GV are thought to contain virus contraindicated for use in individuals implantation of the vaccinia virus into spread through the blood stream. First- with severe immunodeficiency.124 The broken or diseased skin. After time vaccinees are at higher risk for GV treatment of GV may require implantation, the virus spreads from than re-vaccinees. GV is often more hospitalization and the use of vaccinia cell to cell creating extensive lesions. severe among persons with underlying immunoglobulin intravenous (VIGIV). The amount of spread is dependent on immunodeficiency who might have the amount of abnormal skin and the Based on a review of the medical and been inadvertently vaccinated; these individual’s immune system.132 Once scientific literature, the Program’s patients might benefit from early viremia is established, lesions can evidence standard has been met, and GV intervention with vaccinia develop in unbroken skin.133 Positive is a serious physical injury that may be immunoglobulin (VIG). GV should not viral cultures of the lesions are directly caused by the administration or 134 be confused with multiple inadvertent diagnostic of EV. Cases of EV have use of the replication-competent also been reported in individuals with inoculations that might occur in the 125 126 127 128 129 presence of acute or chronic exfoliative, smallpox vaccine. a history of atopic dermatitis but whose erosive, or blistering skin disease. GV is Therefore, GV is proposed to be added condition appeared to resolve over time different from eczema vaccinatum (EV), to the Table with an onset interval of 6– and who had intact skin at the time of which typically occurs in persons with 9 days for the first symptom or vaccination.135 136 a history of atopic dermatitis and is manifestation to occur after vaccination Onset of the characteristic lesions can often associated with systemic as supported by the compelling, reliable occur concurrently or shortly after the illness.120 and valid medical and scientific occurrence of the reaction at the In GV, the initial lesions usually literature.130 The literature supports this vaccination site. There is generally no appear approximately a week after timeframe as the first symptoms of GV visible reaction at the vaccination site immunization on unimmunized skin. generally occur approximately one week before day 3 or 4 post vaccination. On These new lesions have a similar after immunization. Because GV entails approximately day 3 to 4, a papule appearance to the initial immunization the systemic spread of vaccinia virus forms, which progresses to a vesicle by throughout the body causing an immune day 5 to 6, which forms a pustule by day but are generally smaller and heal 137 quickly to a scar (within 5–6 days). In response and then the subsequent 7 to 9. In EV, these lesions occur in extremely rare cases, lesions have been development of satellite lesions on areas away from the primary seen to reoccur at 4 to 6 week intervals unvaccinated skin, the onset of vaccination site, often initially on non- for up to 1 year unless treatment with symptoms typically does not occur prior intact skin, and they may progress to areas of intact skin. EV lesions follow VIG stops the recurrence.121 to 6 days post vaccination. Cases of GV the same Jennerian progression In the U.S., from January 24 through with an onset occurring outside this (progression of dermatological lesions August 8, 2003, 38,257 civilian health timeframe will be considered as non- through the various stages of care workers received the smallpox Table injuries and evaluated on a case- development and resolution) as the vaccination using replication-competent by-case basis based on the Program’s vaccination site in a vaccine recipient. smallpox vaccine. During this period, evidence standard. Confluent (flowing together) or erosive HHS reported there were two suspected (wearing away) lesions can occur. The cases and one confirmed case of GV 5. Eczema Vaccinatum (EV) rash is often accompanied by fever and within the group of vaccine Eczema vaccinatum (EV) is the acute 122 lymphadenopathy and affected persons recipients. onset of widespread painful vesicles are frequently systemically ill. EV tends In the DoD smallpox vaccination and pustules that occur in individuals to be most severe among first-time program (770,000 vaccinated), as of who receive the smallpox vaccine and replication-competent vaccine January 4, 2005, there were 35 who have a history of atopic dermatitis. recipients, unvaccinated close contacts suspected cases of GV. All of these cases Persons with a history of atopic of vaccine recipients, and young were described in the literature as mild, dermatitis are at highest risk for eczema children.138 and all individuals made a full vaccinatum. However, not all Early diagnosis of EV and the recovery.123 individuals who have a history of atopic administration of VIGIV, within 1 or 2 GV is a known, but rare, complication dermatitis and are vaccinated against days of diagnosis, is helpful in reducing of receiving the replication-competent smallpox with a replication-competent the associated morbidity and smallpox vaccine, and its level of vaccine will go on to develop EV. This severity varies from person to person. 131 phenomenon is well documented in the Jennifer L. Reed, Dorothy E. Scott, and Mike The literature indicates the risk of Bray. ‘‘Eczema vaccinatum.’’ Clinical Infectious developing GV is significantly reduced Disease 54(6) (March 15, 2012): 834. 124 with obtaining a complete history and Fulginiti et al. ‘‘Smallpox vaccination: a 132 Fulginiti et al. ‘‘Smallpox vaccination: a review, Part II.’’ 261. review, Part II. 256–258. excluding individuals at risk for 125 Cono et al. ‘‘Smallpox Vaccination and 133 Fulginiti et al. ‘‘Smallpox vaccination: a developing the condition. It is presently Adverse Reactions.’’ 12–13. review, Part II. 256–258. 126 Rosenblatt et al. ‘‘Cutaneous Reactions to 134 Rosenblatt et al. ‘‘Cutaneous Reactions to 120 Cono et al. ‘‘Smallpox Vaccination and Vaccinations.’’ 328. Vaccinations.’’ 328. Adverse Reactions.’’ 2. 127 Kennedy et al. ‘‘Smallpox and vaccinia.’’ 738. 135 Reed et al. ‘‘Eczema vaccinatum.’’ 835. 121 Fulginiti et al. ‘‘Smallpox vaccination: a 128 Poland et al. ‘‘The US smallpox vaccination 136 Vincent Fulginiti et al. ‘‘Smallpox vaccination: review, Part II. 261. program.’’ 2079. a review, Part I. Background, vaccination technique, 122 Centers for Disease Control and Prevention. 129 Claudia Vellozzi et al. ‘‘Generalized vaccinia normal vaccination and revaccination, and ‘‘Update: Adverse events following civilian progressive vaccinia, and eczema vaccinatum are expected normal reactions.’’ Clinical Infectious smallpox vaccination, United States, 2003.’’ rare following smallpox (vaccinia) vaccination: Disease 37. (July 15, 2003): 244. Morbidity and Mortality Weekly Report 52(34) United States surveillance, 2003.’’ Clinical 137 Fulginiti et al. ‘‘Smallpox vaccination: a (August 29, 2003): 819. Infectious Disease 41(5) (September 1, 2005): 689. review Part I.’’ 248. 123 Poland et al. ‘‘The US smallpox vaccination 130 Cono et al. ‘‘Smallpox Vaccination and 138 Fulginiti et al. ‘‘Smallpox vaccination: a program.’’ 2079–2080. Adverse Reactions.’’ 12. review, Part II.’’ 258.

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mortality.139 140 The fatality rate for considered a covered injury. Only those death.158 A diagnosis of PV is made by those experiencing EV ranges from 5 to individuals who actually were the appearance and progression of the 40 percent both with and without administered the smallpox vaccine will lesions at the primary vaccination site treatment, respectively.141 142 be eligible for benefits.151 and other subsequent satellite Complications of EV include secondary lesions.159 Management of PV should 6. Progressive Vaccinia infections caused by fungus and include aggressive therapy with VIGIV. bacteria, septic shock, and fluid and Progressive vaccinia (PV) also known Cidofovir has been included in some electrolyte imbalances.143 Historical as vaccinia necrosum, vaccinia recommendations as a potential second- reports from the era of universal gangrenosa or disseminated vaccinia, is line agent that might be used under an vaccination for smallpox showed greater a rare, severe, and potentially fatal investigational protocol if the patient rates for developing EV with varying complication of receiving replication- does not respond to VIGIV or if supplies severity.144 In the most recent DoD and competent smallpox vaccine. Its of VIGIV are exhausted. In addition, HHS smallpox vaccination programs, frequency of occurrence is estimated to case management should include there were no documented cases of EV be 3 to 5 cases per million intensive monitoring, and tertiary-level in primary vaccine recipients.145 This is vaccinated.152 PV results when a supportive care.160 More recently, attributed to improved pre-screening of vaccination site fails to heal after 14 to recommendations 161 have been posted potential smallpox vaccine recipients 21 days in the presence of a minimal suggesting tecovirimat (recently and excluding those thought to be at inflammatory response and when approved as a smallpox treatment) risk of developing EV. Attenuated vaccinia virus replication persists.153 Of brincidofovir, and cidofovir as antivirals smallpox vaccine may reduce the risk of all of the adverse skin conditions that might be used under certain developing EV in those individuals with associated with smallpox vaccine, PV is circumstances to treat certain vaccine a history of atopic dermatitis. However, the most severe and life threatening.154 complications if treatment with VIGIV the potential of developing EV from PV occurs as the result of a T-cell alone is inadequate or if VIGIV is not receiving the smallpox vaccine must be deficiency within the immune system of readily available. Tecovirimat and weighed against the potential of being the vaccine recipient while the ‘‘B’’ cell brincidofovir were used as part of exposed to the smallpox virus and then function remains intact. As a result, the multifactorial interventions in a case of developing smallpox infection.146 progression and manifestation of this PV though the contribution of any one Based on a review of the medical and condition are limited to the skin intervention to the patient’s outcome scientific literature, the Program’s without viremic spread.155 The skin could not be assessed.162 evidence standard has been met, and EV surrounding the vaccination site During the most recent DoD and HHS is a serious physical injury that may be becomes vaccinia infected due to cell- smallpox vaccination program where directly caused by the administration or to-cell spread, the primary lesion approximately 770,000 individuals were use of the replication-competent (vaccination site) becomes larger in vaccinated, using replication-competent smallpox vaccine.147 148 149 EV is diameter, and secondary metastatic vaccines, there were no documented proposed to be added to the Table with vaccinia lesions can occur in areas away cases of PV. The study results indicate an onset interval for the first symptom from the primary immunization site. As improved screening techniques prior to or manifestation of onset of 3–21 days the lesions increase in size, they leave delivering the vaccine and withholding after vaccination. Three days would be dead skin behind the leading edge of the vaccinations from those at greatest risk the minimum time to mount an immune expanding lesion. of developing an adverse event response and develop symptoms. With The onset of symptoms and rate of contributed to this result.163 treatment, using VIGIV, no additional progress are based on the individual Based on a review of the medical and lesions should occur after 21 days. level of T-cell deficiency, but with an scientific literature, the Program’s Although EV can occur as the result expected onset of 3 to 21 days after evidence standard has been met, and PV of inadvertent transfer of the vaccinia vaccination.156 Primary lesions that fail is a serious physical injury that may be virus to non-vaccinia vaccine to heal by day 21 post-vaccination directly caused by the administration or recipients,150 for the purpose of this should be suspicious for PV.157 use of the replication-competent regulation, the inadvertent or Lesions can appear necrotic (dead), smallpox vaccine.164 165 166 167 PV is intentional inoculation of other persons fungated (ulcerated), piled-up, or well proposed to be added to the Table with by the vaccine recipient and the demarcated (clear margins). an onset interval for the first symptom subsequent development of EV is not Concomitant bacterial superinfection can also occur. Fungal and parasitic 158 Fulginiti et al. ‘‘Smallpox vaccination: a 139 Cono et al. ‘‘Smallpox vaccination and adverse infections have also been documented review, Part II.’’ 263. reactions.’’ 13. in patients diagnosed with PV. 159 Fulginiti et al. ‘‘Smallpox vaccination: a 140 Fulginiti et al. ‘‘Smallpox vaccination: a Progression of PV can lead to toxic or review, Part II.’’ 265. review, Part II.’’ 256–258. 160 Cono et al. ‘‘Smallpox vaccination and adverse 141 septic shock and disseminated Rosenblatt et al. ‘‘Cutaneous reactions to intravascular coagulation (DIC), a blood reactions.’’ 14. vaccinations.’’ 328. 161 https://www.cdc.gov/smallpox/clinicians/ 142 Fulginiti et al. ‘‘Smallpox vaccination: a clotting disorder, generally ending with vaccine-medical-management6.html. review, Part II.’’ 256. 162 E. Lederman et al. ‘‘Progressive vaccinia: Case 143 Rosenblatt et al. ‘‘Cutaneous reactions to 151 42 CFR part 110. description and laboratory-guided therapy with vaccinations.’’ 328. 152 Fulginiti et al. ‘‘Smallpox vaccination: a vaccinia immune globulin, ST–246, and CMX001.’’ 144 Reed et al. ‘‘Eczema vaccinatum.’’ 832. review, Part II.’’ 253. Journal of Infectious Disease, 206 (November 1, 145 Poland et al. ‘‘The US smallpox vaccination 153 Fulginiti et al. ‘‘Smallpox vaccination: a 2012) 1372–1385. program.’’ 2079. review, Part II.’’ 263. 163 Poland et al. ‘‘The US smallpox vaccination 146 Reed et al. ‘‘Eczema vaccinatum.’’ 838. 154 Fulginiti et al. ‘‘Smallpox vaccination: a program.’’ 2079. 147 Cono et al. ‘‘Smallpox vaccination and adverse review, Part II.’’ 263. 164 Cono et al. ‘‘Smallpox vaccination and adverse reactions.’’ 13. 155 Fulginiti et al. ‘‘Smallpox vaccination: a reactions.’’ 13. 148 Rosenblatt et al. ‘‘Cutaneous reactions to review, Part II.’’ 263. 165 Lane et al. ‘‘Adverse Events.’’ 191. vaccinations.’’ 328. 156 Fulginiti et al. ‘‘Smallpox vaccination: a 166 Rosenblatt et al. ‘‘Cutaneous reactions to 149 Fulginiti et al. ‘‘Smallpox vaccination: a review, Part II.’’ 263. vaccinations.’’ 328. review, Part II.’’ 256–258. 157 Fulginiti et al. ‘‘Smallpox vaccination: a 167 Fulginiti et al. ‘‘Smallpox vaccination: a 150 Lane et al. ‘‘Adverse events.’’ 191. review, Part II.’’ 263. review, Part II.’’ 263.

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or manifestation of onset of 3–21 days cases of PVE occurred.176 Complications the CNS.183 Direct infection of the CNS after vaccination. from vaccination were much less by vaccinia virus may result in acute frequent in previously vaccinated cytotoxic neuronal damage and B. The Post-Vaccinial Encephalopathy individuals than those who were inflammation. However, laboratory (PVE), Encephalitis, and vaccinia-naı¨ve. evidence of virus replication is often Encephalomyelitis Spectrum (PVEM) Literature indicates there are two lacking; inflammatory changes are PVEM is a spectrum of overlapping subtypes of PVE associated with the attributed instead to immune response conditions that includes post-vaccinial smallpox vaccine. First, microglial mechanisms. encephalopathy, encephalitis, and encephalitis results in the Histopathological findings of PVE are encephalomyelitis, and, for the demyelination of the subcortical white often similar to those found with acute purposes of this NPRM, is treated as one matter and clinically resembles acute disseminated encephalomyelitis (or injury. Encephalopathy, encephalitis, disseminated encephalomyelitis post-infectious encephalomyelitis). and encephalomyelitis are (ADEM). Second, the cytotoxic form However, a diagnosis of acute inflammations of the parenchyma (the presents with cerebral edema (swelling disseminated encephalomyelitis is functional tissue of an organ) of the of the brain), infiltration of white blood characterized by a longer interval of central nervous system, the brain and cells into the meningeal tissues and onset after immunization and by MRI spinal cord generally due to an hemorrhages around the small blood findings suggesting acute infectious or post-infectious etiology. vessels of the brain.177 178 demyelination.184 Demyelination occurs These conditions have been reported A confirmed diagnosis of PVE as the result of an immune response in after receiving the replication- requires demonstration of CNS which the membrane that covers the competent smallpox vaccine and have inflammation by histopathology or nerves begins to breakdown. been causally associated with the neuroimaging. A suspected diagnosis is Demyelination interferes with nerve replication-competent smallpox made by clinical features alone.179 180 signal transmission. vaccine.168 In addition to the The clinical symptoms of PVE generally PVE is diagnosed by excluding other replication-competent smallpox begin 7 to 14 days post-vaccination. causes of the symptoms prior to 185 vaccine, more than one hundred viruses Clinically significant findings may be associating them with the vaccine. have been identified as causing identified on magnetic resonance Cerebral spinal fluid examination may encephalitis, and there are no known imaging (MRI) as early as day 5 post- show an increased number of white predictors for those individuals who blood cells and increased protein, but vaccination with multifocal lesions 186 will go on to develop encephalitis.169 Of noted throughout the white matter. this is not always the case. Based on a review of the medical and the conditions on the PVEM spectrum, Cerebral spinal fluid may be positive for scientific literature, the Program’s the literature discusses PVE in depth. vaccinia virus, but this does not evidence standard has been met, and In early vaccination campaigns in universally occur. The initial symptoms PVEM (including PVE, encephalitis, and Great Britain, Europe, and the United of PVE may include headache, vomiting, States, cases of PVE were reported after encephalomyelitis) are serious physical drowsiness, and fever in mild cases. injuries that may be directly caused by receipt of the smallpox vaccine with Severe cases may include these same the administration or use of the varying rates of occurrence based on the symptoms, as well as paralysis, replication-competent smallpox type of vaccine used by each incontinence, urinary retention, coma, vaccine. The expected onset interval for country.170 171 The Great Britain and seizures. There is no effective the first symptom or manifestation is 5– incidence of PVE decreased when they treatment for PVE, only supportive care. 14 days after vaccination.187 188 changed the type of replication- Approximately 25 percent of patients competent smallpox vaccine they were with PVE will die, and 1⁄3 of the C. Vaccinial Myocarditis, Pericarditis or using to the Lister strain.172 173 Rates for survivors will experience a broad Myopericarditis (MP) PVE in Dutch military recruits were as spectrum of residual neurological For purposes of the NPRM, MP is high as 1 in 4,000 vaccinated, whereas conditions that include mental vaccinial myocarditis, pericarditis, or in U.S. military recruits, the rate was impairment and paralysis.181 182 myopericarditis. Myocarditis is an estimated to be 1 in 100,000 The pathophysiology of CNS adverse inflammation of the heart muscle vaccinated.174 Statistics from the 1960s reactions attributed to replication- without blockage of the coronary in the U.S. suggest the rates of PVE competent smallpox vaccination is not arteries, and pericarditis is an could range from 9 to 59 in 1 million completely understood, but it is thought inflammation of the fibrous sack vaccinated.175 Among the more than to represent some type of autoimmune surrounding the heart muscle. 700,000 DoD vaccine recipients, three process involving the white matter of Myopericarditis is the term used when the two conditions occur 168 Cornelius Van Dam et al. ‘‘Severe post 176 Van Dam et al. ‘‘Severe post vaccinia vaccinia encephalitis with acute disseminated encephalitis.’’ e47. 183 Fulginiti et al. ‘‘Smallpox vaccination: a encephalomyelitis: recovery with early intravenous 177 Van Dam et al. ‘‘Severe post vaccinia review, Part II.’’ 268. immunoglobulin, high-dose steroids, and vaccinia encephalitis.’’ e47. 184 John Neff et al. ‘‘Monitoring the safety of a immunoglobulin.’’ Clinical Infectious Disease 48(4) 178 James J. Sejvar et al. ‘‘Neurologic adverse smallpox vaccination program in the United States: (February 15, 2009): e47. events associated with smallpox vaccination in the report of the joint smallpox vaccine safety working 169 Fulginiti et al. ‘‘Smallpox vaccination: a United States, 2002–2004.’’ Journal of the American group of the advisory committee on immunization review, Part II.’’ 267. Medical Association 294(21) (December 7, 2005): practices and the armed forces epidemiological 170 Fulginiti et al. ‘‘Smallpox vaccination: a 2744. board.’’ Clinical Infectious Disease 46 (Supplement review, Part II.’’ 267. 179 Cono et al. ‘‘Smallpox vaccination and adverse 3) (2008): S261. 171 Kennedy et al. ‘‘Smallpox and vaccinia.’’ 738. reactions.’’ 15. 185 Cono et al. ‘‘Smallpox vaccination and adverse 172 Fulginiti et al. ‘‘Smallpox vaccination: a 180 Stuart N. Isaacs and Harvey M. Friedman, reactions.’’ 15. review, Part II.’’ 267. ‘‘Vaccinia virus as the smallpox vaccine.’’ 186 Cono et al. ‘‘Smallpox vaccination and adverse 173 Kennedy et al. ‘‘Smallpox and vaccinia.’’ 738. UpToDate (June 03, 2015): 5. reactions.’’ 14. 174 Fulginiti et al. ‘‘Smallpox vaccination: a 181 Fulginiti et al. ‘‘Smallpox vaccination: a 187 Cono et al. ‘‘Smallpox vaccination and adverse review, Part II.’’ 267. review, Part II.’’ 267. reactions.’’ 14. 175 Van Dam et al. ‘‘Severe post vaccinia 182 Kennedy et al. ‘‘Smallpox vaccines for 188 Fulginiti et al. ‘‘Smallpox vaccination: a encephalitis.’’ e47. biodefense.’’ 738. review, Part II.’’ 267.

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simultaneously. Severe cases of The single fatal case of myocarditis was been published in the literature.199 myopericarditis can result in dilated in a female. The report calculated a rate However, these reports are not cardiomyopathy (DCM) characterized by of myopericarditis 7.5-fold higher than compelling, reliable, valid, medical and an enlarged and weakened heart muscle. the expected background rate among scientific evidence demonstrating that Myocarditis and pericarditis can cause 347,516 primary vaccine recipients with the replication-competent smallpox palpitations, shortness of breath, fever, the expected rate being 2.16 per 100,000 vaccine directly causes ischemic heart sweats, or chest pain and can be vaccinated as opposed to the observed disease. Therefore, the Secretary does diagnosed by an abnormal rate of 16.11 per 100,000 vaccinated.192 not propose to add ischemic heart electrocardiogram (ECG), imaging Of 37,901 HHS vaccine recipients, 21 disease to the Table, and claims for this studies (echocardiogram), civilians were diagnosed with mild injury will be considered non-Table histopathology, or elevated cardiac cases of myopericarditis (at a rate of 554 injuries and evaluated on a case-by-case enzymes. Myocardial dysfunction in per million), all of which resolved basis based on the Program’s evidence cases of myopericarditis may result from without further complication.193 standard. direct viral injury or from a triggered Additionally, four DoD and three HHS Other Conditions of Special Interest to immune response that targets the cases of DCM occurred among Smallpox Vaccination myocardium or pericardium. In mouse previously healthy subjects, with two models of infectious myocarditis, the requiring heart transplants.194 Although the conditions listed below virus is only rarely isolated from the The occurrence of the vast majority of may be of special interest to the public myocardium. The absence of direct cardiac adverse events within 30 days of and are being monitored by HHS, the infection of the myocardium suggests the smallpox vaccination, and clustering Secretary does not propose including immune-mediated injury as the within 7–12 days post-vaccination, them on the Table at this time because predominant pathogenic mechanism. provides compelling, reliable, valid, compelling, reliable, valid, medical and Inflammatory processes can be caused medical and scientific evidence of a scientific evidence of causation does not by a number of viral infections and direct link between vaccination with currently exist. The conditions include autoimmune disorders and have live vaccinia virus and incidence of the following: sequelae ranging from self-limiting vaccinia associated cardiac A. Secondary Infection asymptomatic disease to DCM, resulting complications consisting of vaccinial in fulminant (severe and sudden) myocarditis, pericarditis and Secondary infections resulting from congestive heart failure and possibly myopericarditis (MP). Based on a review loss of skin integrity because of death. Myocarditis is blamed for causing of the medical and scientific literature, receiving a replication-competent up to 20 percent of all cases of sudden the Program’s evidence standard has vaccine are common. All instances of death among military recruits. Although been met, and MP is a serious physical secondary infection will be considered cardiac events after the administration injury that may be directly caused by non-Table injuries and evaluated on a or use of replication-competent the administration or use of the case-by-case basis based on the smallpox vaccine were reported in the replication-competent smallpox Program’s evidence standard. literature before 2003, they were largely vaccine. Therefore, MP is proposed to B. Serum Sickness unrecognized during the worldwide be added to the Table with an onset Serum sickness is a systemic, immune eradication campaign and were thought interval for the first symptom or complex–mediated hypersensitivity to occur very rarely. Only six cases of manifestation of 0–21 days after vasculitis classically attributed to the cardiac complications after replication- vaccination.195 196 Although clustering competent smallpox vaccination with therapeutic administration of foreign occurs 7–12 days post-vaccination, serum proteins. It is a classic example the New York City Board of Health symptoms may begin within 24 hours of (NYCBH) strain of vaccinia were 197 of a type III hypersensitivity reaction vaccination. The literature does not caused by antigen-antibody complexes. reported in the United States before indicate that cardiac manifestations 2003.189 In the past decade, cardiac The symptoms of serum sickness have occurred beyond 21 days post- generally begin 7–12 days after injection complications following live vaccinia vaccination based on immune vaccination have been detected more 198 of the foreign material, but may appear response. as late as 3 weeks afterward. Immune often due to the availability of more Anecdotal reports of ischemic heart sophisticated diagnostic techniques. complexes involving heterologous disease, such as angina pectoris or (animal) serum proteins and Cardiac complications resulting from myocardial infarction (heart attacks), live vaccinia vaccination range in complement activation are important occurring in a few individuals following pathogenic mechanisms in serum severity from mild to fatal and include receipt of the smallpox vaccine have myocarditis, pericarditis, arrhythmias, sickness. Reactions originally described 190 as serum sickness—like are now and DCM. 192 Poland et al. ‘‘The US smallpox vaccination Of 730,580 U.S. Armed Forces program.’’ 2079. attributed to drug allergy, triggered in personnel vaccinated with the 193 Morgan et al. ‘‘Myocarditis, pericarditis, and particular by antibiotics (e.g., penicillin, discontinued vaccine, Dryvax, 86 cases dilated cardiomyopathy.’’ S246. cefaclor), and, rarely, to other agents, of myopericarditis with moderate or 194 Neff et al. ‘‘Monitoring the safety of a smallpox such as human immune globulin, severe clinical presentation occurred in vaccination program.’’ S262. humanized monoclonal antibodies, and 195 Centers for Disease Control and Prevention, 191 insect venom. The Program is not aware otherwise healthy vaccine recipients. ‘‘Cardiac adverse events following smallpox vaccination—United States, 2003.’’ Morbidity and of compelling, reliable, valid, medical 189 Juliette Morgan et al. ‘‘Myocarditis, Mortality Weekly Report 52(12) (March 28, 2003): and scientific evidence in literature pericarditis, and dilated cardiomyopathy after 250. demonstrating the smallpox vaccine smallpox vaccination among civilians in the United 196 Dimitri C. Cassimatis et al. ‘‘Smallpox directly causes serum sickness. States, January–October 2003.’’ Clinical Infectious vaccination and myopericarditis: a clinical review.’’ Disease 46 Supplement 3 (2008): S242. Journal of the American College of Cardiology 43(9) Therefore, the Secretary does not 190 Nalca et al. ‘‘ACAM200TM: The New Smallpox (May 5, 2004): 1505. propose to add serum sickness to the vaccine.’’ 76. 197 Centers for Disease Control and Prevention, 191 Poland et al. ‘‘The US smallpox vaccination ‘‘Cardiac adverse.’’ 3. 199 Centers for Disease Control and Prevention, program.’’ 2079. 198 Lane et al. ‘‘Adverse events.’’ 190. ‘‘Cardiac adverse.’’ 2.

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Table, and claims for this injury will be muscles. Since the smallpox vaccine is million persons vaccinated.204 In 1977, considered non-Table injuries and administered in a manner other than an an Australian study of 938 adverse evaluated on a case-by-case basis based intramuscular injection and neither the events related to the replication- on the Program’s evidence standard. vaccine nor the needle reaches the competent smallpox vaccine identified subdeltoid space, there is no 87 cases of EM, which represented 9.3 C. Shoulder Injury Related to Vaccine percent of all of the reported Administration (SIRVA) compelling, reliable, valid, medical and scientific evidence of a direct causal complications.205 Neither of these Shoulder Injury Related to Vaccine association between the smallpox studies specified the severity of EM or Administration (SIRVA) manifests as vaccination and subdeltoid bursitis. mentioned SJS/TEN. shoulder pain and limited range of Therefore, the Secretary does not EM most often manifests as both skin motion occurring after the propose to add subdeltoid bursitis to the and mucosal lesions, but may also administration of a vaccine intended for Table at this time. However, claims for exhibit skin lesions alone. Occasionally, intramuscular administration in the this injury will be considered non-Table EM presents only with mucous upper arm. The symptoms occur in the injuries and evaluated on a case-by-case membrane involvement. Skin lesions arm in which the vaccine was basis based on the Program’s evidence most commonly appear in a administered because of unintended standard. symmetrical distribution on the injection of vaccine antigen or trauma extremities (acral distribution) and from the needle into and around the E. EM spread centripetally (toward the center). underlying bursa of the shoulder EM is a typically mild and self- Skin lesions are usually asymptomatic resulting in an inflammatory reaction. limiting mucocutaneous reaction though some patients experience itching SIRVA is not a neurological injury. characterized by target lesions on the and burning. Oral mucous lesions are The smallpox vaccine is administered skin and mucous membranes.200 common. Mucosal lesions can also be via a bifurcated (two-pronged) needle Historically, EM comprised a disease found in other sites (such as genital area into the deep epidermis when spectrum that was classified by and eyes) but are less common.206 In administering Smallpox (Vaccinia) increasing degrees of severity. The most patients, EM is a transient Vaccine Live, replication-competent or, spectrum included a minor form (EM condition that spontaneously resolves in the case of Smallpox and Monkeypox minor) and a more severe or major form without long-term morbidity. EM Vaccine, Live, Non-replicating (EM major), SJS. TEN completed the lesions usually appear over the course replication-deficient, via a subcutaneous spectrum as the most severe form of the of 3 to 5 days and resolve in (under the skin) injection. Both disease. The unifying clinical features of approximately 2 weeks. Skin lesions do injections generally take place over the these diseases that placed them under not scar, but post-inflammatory deltoid or triceps muscles. As the the EM spectrum were target lesions, hyperpigmentation may remain months smallpox vaccine is administered in a similar mucosal features and epidermal after resolution. Rarely, patients manner other than an intramuscular necrosis. However, current evidence experience complications, such as fluid injection and neither the vaccine nor the suggests that EM, SJS, and TEN are not and electrolyte abnormalities, or those needle reaches the internal structures of in the same continuum. SJS and TEN with eye involvement can have scarring the shoulder, there is no compelling, are the same disease differing only in and visual impairment.207 reliable, valid, medical and scientific the area of involvement and severity of Based on a review of the medical and evidence of a direct causal association systemic findings. EM and SJS/TEN scientific literature, EM is a physical between the smallpox vaccination and differ in their cause, clinical injury that may be directly caused by SIRVA. Therefore, the Secretary does presentation, pathology and therapy.201 the use of the replication-competent not propose to add SIRVA to the Table EM is almost always infectious in smallpox vaccine. However, since EM is at this time, and claims for this injury origin, with herpes simplex virus (HSV) typically a mild and self-limiting will be considered non-Table injuries as the infectious agent in 70–80 percent condition, it is not considered a serious and evaluated on a case-by-case basis of cases.202 Drugs have been estimated injury based on the Program’s standards. based on the Program’s evidence to induce EM in less than 10 percent of Therefore, the Secretary does not standard. cases. The most common precipitators propose to add EM to the Table and D. Subdeltoid Bursitis are non-steroidal anti-inflammatory claims for this injury will be considered drugs, sulfonamides, anti-epileptics and non-Table injuries and evaluated on a Subdeltoid bursitis (e.g., deltoid antibiotics.203 The interpretation of the case-by-case basis, based on the bursitis, subacromial bursitis) is an literature on drug-induced EM is Program’s evidence standard. inflammation of the bursa located complicated by previous classification between the deltoid muscle and the Non-Vaccine Countermeasures of SJS/TEN as part of the EM spectrum. capsule of the shoulder joint. A bursa is This is true for studies involving In addition to the smallpox vaccine, a closed fluid-containing sac that smallpox and EM. A 1968 study noted there are other potential reduces friction between bones and that EM accounted for 13 percent of all countermeasures that might be used tendons, or bones and skin. The bursa complications associated with the either for smallpox or to treat adverse extends below the deltoid muscle, and replication-competent smallpox vaccine it is possible for a deep injection given 204 J. Michael Lane et al. ‘‘Complications of or a rate of 165 cases of EM per 1 high in the shoulder to enter the bursa smallpox vaccination, 1968: Results of ten inadvertently causing an inflammatory statewide surveys.’’ Journal of Infectious Disease 200 P. Michele Williams and Robert J. Conklin. 122(4) (October 1, 1970): 305. bursitis. Subdeltoid bursitis can result ‘‘Erythema multiforme: A review and contract from 205 B.J. Feery, ‘‘Adverse reactions after smallpox in debilitating pain or immobility. Stevens-Johnson syndrome/toxic epidermal vaccinations.’’ Medical Journal of Australia 2 As stated above, the smallpox vaccine necrolysis.’’ Dental Clinics of North America 2005; (August 6, 1977): 181. is administered via a bifurcated (two- 49: 67–76. 206 J. Clark Huff, William Weston, and Marcia 201 pronged) needle into the deep epidermis Williams et al. ‘‘Erythema multiforme.’’ 68. Tonnesen. ‘‘Erythema multiforme: A critical review 202 Williams et al. ‘‘Erythema multiforme.’’ 68. of characteristics, diagnostic criteria and causes.’’ or via a subcutaneous (under the skin) 203 David Wetter. ‘‘Erythema multiforme: Journal of the American Academy of Dermatology injection. Both injections generally take Pathogenesis, clinical features and diagnosis.’’ 2019 8(6) (June 1983): 763–775. place over the deltoid or triceps UpToDate. 207 Huff et al. Erythema multiforme, 767–768.

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events following vaccination including and antibodies. According to the to 72 hours later.216 The late phase vaccinia immunoglobulin intravenous literature, the use of VIGIV poses a risk reaction results from a different (VIGIV), cidofovir, tecovirimat, and of anaphylaxis when used in immunologic mechanism of action. The brincidofovir. The Secretary proposes to individuals who have an late phase reaction is part of a biphasic add VIGIV, cidofovir, tecovirimat and immunoglobulin A (IgA) deficiency and reaction. It is possible for the first brincidofovir to the Table as covered who go on to form immunoglobulin E immediate hypersensitivity reaction to countermeasures. (IgE) antibodies against IgA or who have be relatively mild, unrecognized, or not had a previous allergic reaction to observed. There may be unusual cases Vaccinia Immunoglobulin Intravenous human antibody/blood in which the immediate reaction is (VIGIV) products.209 210 211 The number of delayed and/or cases that the immediate Vaccinia immunoglobulin individuals with IgA deficiency varies reaction is not recognized, with the first intravenous (VIGIV) is a medication that based on geographic location. Estimates apparent manifestation occurring in the is used to treat some of the of IgA deficiency range from 1 in 400 to late phase. These unusual cases do not complications (adverse side effects) of 1 in 3,000 within the U.S. meet the requirements to be considered receiving the smallpox vaccine. It is not Approximately 30–40 percent of this table injuries, and will be evaluated on indicated for treatment of smallpox population also has anti-IgA antibodies. a case-by-case basis based on the infection. Immunoglobulins are a class It is possible to reduce the amount of Program’s evidence standard. of medication used to treat many IgA in VIGIV. However, it is not B. Transfusion-Related Acute Lung autoimmune diseases and primary possible to eliminate the antibody, and Injury (TRALI) immune deficiency, infections, and only very small amounts are necessary complications from the smallpox to cause anaphylaxis.212 Transfusion-related acute lung injury vaccine. Although the clinical use of, Based on the unique nature of the (TRALI) is defined as the onset of and experience with, VIGIV is limited, presentation and timing of anaphylaxis, respiratory distress within 6 hours after this product is derived in the same way the consensus in the medical receipt of plasma containing blood as other types of immunoglobulins and community regarding causation based products in non-critically ill patients. is thought to have the same side effects on IgA antibody reactions, and the However, in critically ill patients, the and potential complications. As a result, existing medical literature, anaphylaxis literature states that it may take as long the possible adverse side effects are is proposed for inclusion on the Table as 72 hours to develop TRALI post- thought to be similar to other because it is a serious physical injury transfusion.217 As VIGIV is derived from immunoglobulins (class effect). that may be directly caused by the human plasma, VIGIV may precipitate VIGIV is harvested from the plasma of administration or use of VIGIV, as TRALI. persons vaccinated with vaccinia virus supported by the Program’s evidence TRALI is a form of non-cardiac and who have had a sufficient immune standard. Consistent with the time pulmonary edema identified by chest response to produce antibodies in an interval for the first manifestation of x-ray and characterized by severe effort to prevent smallpox infection. anaphylaxis after exposure to a foreign respiratory distress, pulmonary edema, Individuals who were vaccinated, as protein and as established in the 1994 hypoxia (oxygen starvation), and fever part of their immune response, develop IOM clinical case definition of in the presence of normal left antibodies after vaccination, and those anaphylaxis 213, the Secretary proposes ventricular function.218 A patient antibodies are collected within donated including anaphylaxis as an injury on experiencing TRALI may require plasma. The plasma is processed into the Table with an onset interval of 0–4 mechanical ventilation to treat the VIGIV. VIGIV may help in ameliorating hours for the first symptom or respiratory distress, pulmonary edema, some complications of vaccinia manifestation to occur after the and hypoxia. The use of mechanical immunization including eczema administration or use of VIGIV.214 This ventilation is associated with other vaccinatum, progressive vaccinia, or timeframe is consistent with other injuries and complications, such as lung severe generalized vaccinia. It may also medications or blood derived products trauma and tracheal stenosis. TRALI has be used to treat autoinoculation to the that may induce anaphylaxis.215 been identified as a major cause of eye or eyelid. VIGIV is not thought to be In rare cases of acute anaphylaxis, mortality in those individuals receiving effective in treating PVE. The current initial symptoms of the immediate plasma-containing transfusions.219 VIGIV product is administered reaction may present up to 12 hours Although not completely understood, intravenously. after exposure. A slow evolving late it is believed that the basis of TRALI The following injuries have been phase hypersensitivity reaction is rests in a host antibody response to associated with the use of possible, with an onset that usually receiving blood products that contain immunoglobulins: (a) anaphylaxis, (b) begins 4–8 hours after the immediate plasma, via transfusion. The host transfusion related acute lung injury, (c) reaction ends. The medical literature receives a transfer of donor anti- acute renal failure, (d) drug-induced contains reports of late phase onset up leukocyte antibodies (antibodies that act aseptic meningitis, (e) hemolysis, and (f) against the patient’s white blood cells) 209 thrombosis.208 Centers for Disease Control and Prevention within the plasma and then develops a (CDC). ‘‘Smallpox supplemental fact sheet: reaction causing the activation of the A. Anaphylaxis Investigational vaccinia immune globulin (VIG) information.’’ (March 10, 2009): 1. endothelial cells and pulmonary A general discussion of anaphylaxis is 210 Hamrock, ‘‘Adverse events associated.’’ 535. neutrophils leading to capillary leakage in the Anaphylaxis section under the 211 Patrick Cherin et al. ‘‘Management of adverse Smallpox Vaccine heading of this events in the treatment of patients with 216 Ruggeberg et al. ‘‘Anaphylaxis: case definition NPRM. Vaccinia immune globulin is a immunoglobulin therapy: a review of evidence.’’ and guidelines.’’ 5677. Autoimmunity Reviews 15 (September 16, 2015): 217 Alexander P.J. Vlaar and Nicole P. Juffermans, product derived from human plasma 75. ‘‘Transfusion-related acute lung injury: a clinical and as such, it contains human proteins 212 Hamrock, ‘‘Adverse events associated.’’ 539. review.’’ Lancet 328 (May 1, 2013): 984. 213 Institute of Medicine, ‘‘Immunization safety 218 ‘‘Vaccinia immune globulin intravenous 208 David J. Hamrock, ‘‘Adverse events associated review vaccination.’’ 5. (human)’’ [package insert]. Cangene Corporation, with intravenous immunoglobulin therapy.’’ 214 Ruggeberg et al. ‘‘Anaphylaxis.’’ 5677–5678. Frederick, MD; (2010): 7. International Immunopharmacol 6 (2006): 535. 215 Ruggeberg et al. ‘‘Anaphylaxis.’’ 5677–5678. 219 Vlaar et al. ‘‘Transfusion-related acute.’’ 984.

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and pulmonary edema (fluid in the amount of paraprotein in the blood); (5) the product.235 The symptoms of DIAM lungs).220 The patient then goes on to sepsis; (6) a faster rate of may reoccur with another exposure to develop the classic symptoms of immunoglobulin infusion; and (7) the the offending agent. Drugs that can TRALI.221 concomitant use of nephrotoxic (kidney cause DIAM include immunoglobulins, Based on the unique nature of the toxic) drugs.226 227 228 non-steroidal anti-inflammatory drugs presentation and timing of TRALI Based on existing scientific and (NSAIDs), drugs delivered via the together with consensus in the medical medical literature, the Program’s intrathecal route (into the spinal canal) community regarding causation, and the evidence standard has been met, and and antibiotics.236 237 existing scientific and medical ARF is as a serious physical injury The incidence of DIAM is estimated literature, the Program’s evidence proposed to be added to the Table. The to occur in approximately 1 percent of standard has been met, and TRALI is as onset of ARF with the use of VIGIV patients receiving immunoglobulins. a serious physical injury proposed to be begins with the onset of renal Most patients who experience added to the Table. The Secretary insufficiency, progressing to renal immunoglobulin-associated DIAM proposes including TRALI as an injury failure, and occurs within 0–10 days recover completely within 5 days of on the Table with an onset interval of after receiving VIGIV. Therefore, the stopping the medication and without 0–72 hours for the first symptom or Secretary proposes adding ARF to the sequelae or permanent injury.238 It manifestation to occur after the Table as an injury associated with the appears that individuals with a history administration or use of VIGIV.222 use of VIGIV with a time of onset within of migraine headaches have an C. Acute Renal Failure 10 days for the first symptom or increased risk for developing manifestation to occur after the immunoglobulin associated DIAM.239 In Acute renal failure (ARF) is the administration or use of addition, the dose delivered may sudden inability of the kidneys to filter VIGIV.229 230 231 232 233 contribute to the development of DIAM. waste products from the blood stream. Doses of immunoglobulin given at 2 g/ This leads to the build-up of waste D. Drug-Induced Aseptic Meningitis kg/cycle appeared to precipitate aseptic products and fluid in the body and can Drug-induced aseptic meningitis meningitis when compared to smaller lead to a metabolic derangement (DIAM) is an inflammation of the doses.240 (chemical imbalance), fluid overload, linings of the brain (meninges) that is Based on existing scientific and and death, if not identified and treated not caused by a bacteria or virus, but by medical literature, the Program’s early. Acute renal failure can occur over a drug or medication. The symptoms of evidence standard has been met, and a matter of hours or days and can meningitis include severe headache, DIAM is a serious physical injury generally be treated and reversed if nuchal (neck) rigidity, drowsiness, proposed to be added to the Table. As diagnosed early. The use of fever, photophobia (light sensitivity), noted by Jolles et al., the anticipated immunoglobulin has been identified as painful eye movements, nausea, and time of onset for the first symptom or a factor leading to the development of vomiting. Discontinuation of the manifestation to occur is within 48 ARF. Between 1985 and 1998, the FDA medication leads to a resolution of the hours after the administration or use of received 120 reports of patients symptoms. It is postulated that DIAM the first dose of VIGIV and no more than developing ARF associated with the use occurs because of an immunological 48 hours after the administration or use of immunoglobulins.223 The majority of hypersensitivity reaction to a specific of the last dose of VIGIV.241 Therefore, cases of renal failure were associated medication.234 In the case of the Secretary proposes adding DIAM with the use of immunoglobulins that immunoglobulins, DIAM may be within this time of onset interval as a contained sucrose as a stabilizing agent. precipitated by the immunologically Table injury. The sucrose caused swelling within the active components within the plasma or kidney and the loss of renal function.224 E. Hemolysis because of the stabilizers used within VIGIV does not contain sucrose, but Hemolysis is the physical breakdown rather maltose, which may decrease the 226 Cono et al. ‘‘Smallpox vaccination and adverse of red blood cells (RBCs) either through incidents of ARF but not eliminate the reactions.’’ 18. natural attrition or as caused by external risk of developing the condition 227 Vaccinia immune globulin intravenous factors. An RBC’s natural life cycle completely.225 package insert. ranges from 110 to 120 days. This cycle The factors that may contribute to or 228 Hamrock, ‘‘Adverse events associated.’’ 538. coincides with the production of RBCs precipitate ARF when using VIGIV 229 H.I.A. Sati, R. Ahya and H.G. Watson, within the bone marrow, which include: (1) Pre-existing renal ‘‘Incidence and associations of acute renal failure complicating high-dose intravenous maintains homeostasis (steady state). insufficiency or use of VIGIV in patients immunoglobulin therapy.’’ British Journal of The RBC’s function is to transport at risk of developing renal insufficiency Haematology 113 (January 4, 2001): 557. oxygen throughout the body in the due to diabetes; (2) age older than 65 230 Doreen Bianchi-Winward and Mary T. Brophy, hemoglobin contained within the RBCs. years; (3) volume depletion ‘‘Acute renal failure after administration of Additionally, the RBCs contain the (dehydration); (4) paraproteinemia (high intravenous immunoglobulin: review of the literature and case report.’’ Pharmacotherapy 15(6) majority of the body’s potassium stores. (1995): 766. When RBCs break down faster than their 220 Vlaar et al. ‘‘Transfusion-related acute.’’ 985. 231 Yelena M. Itkin and Toby C. Trujillo, natural life cycle, the bone marrow 221 Robert S. Makar, Amy Powers and Christopher ‘‘Intravenous immunoglobulin-associated acute Stowell, ‘‘Reducing transfusion-related acute lung renal failure: case series and literature review.’’ 235 injury risk: evidence for and approaches to Pharmacotherapy 25(6) (2005): 889. Jolles et al. ‘‘Drug-induced.’’ 221. 236 transfusion-related acute lung injury mitigation.’’ 232 N. Gupta et al. ‘‘Intravenous gammaglobulin- German Moris and Juan Carlos Garcia- Transfusion Medicine Reviews 26(4) (October 2012): associated acute renal failure.’’ American Journal of Monoco, ‘‘The challenge of drug-induced aseptic 305. Hematology 66 (2001): 1552. meningitis revisited.’’ Journal of the American 222 Medical Association 174(9) (September 2004): 1511. Vlaar et al. ‘‘Transfusion-related acute.’’ 984. 233 Thomas G. Cantu et al. ‘‘Acute renal failure 237 223 M. Jennifer Cheng and Colleen Christmas, associated with immunoglobulin therapy.’’ Jolles et al. ‘‘Drug-induced.’’ 217. ‘‘Special consideration with the use of intravenous American Journal of Kidney Disease 25(2) (February 238 Cherin et al. ‘‘Management of adverse events.’’ immunoglobulin in older persons.’’ Drugs Aging 1995): 228. 75. 28(9) (2011): 732. 234 Stephen Jolles, W.A. Carrock-Sewell and Carol 239 Hamrock, ‘‘Adverse events associated.’’ 537. 224 Hamrock, ‘‘Adverse events associated.’’ 538. Leighton, ‘‘Drug-induced aseptic meningitis.’’ Drug 240 Hamrock, ‘‘Adverse events associated.’’ 537. 225 Hamrock, ‘‘Adverse events associated.’’ 538. Safety 3 (March 2000): 216. 241 Jolles et al. ‘‘Drug-induced.’’ 221.

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cannot produce new cells fast enough to Other Conditions of Special Interest to composition. Some forms of blood maintain RBC levels, resulting in VIGIV glucose monitoring equipment may anemia. The body is unable to transport A. Thrombotic Events falsely identify the presence of maltose oxygen effectively, and the person as an elevated blood glucose level. develops hypoxia (oxygen starvation). A thrombotic event involves the Treating this false reading by providing Additionally, the rapid breakdown of formation of a blood clot within a blood supplemental insulin could result in the cell releases large amounts of vessel. This clot restricts flow of blood hypoglycemia (low blood sugar) in potassium into the blood stream, which back to the heart and lungs in the area patients receiving VIGIV.255 can cause abnormal heart rhythms. distal to (behind) the clot. Once formed There is compelling, reliable, valid, Breakdown of RBCs also releases large the clot poses a risk of dislodging, medical and scientific evidence that the amounts of hemoglobin which may becoming an embolism, floating to a use of VIGIV may lead to false result in renal damage. In severe cases smaller blood vessel in the brain, lung, measurements of elevated blood glucose of hemolysis, a blood transfusion may or heart and causing tissue death in one levels if the appropriate testing methods be required to correct the resulting of these areas resulting in a stroke, are not used. However, these falsely anemia.242 pulmonary embolism, or heart attack, elevated blood glucose levels in and of Conditions that contribute to respectively. People with a history of themselves are not harmful unless hemolysis include immune reactions, atherosclerosis (blood vessel disease), treated inappropriately. Since false test infections, toxins, poisons, multiple cardiovascular risk factors, results alone do not meet the Program’s hemodialysis, and medications. advanced age, impaired cardiac output, definition of a serious injury, the Immunoglobulins cause hemolysis in hypercoagulable disorders (blood Secretary does not propose adding certain individuals due to blood group clotting disorders), prolonged periods of interference with blood glucose testing antibodies. These antibodies cause RBCs immobilization and known or suspected as a Table injury with the use of VIGIV. to be coated with immune globulin, hyperviscosity (thickening of the blood) However, claims of hypoglycemia which leads to an anti-globulin reaction are at increased risk of thrombus resulting from the treatment of falsely 243 249 250 251 252 253 and hemolysis. Individuals with non- formation. Additional risk elevated blood glucose levels will be group O type blood may be more factors for forming a thrombus include considered a non-Table injury and will susceptible to hemolysis in conjunction smoking, obesity, pregnancy, and the be evaluated on a case-by-case basis 244 with the use of immunoglobulin. use of oral contraceptives.254 based on the Program’s evidence There may also be a relationship Medical and scientific literature standard. between hemolysis and the total supports an association between the use accumulative amount of of VIGIV and thrombotic events. There C. Infectious Contamination immunoglobulin received by an are a number of predisposing factors, As immunoglobulins generally and individual. Individuals who have which may increase an individual’s risk VIGIV specifically are products derived received a larger accumulative dose of of developing a thrombus in association from human blood plasma, there is a immunoglobulin had a greater with the use of immunoglobulins. Since risk, however slight, of the product 245 likelihood of developing hemolysis. multiple external factors play a role in being contaminated with human Based on existing scientific and the development of a thrombus, a viruses. Prior to donating plasma, all medical literature, the Program’s timeframe for the onset of a thrombotic donors are tested for certain infectious evidence standard has been met, and event after the use of VIGIV that meets diseases. Additionally, during the development of hemolysis after the use the Program’s evidence standard cannot processing of plasma into VIGIV, it or administration of VIGIV is a serious be determined. Therefore, claims for undergoes treatment to remove and or physical injury proposed to be added to thrombotic events associated with the kill infectious organisms. It is possible, the Table. As noted by Berg, et al., the use of VIGIV will be considered a non- however, that an individual could onset of hemolysis associated with the table injury and evaluated on a case-by- potentially obtain a blood-borne use of VIGIV is anticipated to develop case basis based on the Program’s infection from receiving VIGIV.256 between 12 hours and 14 days from the evidence standard. The medical literature supports the administration of VIGIV.246 247 theoretical possibility of infectious Therefore, the Secretary proposes B. Interference With Blood Glucose contamination of VIGIV; however, as adding hemolysis as a Table injury with Testing there is no compelling, reliable, valid, a time of onset from 12 hours to 14 days As noted above, VIGIV uses maltose, medical or scientific evidence linking for the first symptom or manifestation to a disaccharide or sugar, in its VIGIV to a specific infection meeting the occur after the administration or use Program’s definition of a serious injury, after of VIGIV.248 qualitative analysis of 263 cases reported to four manufacturers between 2003 and 2012.’’ each claim for unintended infections 242 Cherin et al. ‘‘Management of adverse events.’’ Transfusion 55 (July 2015): S40. caused by the receipt of VIGIV will be 78. 249 Cangene Corporation, ‘‘Vaccinia immune considered on a case-by-case basis based 243 Vaccinia immune globulin intravenous globulin intravenous package insert.’’ (2005): 6. on the Program’s evidence standard. package insert. 250 Hamrock, ‘‘Adverse events associated.’’ 538– 244 Cherin et al. ‘‘Management of adverse events.’’ 539. Cidofovir 251 Cherin et al. ‘‘Management of adverse events.’’ 78. Cidofovir is a medication that is only 245 Cherin et al. ‘‘Management of adverse events.’’ 76–77. 78. 252 Gregory W. Daniel et al. ‘‘Immune globulins approved to treat cytomegalovirus 246 Zohra Daw et al. ‘‘Hemolytic transfusion and thrombotic adverse events as recorded in a retinitis in HIV-infected persons. reactions after administration of intravenous large administrative database in 2008 through However, it has been included in some immune (gamma) globulin: a case series analysis.’’ 2010.’’ Transfusion 52 (October 2012): 2117. recommendations as a potential second- Transfusion 48(8) (August 2008): 1598. 253 Cheng et al. ‘‘Special considerations with the 247 Scott Winiecki et al. ‘‘Complementary use of use.’’ 733. line agent that might be used under an passive surveillance and mini-sentinel of better 254 Mayo Clinic, ‘‘Diseases and conditions-Deep characterize hemolysis after immune globulin.’’ vein thrombosis (DVT). (August 10, 2018). 255 Cangene Corporation, ‘‘Vaccinia immune Transfusion 55 (July 2015): s30. Available from https://www.mayoclinic.org/ globulin intravenous package insert.’’ (2005): 6. 248 Roger Berg et al. ‘‘Hemolytic events associated diseases-conditions/deep-vein-thrombosis/ 256 Cangene Corporation, ‘‘Vaccinia immune with intravenous immune globulin therapy: a symptoms-causes/syc-20352557. globulin.’’ 7–8.

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investigational protocol when treatment epithelial cells of the kidney, and this insufficient compelling, reliable, valid, with VIGIV is not sufficient or not combined with other factors can lead to medical and scientific evidence that available to treat adverse events related the development of ARF.259 The factors these injuries are directly caused by to the smallpox vaccine, based on that may contribute to, or precipitate, cidofovir. Therefore, the Secretary does studies in animals.257 It might ARF when using cidofovir include: (1) not propose to add these injuries to the sometimes be used (preferably under an Pre-existing renal insufficiency or use of Table at this time. Claims for these IND protocol) for serious vaccine cidofovir in patients at risk of injuries associated with cidofovir will adverse events, such as eczema developing renal insufficiency; (2) be considered on a case-by-case basis as vaccinatum or progressive vaccinia, if increased baseline serum creatinine non-Table injuries. other potential countermeasures are not concentration greater than 1.5 mg/dL, available or not working. Reports baseline creatinine clearance less than Tecovirimat indicate some activity in the laboratory 55mL/min; (3) baseline urine protein Tecovirimat is a small-molecule against vaccinia and variola viruses, but concentration greater than 100 mg/dL, antiviral oral drug that has been there is currently no human data 2+ proteinuria (protein in the urine); or approved for the treatment of smallpox showing efficacy against any poxvirus (4) glycosuria (glucose or sugar in the under the Animal Rule 262 which in infection. Cidofovir is injected through urine) and concomitant use of 260 certain instances allows for approval a needle into the vein. The co- nephrotoxic drugs. administration of intravenous fluids The compelling, reliable, valid, based on adequate and well-controlled (fluids given through the vein) and medical and scientific evidence, animal efficacy studies. An intravenous probenecid have been shown to regarding the clinical use of this formulation is presently under decrease the renal side effects of medication in treating the complications development. Although extensively cidofovir. Cidofovir is a pregnancy of smallpox vaccination, and other types tested in animal models, the drug has category ‘‘C’’ meaning that can cause of infections, indicates that there is an had no efficacy testing in humans due severe birth defects in pregnant women. increased risk of developing ARF with to the eradication of naturally occurring Cidofovir is excreted in breast milk, the use of cidofovir. However, the smallpox, but an acceptable safety therefore, nursing mothers should not literature does not establish an exact profile has been demonstrated in receive cidofovir or discontinue time of onset for the possible healthy human volunteers. It is also nursing.258 development of ARF after using possible that it would be used as an The major adverse events associated cidofovir. The increased risk of investigational treatment for certain with the use of cidofovir are kidney developing ARF is individually based serious vaccinia vaccine adverse events. injury that can lead to kidney failure and may be influenced by the patient’s In a clinical trial with 359 participants and a decreased number of white blood age, fluid status, baseline renal function, receiving tecovirimat, 21 individuals cells, which may in turn lead to and the level of infection at the time the reported minor adverse side effects.263 increased susceptibility to infections. medication is administered. Because an Due to the limited information regarding Additionally, the following have been exact timeframe for the onset of ARF possible adverse reactions associated reported with the use of cidofovir: with the use of cidofovir cannot be with tecovirimat, there is presently no Decreased pressure in the eye, swelling established by compelling, reliable, and compelling, reliable, valid, medical and and tenderness of the eye, and buildup valid medical and scientific evidence, scientific evidence of any injury directly of acid in the body that can result in the Secretary does not propose caused by tecovirimat. Therefore, the liver abnormalities and inflammation of including ARF after the use of cidofovir Secretary does not propose to add any the pancreas that can result in death. as a Table injury. Claims for ARF injuries to the Table as associated with Other symptoms include fever, associated with the use of cidofovir will tecovirimat at this time, and claims for infection, pneumonia, shortness of be considered a non-Table injury and injuries associated with it will be breath, and nausea with vomiting. evaluated on a case-by-case basis based considered a non-Table injury and At this time, the Secretary is not on the Program’s evidence standard. evaluated on a case-by-case basis based proposing to add any injuries to the Other Conditions on the Program’s evidence standard. Table related to the use of cidofovir. The following injuries have been Claims of injuries associated with the Brincidofovir associated with the use of cidofovir: use of cidofovir will be considered as a neutropenia (abnormally low Brincidofovir is a broad-spectrum non-Table injury and evaluated on a concentration of the white blood cells, antiviral agent, which has activity in the case-by-case basis based on the neutrophils), decreased intraocular laboratory against a number of double Program’s evidence standard. pressure and metabolic acidosis (an stranded DNA (dsDNA) viruses and has Conditions of Special Interest to imbalance of the acid/base balance been under investigation for its Cidofovir within the body).261 Although potential clinical utility. It might be used as an investigational treatment of Acute Renal Failure documented in medical case studies, most of these data were collected from some serious vaccinia vaccine Acute renal failure (ARF), associated patients with significant co-morbidities, complications and is under with the use of cidofovir, can occur after including organ transplants, and/or who development for possible use against as few as one or two doses and in some were taking other medications, such as smallpox, but its role in treating any of cases has been reported as resulting in immunosuppressants. There is these infections has not been dialysis or contributing to death. It is established. Brincidofovir is a believed that cidofovir is toxic to the 259 Hassane Izzedine, Vincent Launay-Vacher and nucleotide analog of the drug, cidofovir; Gilbert Deray, ‘‘Antiviral drug-induced however, brincidofovir is likely to 257 Cono et al. ‘‘Smallpox vaccination and adverse nephrotoxicity.’’ American Journal of Kidney demonstrate a different spectrum of reactions.’’ 14. Diseases 45(5) (May 2005): 804. 258 Mylan Institutional LLC. Cidofovir package 260 Mylan Institutional LLC. Cidofovir package insert. https://dailymed.nlm.nih.gov/dailymed/ insert. 262 See 21 CFR part 314 Subpart I. drugInfo.cfm?setid=56541229-8c1a-4550-8951- 261 Cono et al. ‘‘Smallpox vaccination and adverse 263 U.S. Food and Drug Administration. ‘‘Drug 2415ed08e7e9. reactions.’’ 19–20. Trial Snapshot: TPOXX.’’ (July 13, 2018): 1–2.

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toxicity when compared to cidofovir.264 covered countermeasure is Review Act (5 U.S.C. 804(2)), the Specifically, gastrointestinal toxicity ineffective).266 Regulatory Flexibility Act (RFA) (including severe diarrhea) and (September 19, 1980, Pub. L. 96–354), Other Proposed Changes to Section 42 hepatotoxicity have been observed in section 202 of the Unfunded Mandates CFR 110.100 clinical trials of brincidofovir; however, Reform Act of 1995 (March 2, 1995; Pub. most of these data were collected from In light of the proposed additions L. 104–4), section 654(c) of the Treasury patients with significant co-morbidities, related to the inclusion of the Smallpox and General Government including patients’ post-stem cell or Countermeasure Injury Table, this Appropriations Act of 1999, and solid organ transplantation who were NPRM also proposes changes to section Executive Order 13132 on Federalism taking other medications, such as 110.100. First, revisions are proposed to (August 4, 1999). immunosuppressants.265 the introductory text of paragraph (b). Executive Order 12866 requires all Due to the challenges inherent in These revisions are intended to clarify regulations reflect consideration of evaluating the available safety data that paragraph (b) relates to the alternatives, costs, benefits, incentives, regarding possible adverse reactions Pandemic Influenza Countermeasure equity, and available information. associated with brincidofovir, there is Injury Table in paragraph (a). The Regulations must meet certain no compelling, reliable, valid, medical NPRM also proposes to revise paragraph standards, such as avoiding an and scientific evidence of any injury (c) by deleting the current language and unnecessary burden. Regulations that directly caused by brincidofovir. replacing it with the proposed Smallpox are ‘‘significant’’ because of cost, Therefore, the Secretary does not Countermeasures Injury Table. The adverse effects on the economy, propose to add any injuries to the Table language in current paragraph (c) inconsistency with other agency actions, as associated with brincidofovir at this indicates that the Secretary publishes effects on the budget, or novel legal or time, and claims for injuries associated information about certain covered policy issues, require special analysis. with it will be considered a non-Table countermeasures in the Federal In 2011, President Obama supplemented injury and evaluated on a case-by-case Register. The Secretary proposes to and reaffirmed Executive Order 12866. basis based on the Program’s evidence delete the current language in paragraph Executive Order 13563 provides that, (c) because it is unnecessary and for standard. to the extent feasible and permitted by accuracy as, when declarations are law, the public must be given a Smallpox Infection Diagnostic Testing updated, the language becomes out of meaningful opportunity to comment on Devices date. Finally, the NPRM proposes to add any proposed regulations, with at least Presently, there is no compelling, paragraph (d) to include the Smallpox a 60-day comment period. In addition, reliable, valid, medical and scientific Countermeasures Injury Table’s to the extent feasible and permitted by evidence demonstrating a causal qualifications and aids to interpretation law, agencies must provide timely (table definitions and requirements). association between smallpox infection online access to both proposed and final rules of the rulemaking docket on diagnostic testing devices and any Impact on Family Well-Being serious injuries. Therefore, the Secretary https://www.regulations.gov/, including This NPRM will not adversely affect relevant scientific and technical does not propose to add any injuries to the following elements of family well- findings, in an open format that can be the Table as associated with diagnostic being: family safety, family stability, searched and downloaded. Federal testing devices at this time. Any claims marital commitment; parental rights in agencies must consider approaches to of injury from the use or administration the education, nurture, and supervision maintain the freedom of choice and of smallpox infection diagnostic testing of their children; family functioning, flexibility, including disclosure of devices will be considered as non-Table disposable income, or poverty; or the relevant information to the public. injuries and evaluated on a case-by-case behavior and personal responsibility of Objective scientific evidence guides basis based on the Program’s evidence youth, as determined under section regulations and should be easy to standard. 654(c) of the Treasury and General understand, consistent, and written in The Program will not compensate Government Appropriations Act of plain language. Furthermore, federal claims merely because a diagnostic test 1999. In fact, this NPRM may have a agencies must attempt to coordinate, provides inaccurate results, such as positive impact on the disposable simplify, and harmonize regulations to failure to diagnose the presence of a income and poverty elements of family reduce costs and promote certainty for smallpox infection or yielding a positive well-being to the extent that injured the public. result of a smallpox infection that is not persons or their families may receive Executive Order 13771 (January 30, present. The Program also cannot medical, lost employment income, and/ 2017) requires that the costs associated compensate for injuries that are the or death benefits paid under this part with significant new regulations ‘‘to the direct result of the covered condition or without imposing a corresponding extent permitted by law, be offset by the disease for which the countermeasure burden on them. elimination of existing costs associated was administered or used, and that are with at least two prior regulations.’’ The not the direct result of the IV. Statutory and Regulatory Requirements designation of this rule, if finalized, will administration or use of the covered be informed by public comments countermeasure (for example, if the A. Executive Orders 12866, 13563, and received; however, if finalized as 13771: Regulatory Planning and Review proposed, this rule would be neither 264 Lawrence C. Trost et al. ‘‘The efficacy and HHS examined the impact of this regulatory nor deregulatory for purposes pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: A model of proposed rule as required by Executive of E.O. 13771. There are no additional smallpox disease.’’ Antiviral Research 117 (2015): Order 12866 on Regulatory Planning costs; the proposed rule, if finalized, 115. and Review (September 30, 1993), will only change how HRSA expends 265 Francisco Marty et al. ‘‘A randomized, double- Executive Order 13563 on Improving the appropriated funds. blind, placebo-controlled phase 3 trial of oral Regulation and Regulatory Review brincidofovir for cytomegalovirus prophylaxis in Summary of Impacts allogeneic hematopoietic cell transplantation.’’ (January 18, 2011), the Congressional Biology of Blood and Marrow Transplant 25(2019) In this NPRM, the Secretary proposes 369–381. 266 See 42 CFR 110.20(d). a Table identifying serious physical

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injuries that shall be presumed to result The Secretary also determined that D. Collection of Information from the administration or use of the this NPRM does not meet the criteria for This NPRM has no information covered countermeasures, and the time a major rule as defined by Executive collection requirements. interval in which the onset of the first Order 12866 and would have no major symptom or manifestation of each such effect on the economy or federal List of Subjects in 42 CFR Part 110 serious physical injury must manifest in expenditures. The Secretary determined Biologics, Immunization. order for such presumption to apply. that this NPRM is not a ‘‘major rule’’ The Secretary is also proposing Table Dated: August 24, 2020. within the meaning of the statute Thomas J. Engels, definitions and requirements. This providing for Congressional Review of Administrator, Health Resources and Services proposed rule would have the effect of Agency Rulemaking, 5 U.S.C. 801. affording certain persons a presumption Administration. that particular serious physical injuries This rule is not being treated as a Approved: September 14, 2020. occurred as the result of the ‘‘significant regulatory action’’ under Alex M. Azar II, administration or use of covered section 3(f) of Executive Order 12866. Secretary, Department of Health and Human countermeasures. The Table, if Accordingly, the rule has not been Services. implemented, will establish a reviewed by the Office of Management Therefore, for the reasons stated in the presumption of causation and relieve and Budget. preamble, the Department of Health and Human Services proposes to amend 42 requesters of the burden of B. Unfunded Mandates Reform Act of CFR part 110 as follows: demonstrating causation for covered 1995 injuries listed on the Table. However, PART 110—COUNTERMEASURES this presumption is rebuttable based on The Secretary determined that this INJURY COMPENSATION PROGRAM the Secretary’s review of the evidence. NPRM will not have effects on state, This Table also may afford some local, or tribal governments or on the ■ 1. The authority citation for part 110 requesters a new filing deadline. private sector such as to require continues to read as follows: consultation under the Unfunded Rather than showing that a serious Authority: 42 U.S.C. 247d–6e. Mandates Reform Act of 1995. This physical injury or death directly ■ 2. Amend § 110.100 by revising resulted from an injury included on the NPRM comports with the 2011 paragraph (b) introductory text and Table, individuals may, in the supplemental requirements. paragraph (c), and adding paragraph (d) alternative, receive compensation if they C. Executive Order 13132—Federalism to read as follows: can show that a covered countermeasure caused an injury or death. This NPRM The Secretary also reviewed this § 110.100 Injury Tables. is based upon legal authority. NPRM in accordance with Executive * * * * * The Secretary has determined that Order 13132 regarding federalism, and (b) Qualifications and aids to minimal resources are required to has determined that it does not have interpretation (table definitions and implement the provisions included in ‘‘federalism implications.’’ This NPRM, requirements). The following definitions this NPRM. Therefore, in accordance if implemented, would not ‘‘have and requirements shall apply to the with the Regulatory Flexibility Act of substantial direct effects on the states, or table set forth in paragraph (a) of this 1980 (RFA) and the Small Business on the relationship between the national section and only apply for purposes of Regulatory Enforcement Fairness Act of government and the states, or on the this subpart. 1996, which amended the RFA, the distribution of power and * * * * * Secretary certifies that this NPRM will responsibilities among the various (c) Smallpox countermeasures injury not have a significant impact on a levels of government.’’ table. substantial number of small entities. Table 1 to paragraph (c)

Covered countermeasures Serious physical injury (illness, disability, injury, or Time interval (for first symptom or manifestation of 1 onset of injury after administration or use of covered under declarations condition) countermeasure, unless otherwise specified)

I. Smallpox Vaccines Rep- A. Anaphylaxis ...... A. 0–4 hours. lication-Deficient. B. Vasovagal Syncope ...... B. 0–1 hour. II. Smallpox Vaccines Rep- A. Anaphylaxis ...... A. 0–4 hours. lication-Competent. B. Vasovagal Syncope ...... B. 0–1 hour. C. Significant Local Skin Reaction ...... C. 1–21 days. D. Stevens-Johnson Syndrome/Toxic Epidermal D. 4–28 days. Necrolysis. E. Inadvertent Autoinoculation ...... E. 1–21 days. F. Generalized Vaccinia ...... F. 6–9 days. G. Eczema Vaccinatum ...... G. 3–21 days. H. Progressive Vaccinia ...... H. 3–21 days. I. Post-vaccinial Encephalopathy, Encephalitis or I. 5–14 days. Encephalomyelitis (PVEM). J. Vaccinial Myocarditis, Pericarditis, or Myopericarditis J. 0–21 days. (MP). III. Vaccinia Immunoglobulin A. Anaphylaxis ...... A. 0–4 hours. Intravenous (VIGIV). B. Transfusion-Related Acute Lung Injury (TRALI) ...... B. 0–72 hours. C. Acute Renal Failure (ARF) ...... C. 0–10 days. D. Drug-Induced Aseptic Meningitis (DIAM) ...... D. Within 48 hours after the first dose and up to 48 hours after the last dose of VIGIV.

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Covered countermeasures Serious physical injury (illness, disability, injury, or Time interval (for first symptom or manifestation of 1 onset of injury after administration or use of covered under declarations condition) countermeasure, unless otherwise specified)

E. Hemolysis ...... E. 12 hours to 14 days. IV. Cidofovir ...... A. No Condition Covered 2 ...... A. Not Applicable. V. Tecovirimat ...... A. No Condition Covered 2 ...... A. Not Applicable. VI. Brincidofovir ...... A. No Condition Covered 2 ...... A. Not Applicable. VII. Smallpox Infection Diag- A. No Condition Covered 2 ...... A. Not Applicable. nostic Testing Devices. 1 Serious physical injury as defined in 42 CFR 110.3(z). Only injuries that warranted hospitalization (whether or not the person was actually hospitalized) or injuries that led to a significant loss of function or disability will be considered serious physical injuries. 2 The use of ‘‘No condition covered’’ in the Table reflects that the Secretary at this time does not find compelling, reliable, valid, medical, and scientific evidence to support that any serious injury is presumed to be caused by the associated covered countermeasure. For injuries alleged to be due to covered countermeasures for which there is no associated Table injury, requesters must demonstrate that the injury occurred as the direct result of the administration or use of the covered countermeasure. See 42 CFR 110.20(b), (c).

(d) Qualifications and aids to neurological conditions, psychiatric be involved. Mucosal lesions generally interpretation (table definitions and conditions, seizures, trauma, and manifest as painful lesions in sites, such requirements). The following definitions situational as can occur with urination, as the mouth or eyes. Skin rash or and requirements shall apply to the defecation, or cough. This list is not lesions in SJS/TEN usually consist of Table set forth in paragraph (c) of this complete as other conditions that are red or purple raised areas (erythematous section and only apply for purposes of not associated with the vaccine also macules), blisters, and ulcerations. this subpart. may cause loss of consciousness. (5) Inadvertent Autoinoculation (IA). (1) Anaphylaxis. Anaphylaxis is an Episodes of recurrent syncope occurring IA is the spread of vaccinia virus from acute, severe, and potentially lethal after the applicable timeframe are not an existing vaccination site to a second systemic reaction that occurs as a single considered to be sequelae of an episode location usually by scratching the discrete event with simultaneous of syncope meeting the Table vaccination site and subsequently involvement of two or more organ requirements. spreading the virus, which produces a systems. Most cases resolve without (3) Significant local skin reaction. new vaccinial lesion on the same person sequelae. Signs and symptoms begin Significant local skin reaction is an who received the vaccination. IA is the within minutes to a few hours after unexpected and extreme response at the most common adverse event associated exposure. Death, if it occurs, usually vaccination or inoculation site that with the replication-competent results from airway obstruction caused results in a significant scar that is smallpox vaccine. by laryngeal edema or bronchospasm serious enough to require surgical (6) Generalized Vaccinia (GV). GV is and may be associated with intervention. The onset of this injury is a vaccinial infection that occurs from cardiovascular collapse. Other the initial skin lesion at the vaccination the spread of vaccinia from an existing significant clinical signs and symptoms site that generally occurs with vaccination or inoculation site, with the may include the following: Cyanosis, replication-competent smallpox use or administration of a replication- hypotension, bradycardia, tachycardia, vaccinations. Minor scarring or minor competent smallpox vaccine, to arrhythmia, edema of the pharynx and/ local reactions do not constitute a Table otherwise normal skin, resulting in or trachea and/or larynx with stridor injury. A robust take, defined as an area multiple new areas of vaccinial rash or and dyspnea. There are no specific of redness at the vaccination site that lesions. The vaccinia is believed to be pathological findings to confirm a exceeds 7.5 cm in diameter with spread through the blood. The rash or diagnosis of anaphylaxis. associated swelling, warmth and pain, is lesions, characterized by multiple (2) Vasovagal syncope. Vasovagal generally considered an expected blisters (vesicles or pustules) generally syncope (also sometimes called response to the vaccination or evolve in a similar sequence or manner neurocardiogenic syncope) means loss inoculation. A robust take, in itself, does as the original vaccination site. of consciousness (fainting) and loss of not constitute a Table injury, even when (7) Eczema Vaccinatum (EV). EV is postural tone caused by a transient the redness and swelling involves the the transmission or the spread of decrease in blood flow to the brain entire upper arm with associated vaccinia virus from a vaccination site, occurring after the administration of an enlargement and tenderness of the after the use or administration of a injected countermeasure. Vasovagal glands (lymph nodes) in the underarm replication-competent smallpox syncope is usually a benign condition, (axilla). vaccine, to skin that has been affected but may result in falling and injury with (4) Stevens-Johnson syndrome/Toxic by, or is currently affected with, eczema significant sequelae. Vasovagal syncope Epidermal Necrolysis (SJS/TEN). SJS/ or atopic dermatitis. EV is characterized may be preceded by symptoms, such as TEN is a spectrum of acute by lesions that include multiple blisters nausea, lightheadedness, diaphoresis hypersensitivity reactions that affects (vesicles or pustules), which generally (sweating), and/or pallor. Vasovagal skin, mucous membranes, and evolve in a similar sequence or manner syncope may be associated with sometimes, internal organs (systemic as the original vaccination site. The transient seizure-like activity, but toxicity) associated with the use or lesions may come together to form larger recovery of orientation and administration of replication-competent lesions. Lesions may also spread to consciousness generally occurs smallpox vaccines. For purposes of the patches of skin that have never been simultaneously. Loss of consciousness Table, both skin and mucous membrane involved with eczema or atopic resulting from the following conditions rash or lesions must be present. Rash or dermatitis. The new lesions, if cultured, will not be considered vasovagal lesion distribution must be widespread. will be positive for vaccinia virus. A syncope: Organic heart disease, cardiac Rash must not have a symmetric acral person with EV may become severely ill arrhythmias, transient ischemic attacks, distribution (affecting arms, hands, legs with signs and symptoms that involve hyperventilation, metabolic conditions, or feet). Two or more mucosal sites must the whole body (systemic illness), such

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as fever, malaise, or enlarged glands genetic disorder, or trauma would not there is sufficient evidence in the (lymph nodes). meet this Table definition. medical record of an occurrence of (8) Progressive Vaccinia (PV). PV is (10) Vaccinial Myocarditis, TRALI and the pulmonary edema is not the failure to initiate the healing process Pericarditis, or Myopericarditis (MP). caused by cardiac dysfunction or other in an initial vaccination or inoculation For purposes of the Table, MP is causes and occurs within 72 of receiving site, after the use or administration of a vaccinial myocarditis, pericarditis, or a blood product containing plasma, in replication-competent smallpox myopericarditis. Vaccinial myocarditis this case VIGIV. vaccine, by 21 days after exposure to is defined as an inflammation of the (12) Acute Renal Failure (ARF). ARF vaccinia, with progressive ulceration or heart muscle (myocardium) because of is the sudden loss of the kidneys’ ability necrosis at the vaccination site leading receiving the replication-competent to perform their main function of to a large destructive ulcer. PV is seen smallpox vaccine. Vaccinial pericarditis eliminating excess fluids and in people who are is defined as an inflammation of the electrolytes (salts), as well as waste immunocompromised (have an covering of the heart (pericardium) material from the blood. ARF, which is impaired immune system) and is because of receiving the smallpox also called acute kidney injury, characterized by a complete or near vaccine. Vaccinial myopericarditis is develops rapidly over a few hours or a complete lack of inflammation or defined as an inflammation of both the few days. ARF can be fatal and requires absence of inflammatory cells in the heart muscle and its covering because of intensive treatment; however, ARF may dermis of the skin at the vaccination receiving the smallpox vaccine. The be reversible. ARF may cause site. The diagnosis of PV may be made inflammation associated with MP may permanent loss of kidney function, or before 21 days after exposure, especially range in severity from very mild end-stage renal disease necessitating in a known immunocompromised (subclinical) to life threatening. In many dialysis or transplant. A Table injury for individual who develops a lesion at the mild cases, myocarditis is diagnosed ARF has occurred if there is sufficient vaccination site. PV may spread through solely by; transient electrocardiographic evidence in the medical record of an the blood to any location in the body. (EKG) abnormalities (e.g., ST segment occurrence of ARF within the identified No one who experiences a significant and T wave changes), increased cardiac timeframe and the individual received healing process of the vaccination site enzymes, or mild echocardiographic the associated countermeasure (VIGIV). within 21 days after receipt of the abnormalities. Arrhythmias, abnormal (13) Drug-Induced Aseptic Meningitis replication-competent smallpox vaccine heart sounds, heart failure, and death (DIAM). DIAM is an inflammation of the or exposure to vaccinia has PV. may occur in more severe cases. meninges (linings of the brain) that is (9) Post-vaccinial Encephalopathy, Pericarditis generally manifests with not caused by a bacteria or virus, but is Encephalitis, and Encephalomyelitis chest pain, abnormal heart sounds caused by a drug or medication. The (PVEM). PVEM is a spectrum of (pericardial friction rub), EKG symptoms of meningitis include severe overlapping conditions that includes abnormalities (e.g., ST segment and T headache, nuchal (neck) rigidity, post-vaccinial encephalopathy, wave changes), and/or increased fluid drowsiness, fever, photophobia (light encephalitis, and encephalomyelitis, accumulation around the heart. A Table sensitivity), painful eye movements, and, for the purposes of this Table, is injury of MP requires sufficient nausea, and vomiting. Discontinuation treated as one injury. For the purposes evidence in the medical records of the of the medication leads to a resolution of the Table, PVEM is an autoimmune occurrence of acute MP. of the symptoms. DIAM is thought to central nervous system injury that (11) Transfusion-Related Acute Lung occur because of an immunological occurs after the use or administration of Injury (TRALI). TRALI is defined as the hypersensitivity reaction to a specific a replication-competent smallpox onset of respiratory distress within 6 medication. In the case of vaccine. In rare cases, the vaccinia virus hours in non-critically ill patients, and immunoglobulins, DIAM may be is isolated from the central nervous 72 hours in critically ill patients, after precipitated by the immunologically system. Manifestations usually occur receipt of blood products containing active components within the plasma or abruptly and may include fever, plasma, in this case, VIGIV. The relative because of the stabilizers used within vomiting, loss of appetite (anorexia), level of illness will be determined on a the product. The symptoms of DIAM headache, general malaise, impaired case-by-case basis after reviewing the may reoccur with another exposure to consciousness, confusion, medical records and the medical the offending agent. A Table injury for disorientation, delirium, drowsiness, history. The respiratory distress is the DIAM has occurred in a recipient if seizures, language difficulties (aphasia), result of receiving a plasma containing there is sufficient evidence in the coma, muscular incoordination (ataxia), transfusion (VIGIV) and subsequently medical record of an occurrence of urinary incontinence, urinary retention, developing pulmonary edema, DIAM within the identified timeframe and clinical signs consistent with respiratory distress, and hypoxia. TRALI and the individual received the inflammation of the spinal cord occurs as the result of an antibody associated countermeasure (VIGIV). (myelitis), such as paralysis or response in the host to the donor DIAM occurring in the absence of the meningismus (meningeal irritation). antibodies within the plasma product. use of VIGIV, or DIAM occurring with Long-term central nervous system Pulmonary edema is non-cardiac in the use of VIGIV outside the established impairments, such as paralysis, seizure nature and does not occur more than 72 timeframe of onset, which is any time disorders, or developmental delays are hours after receiving VIGIV. Pulmonary after the first dose and up to 48 hours known to occur as sequelae of the acute edema occurring more than 72 hours after the last dose of this medication, is PVEM. No clinical criteria, radiographic after receiving a blood product not a Table injury. findings, or laboratory tests are specific containing plasma (VIGIV) or associated (14) Hemolysis. Hemolysis is the for the diagnosis of PVEM. Symptoms with cardiac dysfunction is not TRALI physical breakdown of red blood cells that occur before 5 days or more than 14 and is excluded as a countermeasure- (RBCs) either through natural attrition days after receiving the smallpox related injury. TRALI has been or as caused by external factors. The vaccine should not be attributed it. In identified as a major cause of mortality RBC’s function is to transport oxygen addition, encephalopathy caused by an in those individual receiving plasma- throughout the body in the hemoglobin infection, a toxin, a metabolic containing transfusions. A Table injury contained within the RBC. Additionally, disturbance, a structural lesion, a for TRALI has occurred in a recipient if the RBCs contain the majority of the

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body’s potassium stores. With NMFS–2020–0091, by either of the overage, or other appropriate action. hemolysis, the body is unable to following methods: The specification of an ACT, which is transport oxygen effectively, and the • Electronic Submission: Submit all set below the ACL, can help ensure that person develops hypoxia. Additionally, electronic public comments via the the catch does not exceed the ACL. the rapid breakdown of the cell releases Federal e-Rulemaking Portal. Go to When used, an ACT also serves as the large amounts of potassium into the https://www.regulations.gov/ basis for invoking accountability blood stream, which can cause docket?D=NOAA-NMFS-2020-0091, measures. abnormal heart rhythms and cardiac click the ‘‘Comment Now!’’ icon, The Council recommended that arrest. In severe cases of hemolysis, a complete the required fields, and enter NMFS specify ACLs of 30,802 lb and blood transfusion may be required to or attach your comments. ACTs of 25,491 lb for MHI Kona crab for correct the resulting anemia. A Table • Mail: Send written comments to each of the 2020–2023 fishing years. injury for hemolysis has occurred if Michael D. Tosatto, Regional The fishing year for Kona crab is the there is sufficient evidence in the Administrator, NMFS Pacific Islands calendar year. The Council based its medical record of an occurrence of Region (PIR), 1845 Wasp Blvd., Bldg. recommendation on a 2018 benchmark hemolysis, and the patient received the 176, Honolulu, HI 96818. stock assessment of MHI Kona crab, associated countermeasure (VIGIV). Instructions: NMFS may not consider published in 2019, and in consideration Hemolysis occurring in the absence of comments sent by any other method, to of the best available scientific, the use of VIGIV and outside of the any other address or individual, or commercial, and other information timeframe of 12 hours to 14 days after received after the end of the comment about the fishery. The stock assessment receiving VIGIV is not a Table injury. period. All comments received are a estimated the overfishing limit for Kona Hemolysis occurring from a more likely part of the public record and will crab to be 33,989 lb. The proposed ACLs alternative diagnosis, such as infections, generally be posted for public viewing and ACTs are associated with a 38 toxins, poisons, hemodialysis, or on https://www.regulations.gov without percent and 20 percent risk of medications, is not a Table injury. This change. All personal identifying overfishing, respectively. These levels list of conditions that can cause information (e.g., name, address, etc.), are more conservative than the 50 hemolysis, not associated with VIGIV, is confidential business information, or percent risk threshold allowed under not exhaustive, and all additional otherwise sensitive information NMFS guidelines for National Standard diagnoses within the medical submitted voluntarily by the sender will 1 of the Magnuson Stevens Act. Catch documentation will be evaluated. be publicly accessible. NMFS will from State and Federal waters will count toward catch limits. NMFS does [FR Doc. 2020–20806 Filed 10–14–20; 8:45 am] accept anonymous comments (enter ‘‘N/ not anticipate that the fishery would BILLING CODE 4165–15–P A’’ in the required fields if you wish to remain anonymous). reach the proposed limit in any fishing NMFS prepared a draft environmental year, or that fishing for Hawaii Kona crab would be constrained during the DEPARTMENT OF COMMERCE assessment (EA) that describes the potential impacts on the human fishing year. NMFS proposes to implement both in- National Oceanic and Atmospheric environment that could result from the season and post-season AMs. Under the Administration proposed ACL and AM. The draft EA and other supporting documents are in-season AM (which is new for this fishery), when NMFS projects that the 50 CFR Part 665 available from www.regulations.gov. catch of Kona crab will reach the ACT, FOR FURTHER INFORMATION CONTACT: Kate [Docket No. 201008–0267] we would close the commercial and Taylor, NMFS PIRO Sustainable non-commercial fisheries for Kona crab RIN 0648–BJ84 Fisheries, 808–725–5182. in Federal waters for the remainder of SUPPLEMENTARY INFORMATION: Pacific Island Fisheries; 2020–2023 NMFS and the year. For the post-season AM, if Hawaii Kona Crab Annual Catch Limit the Council manage the Kona crab NMFS and the Council determine after and Accountability Measure fishery in the U.S. Exclusive Economic the end of each fishing year that the Zone (generally 3–200 nm from shore) catch exceeded the ACL, NMFS would AGENCY: National Marine Fisheries around Hawaii through the Fishery reduce the ACL and ACT in the Service (NMFS), National Oceanic and Ecosystem Plan for the Hawaiian subsequent fishing year by the amount Atmospheric Administration (NOAA), Archipelago (FEP) under the authority of the overage. In the event that the Department of Commerce. of the Magnuson-Stevens Fishery catch exceeds the ACT, but is below the ACTION: Proposed rule; request for Conservation and Management Act ACL, a post-season correction would not comments. (Magnuson-Stevens Act). The FEP be applied. NMFS will use the best contains a process for the Council and scientific information available to SUMMARY: This proposed rule would NMFS to specify ACLs, ACTs, and AMs; monitor the ACT and ACL, such as the establish annual catch limits (ACLs) of that process is codified at Title 50, Code monthly catch reporting required by 30,802 pound (lb) and annual catch of Federal Regulations, § 665.4 (50 CFR State of Hawaii Commercial Marine targets (ACTs) of 25,491 lb of main 665.4). The regulations require NMFS to License (CML) holders. Since NMFS Hawaiian Islands (MHI) Kona crab in specify an ACL and AM for each stock does not issue Federal fishing permits to 2020, 2021, 2022, and 2023. The and stock complex of management unit fish for Kona crab and instead relies on proposed rule would also establish in- species (MUS) in an FEP, as the CML, we have no way to directly season and post-season accountability recommended by the Council, and inform fishermen of an in-season measures (AMs). The proposed action considering the best available scientific, closure or post-season adjustment. supports the long-term sustainability of commercial, and other information NMFS will provide advance notice to the Hawaii Kona crab fishery. about the fishery. If a fishery exceeds an fishermen and the public through DATES: NMFS must receive comments ACL, the regulations require the Council available print and online publications by November 5, 2020. to take action, which may include if we implement an in-season closure or ADDRESSES: You may submit comments reducing the ACL for the subsequent a post-season correction. We will also on this document, identified by NOAA– fishing year by the amount of the request the State of Hawaii notify CML

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