Countermeasures Injury Compensation Program: Smallpox Countermeasures Injury Table, 65311-65336 [2020-20806]

Agencies

• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 85, Number 200 (Thursday, October 15, 2020)]
[Proposed Rules]
[Pages 65311-65336]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-20806]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

42 CFR Part 110

[Docket No. 2020-0003]
RIN 0906-AB22


Countermeasures Injury Compensation Program: Smallpox 
Countermeasures Injury Table

AGENCY: Health Resources and Services Administration (HRSA), HHS.

ACTION: Notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: The Department of Health and Human Services (HHS) proposes 
adding a Smallpox Countermeasures Injury Table (Table) for designated 
covered smallpox countermeasures identified in a declaration. The 
proposed Smallpox Countermeasures Injury Table includes a list of 
smallpox countermeasures, proposed time intervals for the first symptom 
or manifestation of onset of injury, and Qualifications and Aids to 
Interpretation, which set forth the definitions and requirements 
necessary to establish the Table injuries.

DATES: Written comments and related material to this proposed rule must 
be received to the online docket via www.regulations.gov, or to the 
mail address listed in the ADDRESSES section below, on or before 
December 14, 2020.

ADDRESSES: You may submit comments on this proposed rule identified by 
HHS Docket No. HRSA-2020-0003, by any one of the following methods:
    1. Federal eRulemaking Portal (preferred): www.regulations.gov.

[[Page 65312]]

Follow the website instructions for submitting comments.
    2. Mail: You may mail written comments to the following address 
only: Health Resources and Services Administration, Department of 
Health and Human Services, Attention: HRSA Regulations Officer, 5600 
Fishers Lane, Room 13N82, Rockville, MD 20857. Mail must be postmarked 
by the comment submission deadline.
    Because of staffing and resource limitations, and to ensure that no 
comments are misplaced, the Program cannot accept comments by facsimile 
(FAX) transmission. When commenting by any of the above methods, please 
refer to file code: #0906-AB22.

FOR FURTHER INFORMATION CONTACT: Please visit the Countermeasures 
Injury Compensation Program's website, https://www.hrsa.gov/cicp/, or 
contact Tamara Overby, Acting Director, Division of Injury Compensation 
Programs, Healthcare Systems Bureau, HRSA, 5600 Fishers Lane, Room 
08N146B, Rockville, MD 20857. Phone calls can be directed to (855) 266-
2427. This is a toll-free number.

SUPPLEMENTARY INFORMATION:

I. Public Participation

    HHS urges all interested parties to examine this regulatory 
proposal carefully and share your views, including data, to support 
your positions. We must consider all written comments received during 
the comment period before issuing a final rule. Subject to 
consideration of the comments received, the Secretary of Health and 
Human Services (the Secretary) intends to publish a final regulation.
    If you are a person with a disability and/or a user of assistive 
technology who has difficulty accessing this document, please see the 
website: https://www.hrsa.gov/about/508-resources.html to obtain this 
information in an accessible format. Please visit https://www.HHS.gov/regulations for more information on HHS rulemaking and opportunities to 
comment on proposed and existing rules.

II. Background and Purpose

    The Public Readiness and Emergency Preparedness Act (PREP Act) of 
2005, enacted as Division C of the Department of Defense, Emergency 
Supplemental Appropriations to Address Hurricanes in the Gulf of 
Mexico, and Pandemic Influenza Act, 2006 (Public Law 109-148), directs 
the Secretary to establish, through regulation, a Covered 
Countermeasures Injury Table (Table) identifying serious physical 
injuries presumed to be directly caused by the administration or use of 
covered countermeasures identified in PREP Act declarations issued by 
the Secretary. The Secretary may only add injuries to a Table if it is 
determined based on ``compelling, reliable, valid, medical and 
scientific evidence'' that the administration or use of the covered 
countermeasure directly causes such covered injuries.\1\ Such a Table 
informs the public about serious physical injuries supported by medical 
and scientific evidence known to be directly caused by covered 
countermeasures.
---------------------------------------------------------------------------

    \1\ Section 319F-4(b)(5)(A) of the Public Health Service Act, as 
amended (42 U.S.C. 247d-6e(b)(5)(A)).
---------------------------------------------------------------------------

    The purpose of a PREP Act declaration is to identify a disease, 
health condition, or threat to health that is currently, or may in the 
future constitute, a public health emergency. In addition, the 
Secretary, through a declaration, may recommend and encourage the 
development, manufacturing, distribution, dispensing, administration, 
or use of one or more covered countermeasures to treat, prevent, or 
diagnose the disease, condition, or threat specified in the 
declaration.\2\
---------------------------------------------------------------------------

    \2\ Section 319F-3(b) of the PHS Act (42 U.S.C 247d-6d(b)).
---------------------------------------------------------------------------

    This notice of proposed rulemaking (NPRM) concerns only the 
compensation program authorized by the PREP Act, not the liability 
protections set forth therein. Specifically, the PREP Act authorizes 
the Secretary to establish and administer the Countermeasures Injury 
Compensation Program (CICP or the Program) to provide timely, uniform, 
and adequate compensation to certain individuals who develop serious 
physical injuries or to certain survivors of individuals who die as a 
direct result of the use or administration of a covered countermeasure 
identified in a declaration.\3\ The Secretary delegated responsibility 
for establishing and administering the Program to HRSA.
---------------------------------------------------------------------------

    \3\ Section 319F-4(a) of the PHS Act (42 U.S.C. 247d-6e(a)).
---------------------------------------------------------------------------

    The PREP Act authorizes the Secretary to publish regulations to 
establish and administratively implement the Program. Specifically, the 
PREP Act authorizes the Secretary to determine Program eligibility, the 
process to apply for benefits, the methods of payments and amounts of 
compensation, and the process for further review of ``Requests for 
Benefits'' submitted by, or on behalf of, requesters. To be considered 
for compensation for any serious physical injury or death, an 
individual must submit a timely Request for Benefits with the required 
information.
    The Secretary published the interim final rule implementing the 
Program on October 15, 2010.\4\ The final rule, published on October 7, 
2011, explains the Program's policies, procedures, and requirements. 
Title 42 of the Code of Federal Regulations (CFR) Sec.  110.20(a) 
states that individuals must establish that a covered injury occurred 
to be eligible for benefits under the Program. A covered injury is a 
death or a serious injury determined to have occurred as a direct 
result of the administration or use of a covered countermeasure. The 
Secretary has determined that the list includes: (1) An injury meeting 
the requirements of covered countermeasures placed on an injury table, 
unless the Secretary determines there is another more likely cause; or 
(2) an injury (or health complications) that is the direct result of 
the administration or use of a covered countermeasure. This includes 
serious aggravation of a pre-existing condition caused by a covered 
countermeasure.\5\
---------------------------------------------------------------------------

    \4\ 75 FR 63656-63688; 42 CFR part 110.
    \5\ 42 CFR 110.3(g).
---------------------------------------------------------------------------

    Serious injury means serious physical injury. Serious injuries may, 
in certain circumstances, be considered physical or biochemical 
alterations leading to physical changes and serious functional 
abnormalities at the cellular or tissue level in any bodily function. 
As a general matter, 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 (whether or not 
hospitalization was warranted) will be considered serious injuries.\6\
---------------------------------------------------------------------------

    \6\ 42 CFR 110.3(z).
---------------------------------------------------------------------------

    The Secretary proposes adding a Smallpox Countermeasures Injury 
Table to subpart K of 42 CFR part 110 for designated covered smallpox 
countermeasures identified in declarations. The proposed Smallpox 
Countermeasures Injury Table includes a list of smallpox 
countermeasures, proposed time intervals for the first symptom or 
manifestation of onset of injury, and Qualifications and Aids to 
Interpretation, which set forth the definitions and requirements 
necessary to establish the Table injuries.
    The Table proposed in this NPRM is limited to covered smallpox 
countermeasures. To date, the CICP published a Pandemic Influenza 
Countermeasures Injury Table.\7\ Since the PREP Act mandates the

[[Page 65313]]

establishment of a Table identifying covered injuries that may be 
presumed to be directly caused by the administration or use of a 
covered countermeasure, the CICP may establish future Tables for other 
countermeasures relating to threats to health that pose or constitute 
potential public health emergencies. The PREP Act authorized the 
Secretary to create Tables for each covered countermeasure identified 
in a declaration if there is compelling, reliable, valid, medical and 
scientific evidence that the countermeasure directly causes a covered 
injury. Declarations have been issued with respect to countermeasures 
against pandemic influenza A viruses, anthrax, botulism, smallpox, 
acute radiation syndrome, Ebola, Zika, COVID-19, and nerve agents and 
certain insecticides (organophosphorus and/or carbamate). In the 
future, the Secretary may publish tables in the Federal Register 
through separate amendments to 42 CFR part 110 addressing additional 
covered countermeasures.
---------------------------------------------------------------------------

    \7\ 80 FR 47411, August 7, 2015.
---------------------------------------------------------------------------

    The CICP's Smallpox Countermeasures Injury Table is distinct from 
the Smallpox Vaccine Injury Table authorized under the Smallpox 
Emergency Personnel Protection Act of 2003 (SEPPA) (42 U.S.C. 239 et 
seq.). The SEPPA, enacted on April 30, 2003, authorized the Secretary 
to establish the Smallpox Vaccine Injury Compensation Program (SVICP). 
The SVICP provided benefits to certain persons who sustained a covered 
injury as the direct result of the administration of the smallpox 
vaccine or other covered countermeasure, and to certain individuals who 
sustained a covered injury as the direct result of accidental vaccinia 
inoculation (and/or death benefits to certain survivors of these 
individuals). The SVICP's implementing regulation was codified at 42 
CFR part 102, and included a Smallpox Vaccine Injury Table. The SEPPA's 
Declaration Regarding Administration of Smallpox Countermeasures, 
expired on January 23, 2008, and was not renewed. Vaccine recipients 
and accidental vaccinia contacts had 1 and 2 years, respectively, to 
file a request for program benefits. The SVICP ended on January 23, 
2010, and its outmoded regulations were rescinded on November 14, 2016. 
See 81 FR 62817-62818.
    Relying instead on later-enacted legislation, based on a credible 
risk that the threat of exposure to variola virus, the causative agent 
of smallpox, constitutes a public health emergency, the Secretary 
issued a Declaration (73 FR 61869-61871) covering smallpox 
countermeasures under the Public Readiness and Emergency Preparedness 
Act of 2005 (PREP Act), with an effective date of January 24, 2008. The 
PREP Act authorizes the establishment and administration of the CICP. 
The CICP's implementing regulation, at 42 CFR part 110, is based on the 
SVICP's regulation and provides similar benefits. On December 9, 2015, 
the PREP Act Declaration for smallpox countermeasures was amended and 
republished (80 FR 76546-76553), extending the effective time period to 
December 31, 2022, and deleting obsolete language referring to SEPPA.

Definition of Covered Countermeasure

    A ``covered countermeasure'' is defined in the PREP Act and 
includes three categories.\8\ The first category, consisting of 
``qualified pandemic or epidemic product[s],'' is defined in section 
319F-3(i)(7) of the PHS Act.\9\ A qualified pandemic or epidemic 
product means a drug or device, as defined in the Federal Food, Drug, 
and Cosmetic Act (FD&C Act), or a biological product, as defined in the 
PHS Act \10\ that is: (i) Manufactured, used, designed, developed, 
modified, licensed, or procured to diagnose, mitigate, prevent, treat, 
or cure a pandemic or epidemic or to limit the harm such pandemic or 
epidemic might otherwise cause; (ii) manufactured, used, designed, 
developed, modified, licensed, or procured to diagnose, mitigate, 
prevent, treat, or cure a serious or life-threatening disease or 
condition caused by such a drug, biological product, or device; (iii) 
or a product or technology intended to enhance the use or effect of 
such a drug, biological product, or device.\11\ To qualify as a 
pandemic or epidemic product, a drug, biologic, or device must be: (1) 
Approved or cleared under the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) or licensed under the PHS Act; (2) the subject of research 
for possible use and subject to an exemption under sections 505(i) or 
520(g) of the FD&C Act; or (3) authorized for emergency use in 
accordance with section 564, 564A, or 564B of the FD&C Act.
---------------------------------------------------------------------------

    \8\ Section 319F-3(i)(1) of the PHS Act (42 U.S.C. 247d-
6d(i)(1)).
    \9\ 42 U.S.C. 247d-6d(i)(7).
    \10\ 21 U.S.C. 321(g)(1), (h); 42 U.S.C. 262(i).
    \11\ Section 319F-3(i)(7)(A)(ii) of the PHS Act (42 U.S.C. 247d-
6d(i)(7)(A)(ii)).
---------------------------------------------------------------------------

    The second category includes ``security countermeasures.'' A 
security countermeasure, as defined in section 319F-2(c)(1)(B) of the 
PHS Act, is a drug or device \12\, as defined in the FD&C Act, or a 
biologic product, as defined in the PHS Act,\13\ that the Secretary 
determines is: (1) A priority to diagnose, mitigate, prevent harm or 
treat any biological, chemical, radiological, or nuclear agent 
identified as a material threat by the Secretary of Homeland Security, 
or to diagnose, mitigate, prevent harm or treat a condition that may 
result in adverse health consequences or death and may be caused by 
administering a drug, biological product, or device against such an 
agent; (2) is a necessary countermeasure to protect public health as 
determined by the Secretary of Health and Human Services; \14\ and (3) 
is approved or cleared under the FD&C Act \15\ or will likely be 
approved, cleared, or licensed within 10 years after the Department's 
determination that procurement of the countermeasure is appropriate or 
is authorized for emergency use under sections 564 of the FD&C Act.\16\
---------------------------------------------------------------------------

    \12\ 21 U.S.C. 321(g)(1), (h);42 U.S.C. 262(i).
    \13\ 21 U.S.C. 321(g)(1), (h);42 U.S.C. 262(i).
    \14\ 42 U.S.C. 247d-6d(i)(1)(B),(c)(1)(B).
    \15\ 21 U.S.C. 301 et seq.
    \16\ 21 U.S.C. 360bbb-3, 360bbb-3a, 360bbb-3b.
---------------------------------------------------------------------------

    The final category consists of drugs,\17\ biologics,\18\ or devices 
\19\ authorized for emergency use in accordance with section 564, 564A, 
or 564B of the FD&C Act.
---------------------------------------------------------------------------

    \17\ As defined in section 201(g)(1) of the FD&C Act (21 U.S.C. 
321(g)(1)).
    \18\ As defined in section 351(i) of the PHS Act (42 U.S.C. 
262(i)).
    \19\ As defined in section 201(h) of the FD&C Act (21 U.S.C. 
321(h)).
---------------------------------------------------------------------------

    To be eligible for the liability protections of the PREP Act or to 
receive benefits under the compensation provisions of the PREP Act, a 
covered countermeasure must meet one of these three categories and must 
be described in a declaration.

Covered Smallpox Countermeasures

    The Secretary issued two PREP Act declarations concerning smallpox 
countermeasures, pursuant to section 319F-3(b) of the PHS Act.\20\ On 
December 9, 2015, the Secretary amended the smallpox countermeasures 
declaration issued on October 10, 2008 \21\, pursuant to section 319F-3 
of the PHS Act \22\ to: (1) Include countermeasures authorized for use 
under section 564A and/or prepositioned under section 564B of the FD&C 
Act; \23\ (2) clarify the description of covered countermeasures; (3) 
extend the effective time period of the declaration; (4) reformat the 
declaration;

[[Page 65314]]

(5) modify or clarify terms of the declaration; and, (6) republish the 
declaration in its entirety, as amended.\24\
---------------------------------------------------------------------------

    \20\ See 73 FR 61869, October 10, 2008, as amended by 80 FR 
76546, December 9, 2015.; 42 U.S.C. 247d-6d(b).
    \21\ 73 FR 61869 (October 10, 2008); https://www.gpo.gov/fdsys/pkg/FR-2008-10-17/pdf/E8-24737.pdf.
    \22\ 42 U.S.C. 247d-6d.
    \23\ 21 U.S.C. 360bbb-3a and 360bbb-3b.
    \24\ 80 FR 76546 (December 9, 2015); https://www.gpo.gov/fdsys/pkg/FR-2015-12-09/pdf/2015-31092.pdf.
---------------------------------------------------------------------------

    Covered countermeasures under the declaration are ``any vaccine, 
including all components and constituent materials used in the 
administration of these vaccines, and all devices and their constituent 
components used in the administration of these vaccines; any antiviral; 
any other drug; any biologic; or any diagnostic or other device to 
identify, prevent or treat smallpox or orthopoxvirus or adverse events 
from such countermeasures.'' \25\ Moreover, these covered 
countermeasures ``must be `qualified pandemic or epidemic products,' or 
`security countermeasures,' or drugs, biological products, or devices 
authorized for investigational or emergency use as those terms are 
defined in the PREP Act, the FD&C Act, and the PHS Act.'' \26\ The 
covered countermeasures subject to this declaration that will be 
included on the proposed Table include smallpox vaccines, vaccinia 
immunoglobulin, cidofovir, tecovirimat, brincidofovir, and smallpox 
infection diagnostic testing.
---------------------------------------------------------------------------

    \25\ 80 FR 76546, 76552 (December 9, 2015).
    \26\ 80 FR 76546, 76552 (December 9, 2015).
---------------------------------------------------------------------------

General Information

    The Secretary proposes a Table for injuries directly resulting from 
the use or administration of covered smallpox countermeasures 
identified in the above-referenced declaration. The proposed Table 
lists serious physical injuries demonstrated by compelling, reliable, 
valid, medical and scientific evidence to be directly caused by the 
administration or use of the covered countermeasures (hereafter 
referred to as ``evidence standard'').\27\ Only injuries supported by 
this evidence standard are proposed for inclusion on the Table.
---------------------------------------------------------------------------

    \27\ Section 319F-4(b)(5)(A) of the PHS Act (42 U.S.C. 247d-
6e(b)(5)(A)).
---------------------------------------------------------------------------

    For each covered countermeasure, the proposed Table will include 
the covered injuries and/or conditions directly caused by such 
countermeasure and the applicable time intervals for the first symptom 
or manifestation of onset of injuries. The Program's statute directs 
that covered injuries presumed to be caused by the administration or 
use of a covered countermeasure must be included on a Table.\28\ The 
Secretary also proposes to indicate on the Table if no injuries or 
conditions qualify for a Table presumption for a particular 
countermeasure at this time. This is to reflect that consideration was 
given regarding the possibility of Table injuries for these covered 
countermeasures. Claims related to any injuries alleged to be caused by 
these countermeasures will be considered on a case-by-case basis.
---------------------------------------------------------------------------

    \28\ Section 319F-4(b)(5)(A) of the PHS Act (42 U.S.C. 247d-
6e(b)(5)(A)).
---------------------------------------------------------------------------

III. Discussion of Proposed Rule

    This NPRM proposes to amend the Program's implementing regulation 
\29\ and, if adopted, would establish a table of injuries resulting 
from the administration or use of smallpox covered countermeasures. 
Certain conditions that are currently not being proposed for inclusion 
on the Table also are discussed in this NPRM.
---------------------------------------------------------------------------

    \29\ 42 CFR part 110.
---------------------------------------------------------------------------

General Requirement of Serious Physical Injuries or Deaths

    By statute, only serious physical injuries or deaths directly 
resulting from the use or administration of a covered countermeasure 
may be compensable under the Program regardless of whether the injury 
is a Table injury or a non-Table injury. Because the requirement of a 
serious physical injury applies to all Requests for Benefits filed with 
the Program, the Secretary considered this requirement while drafting 
the proposed Table included in this NPRM.
    In general, only injuries or serious aggravation of injuries that 
warranted hospitalization (whether or not the person was actually 
hospitalized) or that led to a significant loss of function or 
disability will be considered serious physical injuries.\30\ It is 
recognized that the term ``disability'' can be defined in many ways, 
and there are several definitions used by the federal government 
specific to various programs and services. To provide further clarity 
as to the type of disability that would qualify as a serious injury for 
the Program, under this NPRM, the term ``disability'' is defined as ``a 
physical or mental impairment that substantially limits one or more 
major life activities of an individual.'' This definition corresponds 
with the first listed definition of disability in the Americans with 
Disabilities Act, 42 U.S.C. 12102(1)(A). This definition was chosen 
because it is consistent with the Program's existing authorities and 
adds further guidance by using a widely accepted definition familiar to 
the general public.
---------------------------------------------------------------------------

    \30\ 42 CFR 110.3(z).
---------------------------------------------------------------------------

    In addition, pursuant to 42 CFR 110.3(z), ``physical biochemical 
alterations leading to physical changes and serious functional 
abnormalities at the cellular or tissue level in any bodily function 
may, in certain circumstances, be considered serious physical 
injuries.'' According to the preamble to the CICP Administrative 
Implementation interim final rule, 42 CFR part 110, serious physical 
injuries also include ``instances in which there may be no measurable 
anatomic or structural change in the affected tissue or organ, but 
there is an abnormal functional change. For example, many psychiatric 
conditions are caused by abnormal neurotransmitter levels in key 
portions of the central nervous system. It is possible that certain 
serious psychiatric conditions will qualify as serious physical 
injuries if the psychiatric conditions are a manifestation of a 
physical biochemical abnormality in neurotransmitter level or type 
caused by a covered countermeasure. One way of determining that an 
abnormal physical change in neurotransmitter level is causing the 
injury would be a clinical challenge that demonstrates a positive 
clinical response to a medication that is designed to restore the 
balance of appropriate neurotransmitters necessary for normal function 
in an injured countermeasure recipient.'' \31\
---------------------------------------------------------------------------

    \31\ 75 FR 63656, 63661.
---------------------------------------------------------------------------

    Minor injuries do not meet the definition of a serious physical 
injury. For example, covered injuries do not include common and 
expected skin reactions (such as localized swelling or warmth that is 
not of sufficient severity to warrant hospitalization and does not lead 
to significant loss of function or disability). Expected minor 
reactions, such as headaches and body aches that commonly occur with 
other types of vaccinations, are not considered serious. However, if a 
minor injury leads to a serious physical injury, and the minor injury 
was directly caused by a covered countermeasure, the Program may 
compensate the individual for the serious physical injury. The injury's 
causal link to the countermeasure must be based on compelling, 
reliable, valid, medical and scientific evidence. Therefore, the 
Program will consider such claims on a case-by-case basis.

Serious Aggravation of Pre-Existing Conditions

    Injuries covered under the Program may include serious aggravations 
of pre-existing conditions if such aggravations were caused by a 
covered countermeasure (e.g., any disorder that is proven to the 
satisfaction of the Secretary to have been made significantly more 
severe as the direct

[[Page 65315]]

result of the administration or use of the covered countermeasure). The 
serious aggravation of the pre-existing condition must be supported by 
compelling, reliable, valid, medical and scientific evidence and show a 
direct causal link between the aggravation or worsening of the pre-
existing condition and the countermeasure. The Program will consider 
claims involving serious aggravations of pre-existing conditions on a 
case-by-case basis.

Table Time Intervals

    For each covered injury, the proposed Table describes the time 
interval between the administration or use of the covered 
countermeasure and the first symptom or manifestation of onset of 
injury after the administration or use of the countermeasure. In 
addition to meeting the requirements of the Table injury, the symptom 
or manifestation of onset of injury must have occurred within the Table 
time interval. The time intervals are based on compelling, reliable, 
valid medical and scientific evidence in which nearly all of the cases 
of injury are known to be actually caused by the covered 
countermeasure. As is the case for non-Table injuries, Table injuries 
not meeting the Table time intervals may be compensated, on a case-by-
case basis, based on adequate demonstration of compelling, reliable, 
valid, medical and scientific evidence supporting that the 
countermeasure had a causal role.

Table Definitions and Requirements

    The proposed Table also includes Qualifications and Aids to 
Interpretation, which set forth the definitions and requirements 
necessary to establish the Table injuries. For this reason, the Table 
definitions and requirements are part of the Table. To receive 
compensation for a Table injury, the individual must meet the time 
interval, Table definition, and any other Table requirements, in 
addition to the other Program requirements.

Presumption Created for Table Injuries

    For purposes of this Program, a rebuttable presumption exists that 
a Table injury was directly caused by the administration or use of a 
covered countermeasure if the first symptom or manifestation of onset 
of an injury listed on the Table occurred within the timeframe 
indicated, and the Table's definitions and requirements are satisfied. 
By statute, this presumption only applies to Table injuries.\32\ An 
individual may obtain this presumption of causation by submitting 
medical documentation demonstrating the covered injury occurred, that 
it began within the time interval specified on the Table after 
administration or use of a covered countermeasure and all other 
applicable Table requirements and definitions are met. Nevertheless, it 
may be rebutted if, based on review of the relevant medical and 
scientific evidence, the Secretary determines the Table injury was more 
likely caused by other factors and not directly caused by the 
countermeasure.
---------------------------------------------------------------------------

    \32\ Section 319F-4(b)(5)(A) of the PHS Act (42 U.S.C. 247d-
6e(b)(5)(A)).
---------------------------------------------------------------------------

Non-Table Injuries

    Compensation may be available for individuals who: (1) Develop an 
injury not included on the Table, (2) develop an injury that is 
included on the Table but the injury began outside the allotted time 
interval provided by the Table, or (3) develop an injury that does not 
satisfy the definition or requirements included in the Qualifications 
and Aids to Interpretation that accompanies the Table with respect to 
such injury. In these cases, the injured countermeasure recipient does 
not receive the presumption of causation for a Table injury and must 
demonstrate that the use or administration of the covered 
countermeasure directly caused the injury. The regulation 
administratively implementing the Program includes more information 
about the requirements for such an injury.\33\ For example, a temporal 
association between the administration or use of a covered 
countermeasure and onset of the injury (e.g., the injury occurs a 
certain time after the administration or use of the countermeasure) 
alone is not sufficient to show that an injury is the direct result of 
a covered countermeasure.\34\ Proof of a causal association for the 
non-Table injury must be based on compelling, reliable, valid, medical 
and scientific evidence.
---------------------------------------------------------------------------

    \33\ 42 CFR 110.20(c).
    \34\ 42 CFR 110.20(c).
---------------------------------------------------------------------------

Sequelae (Health Complications) of Table and Non-Table Injuries

    A requester may be entitled to benefits if the Program determines 
that the sequelae (health complications), including death, resulted 
from a Table injury. This is also applicable to a requester who 
develops sequelae from a non-Table injury, but only if the non-Table 
injury is shown to be directly caused by a covered countermeasure based 
on compelling, reliable, valid, medical and scientific evidence. The 
Program will consider compensation for sequelae that develop from Table 
and non-Table injuries on a case-by-case basis.

Injuries Sustained as a Result of the Smallpox Virus

    An individual will not have suffered a covered injury if a covered 
countermeasure is ineffective in diagnosing, preventing, or treating 
the underlying condition or disease for which the countermeasure was 
administered or used, and the individual sustains an injury caused by 
the condition or disease and not by the covered countermeasure. An 
injury sustained as the direct result of a disease, health condition or 
threat to health, for which the Secretary recommended the 
administration or use of a covered countermeasure in a declaration, is 
not a covered injury. The injury is not covered because it resulted 
from the disease itself and not from the administration or use of a 
covered countermeasure. For more information, see 42 CFR 110.20(d).

Amendments to the Proposed Table of Injuries

    The Secretary has the discretion to amend or modify the Table at 
any time while the Program remains operational. For example, the 
Secretary may amend the Table by adding or removing injuries, modifying 
the governing time intervals, and/or revising the Table definitions and 
requirements. New studies and evolving medical and scientific evidence 
will be reviewed by the Secretary to determine causal relationships 
between covered countermeasures and injuries or deaths. Changes to the 
Table will be implemented as amendments to 42 CFR part 110 and will be 
published in the Federal Register.

The Table in Effect at the Time a Claim is Filed

    The Table in effect when the Request for Benefits form is filed 
should be used, unless another Table is published after the claim is 
filed that provides greater benefit to the requester. If a new Table or 
an amendment to an existing Table would benefit a requester, as 
described in the following section, the requester may have an 
additional opportunity to file a Request for Benefits.

Filing Deadlines and Table Additions or Amendments

    In accordance with 42 CFR 110.42(f), in the event that the 
Secretary issues a new Covered Countermeasures Injury Table or amends a 
previously published Table, requesters may have an extended filing 
deadline based on the effective date of the Table amendment. An

[[Page 65316]]

extended filing deadline will apply only if the Table amendment enables 
requesters to establish an injury when they could not establish one 
previously. If the Table proposed in this NPRM is adopted, any person 
who meets the Table requirements for a newly listed injury after 
receiving the smallpox vaccine would have 1 year from the effective 
date of the Table's adoption to file a Request for Benefits. This 
filing deadline applies regardless of whether the requester previously 
filed a Request for Benefits with the Program.
    Individuals may seek compensation for one or more injuries stemming 
from a single administration of a covered countermeasure. However, if 
individuals previously received compensation for an injury through the 
Program, they may not re-file a claim for compensation if the same 
injury is later added to a Table. Not being able to re-file such claims 
avoids giving individuals the opportunity to receive additional 
compensation for the same serious physical injury. However, this does 
not preclude filing a Request for Benefits for an injury or aggravation 
of an injury, resulting from the subsequent administration or use of 
the same type of covered countermeasure. It also does not preclude 
subsequent Requests for Benefits for an injury, or an aggravation of a 
pre-existing condition, resulting from the administration or use of a 
different covered countermeasure or a different injury from the same 
countermeasure.
    Eligible requesters have one year from the date of administration 
or use of a covered countermeasure to file a Request for Benefits. 
Also, if an injury is added to a countermeasure injury table, then a 
requester has 1 year from the effective date of publication of the 
table revision to file a Request for Benefits for that injury.
    It is important to note that the additional filing deadline 
described in 42 CFR 110.42(f) is only available to persons whose 
Request for Benefits relates to a new or amended Table injury and 
otherwise meets the requirements of: (1) The new Table or the 
amendment(s) to a Table, (2) the Table time interval(s), (3) Table 
definitions, and (4) any other Table requirements. In this case, such 
persons may be eligible for the presumption of causation. Persons who 
sustained injuries not included on the new or amended Table, or those 
who do not meet all of the requirements for such a Table injury but may 
prove causation of the injury through other means, will not be afforded 
an additional 1-year filing deadline based on the Table amendment. 
Because the Table amendment would not enable such individuals to 
establish a Table injury, they would be subject to the standard filing 
deadline described in 42 CFR 110.42(a) (e.g., 1 year from the date of 
administration or use of the covered countermeasure).
    Eligible requesters have 1 year from the date of administration or 
use of a covered countermeasure to file a Request for Benefits. Also, 
if an injury is added to a countermeasure injury table, then the 
requester has 1 year from the effective date of publication of the 
table revision to file a Request for Benefits for that injury.
    It is important to note that the additional filing deadline 
described in 42 CFR 110.42(f) is only available to persons whose 
Request for Benefits meet the requirements of: (1) A new Table or an 
amendment(s) to a Table; (2) the Table time interval(s); (3) Table 
definitions; and (4) any other Table requirements. In this case, such 
persons may be eligible for the presumption of causation. Persons who 
sustained injuries not included on the Table, or those who do not meet 
all of the requirements for such a Table injury but may prove causation 
of the injury through other means, will not be afforded an additional 
1-year filing deadline based on the Table amendment. Because the Table 
amendment would not enable such individuals to establish a Table 
injury, they would be subject to the standard filing deadline described 
in 42 CFR 110.42(a) (e.g., 1 year from the date of administration or 
use of the covered countermeasure).

Smallpox Countermeasures Injury Table

    The proposed Table lists serious covered injuries directly caused 
by covered smallpox countermeasures. Although the occurrence of many of 
the injuries included on the Table is rare, the Secretary is including 
such injuries on the Table to ensure that people who are otherwise 
eligible for benefits and/or compensation under the Program will 
receive the Table's presumption of causation. The Table presumption can 
be rebutted if the Secretary determines, based on a review of the 
relevant evidence, that an injury meeting the Table requirements was 
more likely caused by other factors and not directly caused by the 
smallpox countermeasure. Claims involving injuries that do not meet the 
requirements of the Table may qualify as non-Table injuries and will be 
reviewed on a case-by-case basis by the Program.

Smallpox Background

    Smallpox is a highly contagious disease that may cause fever, a 
severe rash, and a high death rate. The variola virus causes smallpox 
disease. Variola is a large orthopoxvirus within the Poxviridae family. 
Other poxviruses that infect humans include molluscum contagiosum, 
vaccinia (the virus used in smallpox vaccine), and monkeypox.\35\
---------------------------------------------------------------------------

    \35\ Zack S. Moore, Jane F. Seward and J. Michael Lane, 
``Smallpox.'' Lancet 367; 9508: (2006): 425.
---------------------------------------------------------------------------

    The variola virus usually enters the body through the respiratory 
system. The virus can also enter through the skin and, rarely, through 
the eyes, or crosses the placenta.\36\ It then rapidly enters the 
regional lymph nodes. On the third or fourth day after infection, the 
virus is circulating in the blood even though the infected person may 
not show symptoms. The virus then spreads further into the spleen, bone 
marrow, and other lymph nodes. Increased virus levels within lymph 
tissue leads to secondary viremia (elevated virus levels in the 
bloodstream), which causes fever and the characteristic smallpox rash. 
During the 8th to 12th day after infection, secondary viremia occurs 
leading to severe illness.\37\
---------------------------------------------------------------------------

    \36\ Frank Fenner et al. ``Smallpox and its eradication.'' World 
Health Organization, Geneva: (1988): 182.
    \37\ Fenner et al. ``Smallpox and its eradication.'' 188.
---------------------------------------------------------------------------

    During the first week after the rash starts, patients are most 
infectious when sores in the mouth open and release large amounts of 
virus into the saliva. The ability to pass the infection to others has 
been estimated as being highest from 3 to 6 days after the onset of 
fever.\38\ The period of infectiousness lasts until all the lesions 
have scabbed over and the scabs have fallen off. Although, viral 
particles can be detected in scabs, scabs are considered relatively 
non-infectious, since the viral particles are bound in the scab.\39\ 
Once the smallpox infection resolves, the person cannot infect others.
---------------------------------------------------------------------------

    \38\ Hiroshi Nishiura and Martin Eichner, ``Infectiousness of 
smallpox relative to disease age: Estimates based on transmission 
network and incubation period.'' Epidemiology and Infection 135, no. 
7 (2007): 1147.
    \39\ Fenner et al. ``Smallpox and its eradication.'' 188.
---------------------------------------------------------------------------

    Naturally occurring smallpox virus has been eliminated. The absence 
of endemic smallpox led to the halt of routine vaccination in the 
United States in 1972.\40\ In 1980, the World Health Organization 
declared that the smallpox

[[Page 65317]]

vaccine was essential for the successful global eradication of smallpox 
virus.
---------------------------------------------------------------------------

    \40\ Richard B. Kennedy, Inna Ovsyannikova and Gregory A. 
Poland, ``Smallpox vaccines for biodefense.'' Vaccine 5; 27 
Supplement 4 (November 2009): D73.
---------------------------------------------------------------------------

    Even though smallpox no longer occurs in nature because of the 
administration of the smallpox vaccine, concern exists that the 
smallpox virus could be used as a biological weapon. All of the known 
samples of variola virus in the world are kept in two designated 
laboratories. However, it is unknown if other samples of the virus 
exist outside those in these two laboratories. This creates the 
potential of an accidental or intentional release of the virus back 
into the environment and the need for the ability to provide mass 
vaccination against smallpox. The use of smallpox as a biological 
weapon is a concern for several reasons. First, much of the population 
is susceptible to infection because smallpox vaccination programs have 
stopped, and thus, the general population is not routinely given the 
smallpox vaccine. In addition, the virus is infectious via the 
respiratory system, requires only a small amount of the virus to cause 
infection, and is transmissible from person to person. Furthermore, the 
disease has a long asymptomatic incubation period and a high rate of 
morbidity and mortality. Also, very few treatments exist, and 
experience has shown that the presence of smallpox virus creates havoc 
and panic.\41\ The ability of individuals to travel rapidly over great 
distances by air increases the risk of rapid dissemination of the 
disease. Additionally, the impact of smallpox on the general population 
would be greater today because the prevalence of immunosuppressed 
individuals is higher. This includes people living with Human 
Immunodeficiency Virus (HIV) and individuals taking certain medications 
that suppress their immune systems to ameliorate specific medical 
conditions.\42\
---------------------------------------------------------------------------

    \41\ Tara O' Toole, Michael Mair and Thomas V. Inglesby, 
``Shining light on dark winter.'' Clinical Infectious Disease 34(7) 
(April 1, 2002): 972.
    \42\ Louisa E. Chapman, Gina T. Mootrey and Linda J. Neff, 
``Vaccination against smallpox in the post eradication era.'' 
Clinical Infectious Disease 15;46 Supplement 3: (March 2008): S155.
---------------------------------------------------------------------------

Smallpox Vaccines

    After confirmation of one or more human smallpox cases, the primary 
strategy for controlling the spread of disease involves the use of the 
smallpox vaccine in combination with other surveillance and containment 
activities. As demonstrated during the eradication campaign, the immune 
response generated by smallpox vaccination is one of the most effective 
tools for halting the transmission of smallpox.
    Smallpox vaccines are either replication-competent or replication-
deficient. The replication-competent vaccines are administered via the 
intradermal scarification method and the virus in the vaccine 
reproduces within the vaccine recipient. This method uses a bifurcated 
needle that punctures the skin multiple times while placing a drop of 
live-attenuated vaccinia virus vaccine in the wound created by the 
needle. This method creates a vaccination site. There is a risk of 
transferring the vaccinia virus from the vaccination site to other 
parts of the individual's body or to others. This type of vaccine also 
has an increased risk of adverse side effects in individuals with 
immunodeficiencies or skin disorders.
    A second type of vaccine involves the use of replication-deficient 
vaccinia virus. This vaccine contains a live-attenuated virus; and is 
administered subcutaneously; however, the viral agent does not 
reproduce in human cells. This reduces the risk of transferring the 
vaccine to other parts of the body or to others. Individuals with 
certain skin disorders or who are HIV-infected were included in 
clinical studies, the frequencies of solicited local and systemic 
adverse reactions among these adults were generally similar to those 
observed in healthy adults.
    The current Food and Drug Administration (FDA) approved smallpox 
vaccines contain live vaccinia viruses that protect against smallpox 
disease. They do not contain variola virus, the causative agent of 
smallpox. The U.S. Government has three different smallpox vaccines 
available in the U.S. Strategic National Stockpile (SNS): Smallpox 
(Vaccinia) Vaccine Live (replication-competent), Smallpox and Monkeypox 
Vaccine, Live, Non-replicating (replication-deficient), and APSV 
(Aventis Pasteur Smallpox Vaccine) (replication-competent). Smallpox 
(Vaccinia) Vaccine Live and Smallpox and Monkeypox Vaccine, Live, Non-
replicating are licensed by the FDA, whereas APSV, which is an 
investigational vaccine and is not licensed by the FDA, would be made 
available under an Investigational New Drug (IND) or under Emergency 
Use Authorization (EUA). Although an EUA cannot be issued until an 
emergency determination and declarations are in place, a product 
sponsor can submit and the FDA can review product data as pre-EUA 
submissions before a formal EUA request.'' \43\ Such a pre-EUA 
submission does not imply that any specific set of qualifications has 
been met, but instead represents the initiation of a series of 
preliminary interactions between the FDA and a product sponsor to 
discuss potential suitability for EUA consideration.\44\
---------------------------------------------------------------------------

    \43\ Brett W. Petersen et al. ``Clinical guidelines for smallpox 
vaccine use in a post-event vaccination program.'' Morbidity and 
Mortality Weekly Report: Recommendations and Reports 64(2): (Feb 20, 
2015): 11.
    \44\ U.S. Department of Health and Human Services, Food and Drug 
Administration, ``Emergency Use Authorization of Medical Products 
and Related Authorities, Guidance for Industry and Other 
Stakeholders,'' January 2017; https://www.fda.gov/media/97321/download.
---------------------------------------------------------------------------

    Dryvax, a type of smallpox vaccine, is no longer manufactured or 
used. It has been replaced by Smallpox (Vaccinia) Vaccine Live, which 
was derived from Dryvax. Smallpox (Vaccinia) Vaccine Live may cause 
myocarditis and pericarditis, conditions involving inflammation and 
swelling of the heart and surrounding tissues. Most of these cases are 
mild, resolve on their own, and do not have symptoms, but some can be 
very serious. Based on clinical studies, myocarditis and/or 
pericarditis occur in 1 in 175 adults who get this vaccine for the 
first time.\45\
---------------------------------------------------------------------------

    \45\ ``ACAM2000 (smallpox vaccine): Questions and answers.'' 
United States Food and Drug Administration, (March 23, 2018): 2.
---------------------------------------------------------------------------

    In the Smallpox (Vaccinia) Vaccine Live clinical trial, 7 of the 
2,983 first-time vaccine recipients were suspected of having 
myocarditis and/or pericarditis. Three of the 868 first-time recipients 
used the smallpox vaccine (Dryvax). No cases of myocarditis and/or 
pericarditis were reported among participants who had been previously 
vaccinated with a smallpox vaccine. In Smallpox (Vaccinia) Vaccine Live 
(replication-competent) clinical trials, among vaccinees na[iuml]ve to 
vaccinia, 8 cases of suspected myocarditis and pericarditis were 
identified across both treatment groups, for a total incidence rate of 
6.9 per 1,000 vaccinees (8 of 1,162). The rate for the Smallpox 
(Vaccinia) Vaccine Live (replication-competent) treatment group were 
similar: 5.7 (95 percent CI: 1.9-13.3) per 1,000 vaccinees (5 of 873 
vaccinees) and for the Dryvax[supreg] group 10.4 (95 percent CI: 2.1-
30.0) per 1,000 vaccinees (3 of 289 vaccinees). No cases of myocarditis 
and/or pericarditis were identified in 1,819 previously vaccinated 
subjects.\46\ Commonly observed side effects included itching, sore 
arm, fever, headache, body ache, mild rash, and fatigue.\47\
---------------------------------------------------------------------------

    \46\ ACAM2000, Smallpox (vaccinia) vaccine, live. Package 
Insert, Emergent Product Development. Revised 03/2018, https://www.fda.gov/media/75792/download.
    \47\ Petersen et al. ``Clinical guidelines for smallpox.'' 7.

---------------------------------------------------------------------------

[[Page 65318]]

    Another smallpox vaccine available for use is Smallpox and 
Monkeypox Vaccine, Live, Non-replicating. This vaccine uses a modified 
Vaccinia Ankara virus in its composition. Smallpox and Monkeypox 
Vaccine, Live, Non-replicating is administered via subcutaneous 
injection. The vaccine virus is replication-deficient; therefore, 
Smallpox and Monkeypox Vaccine, Live, Non-replicating does not present 
a risk of secondary transmission. This vaccine requires two doses, 28 
days apart. Clinical trials evaluating the safety of Smallpox and 
Monkeypox Vaccine, Live, Non-replicating found that among the smallpox 
vaccine-na[iuml]ve subjects, serious adverse events (SAEs) were 
reported for 1.5 percent of Smallpox and Monkeypox Vaccine, Live, Non-
replicating (replication-deficient) recipients and 1.1 percent of 
placebo recipients. Among the smallpox vaccine-experienced subjects 
enrolled in studies without a placebo comparator, SAEs were reported 
for 2.3 percent of Smallpox and Monkeypox Vaccine, Live, Non-
replicating (replication-deficient) recipients. Across all studies, a 
causal relationship to Smallpox and Monkeypox Vaccine, Live, Non-
replicating (replication-deficient) could not be excluded for four 
SAEs, all non-fatal, which included Crohn's disease, sarcoidosis, 
extraocular muscle paresis and throat tightness.\48\
---------------------------------------------------------------------------

    \48\ JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Non-
replicating. Package Insert, Bavarian Nordic A/S. Aug 2019. https://www.fda.gov/media/131078/download.
---------------------------------------------------------------------------

    APSV, sometimes called ``WetVax'' was manufactured from 1956 to 
1957. It is a replication-competent vaccine. It has been maintained in 
cold storage since it was produced. It was manufactured from the same 
vaccinia virus strain as Dryvax. It contains live vaccinia virus 
without preservatives or antibiotics. Testing of samples indicate that 
it is safe to use from a bioburden (presence of bacteria within the 
sample) perspective. The vaccine is administered in a single dose with 
a bifurcated needle and the appropriate number of punctures at the 
vaccination site. The preferred site of vaccination is on the upper arm 
over the deltoid muscle. Once appropriately diluted, each vial contains 
approximately 500 doses of vaccine. It has a similar side effect 
profile as Dryvax and a safety profile similar to Dryvax and Smallpox 
(Vaccinia) Vaccine Live. It is thought to be 95 percent effective when 
used as pre-exposure prophylaxis. The most frequently encountered 
serious complications of APSV include: encephalitis, progressive 
vaccinia (PV), and eczema vaccinatum.\49\ APSV would be used if there 
is a shortage of Smallpox (Vaccinia) Vaccine, Live and of Smallpox and 
Monkeypox Vaccine, Live, Non-replicating.
---------------------------------------------------------------------------

    \49\ Petersen et al. ``Clinical guidelines for smallpox.'' 10.
---------------------------------------------------------------------------

    Smallpox vaccination for pre-exposure prophylaxis using 
replication-competent vaccine is contraindicated in people with severe 
immunodeficiency (such as individuals undergoing bone marrow 
transplantation or those with primary or acquired immunodeficiency 
requiring isolation). A vaccine containing replication competent virus 
should be used with caution in the following groups: (1) Anyone who is 
allergic to the vaccine or any of its components; (2) anyone younger 
than 12 months of age; (3) people who have, or have had, certain skin 
conditions (especially eczema or atopic dermatitis); (4) people who 
have been diagnosed as having a heart condition, or having three or 
more known major cardiac risk factors; (5) women who are pregnant or 
planning to become pregnant within 4 weeks after vaccination; (6) 
persons with congenital or acquired immune deficiency disorders (e.g., 
HIV/AIDS, leukemia, lymphoma); and (7) persons using corticosteroid eye 
drops. Within these identified groups, the risk of vaccination must be 
weighed against the risk of potential smallpox virus exposure.\50\
---------------------------------------------------------------------------

    \50\ ACAM2000, Smallpox (vaccinia) vaccine, live. Package 
Insert, Emergent Product Development.
---------------------------------------------------------------------------

    Smallpox vaccination using replication-deficient vaccine has no 
absolute contraindication for administration, it should be noted, 
however, that this vaccine has not been studied in individuals less 
than 18 years old.\51\ Warning and precautions for this product 
include: Severe allergic reactions; altered immunocompetence 
(``Immunocompromised persons, including those receiving 
immunosuppressive therapy, may have a diminished immune response.'') 
and limitations of vaccine effectiveness.\52\
---------------------------------------------------------------------------

    \51\ JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Non-
replicating. Package Insert, Bavarian Nordic A/S. Aug 2019. https://www.fda.gov/media/131078/download.
    \52\ JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Non-
replicating. Package Insert, Bavarian Nordic A/S. Aug 2019. https://www.fda.gov/media/131078/download.
---------------------------------------------------------------------------

    In a smallpox bioterrorism emergency, pregnant women at high risk 
of exposure may be advised to be vaccinated, since the risk of death 
and serious illness from smallpox in that situation would likely 
outweigh risks to the fetus from fetal vaccinia caused by replication-
competent vaccines. A study of 376 women enrolled in the National 
Smallpox Vaccine in Pregnancy Registry showed that women vaccinated 
during pregnancy with replication-competent vaccine did not have 
higher-than-expected rates of pregnancy loss, preterm birth, or birth 
defects compared with pregnant women not receiving the smallpox 
vaccine. Most of the women in the registry (77 percent) were vaccinated 
near the time of conception, before results of a standard pregnancy 
test would have been positive. No cases of fetal vaccinia were 
identified. A retrospective cohort study employing information from 
Department of Defense databases examined outcomes among 31,420 infants 
born to active-duty military women during 2003-2004. There were 7,735 
infants born to women who had previously been vaccinated against 
smallpox. An additional 672 infants were delivered by women who had 
been vaccinated for smallpox in the first trimester of pregnancy. 
Analysis revealed that maternal smallpox vaccination during pregnancy 
was not associated with preterm or extreme preterm delivery.\53\ 
Maternal smallpox vaccination during the first trimester was not 
significantly associated with overall birth defects.\54\ Live born 
infants who experience a covered injury as the direct result of a 
covered countermeasure administered to or used by a pregnant woman, 
such as a smallpox vaccine, are eligible for compensation from the 
CICP.\55\
---------------------------------------------------------------------------

    \53\ Margaret Ryan and Jane F. Seward, Pregnancy, birth, and 
infant health outcomes from the national smallpox vaccine in 
pregnancy registry, 2003-2006. Clinical Infectious Disease 2008:46 
(Suppl 30): S222.
    \54\ Margaret Ryan, et al. Evaluation of preterm births and 
birth defects in liveborn infants of US military women who received 
smallpox vaccine. Birth Defect Research (Part A): Clinical and 
Molecular Teratology 82:2008, 533-539.
    \55\ 42 CFR 110.3(n)(3).
---------------------------------------------------------------------------

    Serious adverse reactions to smallpox vaccination can occur.\56\ It 
has been estimated that during mass vaccinations campaigns with 
replication-competent vaccines, 1 to 2 deaths and hundreds of 
complications severe enough to require hospitalization occurred for 
every 1 million people vaccinated. Estimates from the medical and 
scientific literature indicate that if the current population of the 
United States was vaccinated with the replication-competent smallpox 
vaccine, hundreds of deaths and thousands of hospitalizations could 
occur.\57\ Statistics from the 1960s and 1970s documented the rate of 
serious complications after receipt of the smallpox vaccine. These 
rates may be higher today as more

[[Page 65319]]

individuals are immunocompromised, immunosuppressed or immunodeficient. 
However, the licensure of a vaccine with an improved safety profile is 
expected to decrease serious complications resulting from smallpox 
vaccination. Earlier studies primarily sought information only 
regarding what was already known to occur because of the administration 
of the smallpox vaccine. It is possible that previously unrecognized 
adverse reactions will become more evident with improved surveillance.
---------------------------------------------------------------------------

    \56\ Petersen et al. ``Clinical guidelines for smallpox.''
    \57\ Kennedy et al. ``Smallpox Vaccines,'' D75.
---------------------------------------------------------------------------

    Minor adverse events following smallpox vaccination occur.\58\ 
These include tenderness and erythema (redness) at the injection site 
and other localized reactions. With replication- competent vaccines, 
minor reactions also include allergic reactions to tape adhesives and 
``robust takes.'' ``Robust takes'' are local reactions that are larger 
than expected and generally greater than 7.5 centimeters (cm), and are 
accompanied by some or all of the following signs and symptoms: 
Erythema, induration (firmness of the skin extending beyond the 
vaccination site), tenderness and warmth in the absence of secondary 
cellulitis (a bacterial infection of the skin). Robust takes are not 
generally considered a Table injury. In addition to localized 
reactions, systemic reactions such as fever of at least 100 [deg]F, 
body aches, muscle pain, and local enlargement of the lymph nodes can 
occur and have been associated with replication-competent vaccines.
---------------------------------------------------------------------------

    \58\ ACAM2000, Smallpox (vaccinia) vaccine, live. Package 
Insert, Emergent Product Development.
---------------------------------------------------------------------------

    The vaccinia virus in the replication-competent smallpox vaccines 
is live and can be transmitted to other parts of the body of the 
vaccine recipient. For purposes of this NPRM, the term ``vaccination'' 
refers to the administration and receipt of the vaccinia virus through 
the smallpox vaccine and not through contact, whereas, the term 
``inoculation'' refers to transmission of, and subsequent infection 
with, the vaccinia virus through a means other than smallpox 
vaccination. Autoinoculation occurs when vaccine recipients touch their 
vaccination site before it has healed and then touch another part of 
their body. Accidental or inadvertent, person-to-person inoculation 
occurs when a person or the vaccine recipient touches a vaccination 
site before it has healed and then touches another person.
    The proposed Table lists the following injuries for the smallpox 
vaccines.

Injuries Associated With Both Replication-Competent and Replication-
Deficient Smallpox Vaccines

A. Anaphylaxis
    Anaphylaxis is a single discrete event that presents as a severe 
and potentially life threatening multi-organ reaction, particularly 
affecting the skin, respiratory tract, cardiovascular system, and the 
gastrointestinal tract. In an anaphylactic reaction, an immediate 
reaction generally occurs within minutes after exposure, and in most 
cases, the individual develops signs and symptoms within 4 hours after 
exposure to the antigen (substance causing the reaction). The immediate 
reaction leads to a combination of skin rash, mucus membrane swelling, 
leakage of fluid from the blood into surrounding tissues, restriction 
of the air passages in the lungs with tissue swelling, and 
gastrointestinal symptoms that can lead to shock, organ damage, and 
death if not promptly treated. Death, if it occurs, usually results 
from airway obstruction caused by laryngeal edema (throat swelling) or 
bronchospasm and may be associated with cardiovascular collapse.\59\
---------------------------------------------------------------------------

    \59\ The Brighton Collaboration Anaphylaxis Working Group, 
``Anaphylaxis: Case Definition and Guidelines for Data Collection, 
Analysis, and Presentation of Immunization Safety Data,'' Vaccine, 
Aug. 2007; 5676.
---------------------------------------------------------------------------

    Anaphylaxis may occur following exposure to allergens from a 
variety of sources including food, aeroallergens, insect venom, drugs, 
and immunizations. Most treated cases resolve without additional 
complications. Anaphylaxis can be due to an exaggerated acute systemic 
hypersensitivity reaction. It is not an initial episode of a chronic 
condition, such as chronic hives.
    Anaphylaxis following immunization is a rare occurrence with 
estimates in the range of 1-10 per 1 million doses distributed, 
depending on the vaccine studied.\60\ In 2003, the Institute of 
Medicine (IOM) reported that evidence favors acceptance of a causal 
relationship between certain vaccines and anaphylaxis based on case 
reports and case series. The IOM reported that causality could be 
inferred with reasonable certainty based on one or more case reports 
because of the unique nature and timing of anaphylaxis following 
vaccine administration and provided there is an absence of alternative 
causes.\61\
---------------------------------------------------------------------------

    \60\ Jens U. Ruggeberg et al. ``Anaphylaxis: case definition and 
guidelines for data collection, analysis, and presentation of 
immunization safety data.'' Vaccine. (August 2007): 5676.
    \61\ Institute of Medicine, ``Immunization safety review 
vaccination and sudden unexpected death in infancy.'' The National 
Academies Press, (2003): 31.
---------------------------------------------------------------------------

    Smallpox vaccines are currently prepared using various techniques 
that result in the final products containing a limited quantity of 
foreign protein that can induce immediate hypersensitivity reactions in 
some persons with severe protein mediated allergies. It is established 
that smallpox vaccines can cause anaphylaxis similar to that seen in 
other vaccines.62 63
---------------------------------------------------------------------------

    \62\ Joanne Cono, Christine G. Casey and David M. Bell, 
``Smallpox vaccination and adverse reactions. Guidance for 
clinicians.'' Morbidity and Mortality Weekly Report, 52(RR04) 
(February 21, 2003): 2.
    \63\ Werner J. Pichler et al. ``Drug hypersensitivity reactions: 
pathomechanism and clinical symptoms.'' Medical Clinics of North 
America 94, (July 2010): 646.
---------------------------------------------------------------------------

    A 1994 IOM Report supports the causal association between vaccines 
and a biologic gradient of host responses, ranging from true 
anaphylaxis to milder forms of hypersensitivity reactions. Biological 
gradient refers to the observation of a spectrum of responses from mild 
to severe. In the case of hypersensitivity reactions, the reported 
spectrum after the vaccine runs from mild skin manifestations to chest 
and throat tightness and cardiovascular events to full blown 
anaphylaxis. The IOM also stated that the onset of anaphylaxis 
generally occurs within a few hours of exposure.\64\ Consistent with 
the time interval for the first manifestation of anaphylaxis after 
vaccines covered by the National Vaccine Injury Compensation Program 
and the CICP's Pandemic Influenza Countermeasure Injury Table, the 
Secretary proposes an onset interval for the first symptom or 
manifestation of 0-4 hours for anaphylaxis to be covered under the 
proposed Table.
---------------------------------------------------------------------------

    \64\ Institute of Medicine, ``Adverse events associated with 
childhood vaccines evidence bearing on causality.'' The National 
Academies Press, (1994): 22.
---------------------------------------------------------------------------

    Based on the nature and timing of anaphylaxis, and the medical and 
scientific literature, the Program's evidence standard has been met, 
and anaphylaxis is proposed for inclusion on the Table because it is a 
serious physical injury that may be directly caused by the 
administration or use of either the replication-competent or 
replication-deficient smallpox vaccine.
    In rare cases of acute anaphylaxis, initial symptoms of the 
immediate reaction may present up to 12 hours after exposure. A slow 
evolving late phase hypersensitivity reaction is possible, with an 
onset that usually begins 4-8 hours after the immediate reaction ends. 
The medical literature contains reports of late phase onset up

[[Page 65320]]

to 72 hours later.\65\ The late phase reaction results from a different 
immunologic mechanism of action. The late phase reaction is part of a 
biphasic reaction. It is possible for the first immediate 
hypersensitivity reaction to be relatively mild, unrecognized, or not 
observed. There may be unusual cases in which the immediate reaction is 
delayed and/or cases that the immediate reaction is not recognized, 
with the first apparent manifestation occurring in the late phase. 
These unusual cases do not meet the requirements to be considered table 
injuries, and will be evaluated on a case-by-case basis based on the 
Program's evidence standard.
---------------------------------------------------------------------------

    \65\ Ruggeberg et al. ``Anaphylaxis: case definition and 
guidelines.'' 5677.
---------------------------------------------------------------------------

B. Vasovagal Syncope
    Vasovagal syncope is a temporary loss of consciousness (fainting) 
and postural tone, which includes a reflex drop in blood pressure and 
may be triggered by an event associated with pain or anxiety. This 
reaction is known to occur when a vaccine is administered with a needle 
which pierces the skin. Some people may experience jerking movements 
after losing consciousness, which generally are not seizures.
    In its 2012 report, Adverse Effects of Vaccines, the IOM concluded, 
based on mechanistic evidence (mechanism of action), that the evidence 
convincingly supports a causal relationship between the injection of a 
vaccine and vasovagal syncope. Vasovagal syncope after vaccination is 
usually not associated with serious injuries; however, some cases of 
vasovagal syncope will result in serious injury related to physical 
trauma from an associated fall or other related accidents.
    Based on a review of the medical and scientific literature, the 
Program's evidence standard has been met, and vasovagal syncope may be 
a serious physical injury that may be directly caused by the 
administration or use of any injected smallpox vaccine.\66\ Since most 
cases of vasovagal syncope occur within 1 hour of vaccination, syncope 
is proposed to be added to the Table with an onset interval for the 
first symptom or manifestation of 0-1 hour after vaccination with the 
injected smallpox vaccine.
---------------------------------------------------------------------------

    \66\ Institute of Medicine, Adverse effects of vaccines: 
Evidence and causality. (Washington, DC The National Academies 
Press, 2012): 18.
---------------------------------------------------------------------------

Injuries Associated With Only Replication-Competent Smallpox Vaccines

A. Skin Reactions
    Certain skin reactions are associated with the administration of 
replication-competent smallpox vaccines. These include: (1) Significant 
local skin reaction, (2) Stevens-Johnson syndrome/toxic epidermal 
necrolysis (SJS/TEN), (3) inadvertent autoinoculation, (4) eczema 
vaccinatum, (5) generalized vaccinia, and (6) progressive vaccinia, 
previously termed ``vaccinia necrosum.'' \67\ Widespread skin reactions 
are larger than a simple skin reaction and include two groups. The 
first group includes significant skin reactions (such as SJS/TENS) and 
other nonspecific post-vaccination rashes with lesions that are thought 
to be free of the vaccinia virus. The second group includes adverse 
reactions thought to be caused by replicating vaccinia virus recovered 
from skin lesions, which can be associated with risk for 
autoinoculation or contact transmission.68 69 70 71 72 73
---------------------------------------------------------------------------

    \67\ Aysegul Nalca and Elizabeth E. Zumbrun, ``ACAM2000: The new 
smallpox vaccine for United States strategic national stockpile,'' 
Drug Design, Development and Therapy 4. (2010): 76.
    \68\ Cono et al. ``Smallpox vaccination and adverse reaction.'' 
2.
    \69\ Cono et al. ``Smallpox vaccination and adverse reactions.'' 
3.
    \70\ Lane and Goldstein, ``Adverse Events.'' 191-192.
    \71\ Kent A. Sepkowitz, ``How contagious is vaccinia?'' New 
England Journal of Medicine 348(5) (January 30, 2003): 443-445.
    \72\ Vincent A. Fulginiti et al. ``Smallpox vaccination: a 
review, part II. Adverse events.'' Clinical Infectious Disease 37 
(July 15, 2003): 252.
    \73\ Ellen R. Wertheimer et al. ``Contract transmission of 
vaccinia virus from smallpox vaccinees in the United States, 2003-
2011.'' Vaccine 30. (2012): 986.
---------------------------------------------------------------------------

1. Significant Local Skin Reaction
    A significant local skin reaction is, for purposes of the Table, an 
unexpected and extreme response to the inoculation of the vaccinated 
person. The expected onset of this injury is the initial skin lesion at 
the smallpox vaccination or inoculation site. The replication-competent 
smallpox vaccine is administered through a multiple puncture technique 
known as scarification. The dose of vaccine is placed on a needle, 
which is then penetrated multiple times into the skin, commonly, in the 
upper arm.\74\ Other sites for vaccine administration may be selected 
utilizing this same technique. The vaccinia virus in the vaccine 
replicates and causes damage in the cells resulting in a localized 
lesion.\75\ This can result in a typical local skin reaction in a 
na[iuml]ve (first-time) vaccine recipient composed of a papule, which 
develops 3 to 4 days post-vaccination. The papule then goes on to 
mature into a vesicle and a pustule over the next 4 to 5 days. The 
vaccine lesion is generally at its maximum size by day 8 post-
vaccination. The primary lesion is surrounded by erythema and 
inflammation, and regional lymphadenopathy is generally present. The 
scab formed by the healing pustule separates by day 21 post-
vaccination. The cutaneous reaction in individuals being revaccinated 
may be reduced in severity or entirely absent. In previously immunized 
individuals who fail to develop a skin response with the second 
immunization, no additional smallpox immunizations are required.\76\
---------------------------------------------------------------------------

    \74\ Richard B. Kennedy et al. Vaccines. (Philadelphia: 
Elsevier-Saunders, 2013): 730.
    \75\ Xiaolin Tan et al. ``Failure of the smallpox vaccine to 
develop a skin lesion in vaccinia virus-na[iuml]ve individuals is 
related to differences in antibody profiles before vaccination, not 
after.'' Clinical and Vaccine Immunology 19(3) (March 2012): 418.
    \76\ ACAM2000, Smallpox (vaccinia) vaccine, live. Package 
Insert, Emergent Product Development.
---------------------------------------------------------------------------

    Cono et al. found that approximately 10 percent of first time 
vaccinees will go on to develop a large vaccination reaction, defined 
as a reaction greater than 10 cm in diameter at the site of the 
inoculation. This is a normal variant within the population.\77\
---------------------------------------------------------------------------

    \77\ Cono et al. ``Smallpox vaccination and adverse reaction.'' 
5.
---------------------------------------------------------------------------

    In an examination of the data generated in the most recent mass 
smallpox vaccination program completed in the U.S. with HHS and the 
U.S. Department of Defense (DoD) in 2003 and 2004, using replication-
competent vaccine, significant local skin reactions leading to 
hospitalization were not identified.\78\ Of the nearly 770,000 
individuals (both first time and revaccinated) vaccinated during this 
program, there were no reported cases of local skin reaction requiring 
hospitalization. The improved pre-screening of smallpox vaccine 
recipients is thought to have reduced the incidence of significant 
local skin reactions.\79\
---------------------------------------------------------------------------

    \78\ Gregory A. Poland, John D. Grabenstein and John M. Neff, 
``The US smallpox vaccination program: a review of a large modern 
era smallpox vaccination implementation program.'' Vaccine 23 
(February 4, 2005): 2079.
    \79\ Poland et al. ``The US smallpox vaccination program.'' 
2081.
---------------------------------------------------------------------------

    In the 2003 Grabenstein and Winkenwerder study, the data indicates 
that 16 of 450,000 military patients vaccinated were hospitalized due 
to the uncertainty of the communicability of their skin conditions 
after receiving the replication-competent smallpox

[[Page 65321]]

vaccine. After additional evaluation, each patient was returned to 
duty. The authors also describe 36 cases of suspected mild generalized 
vaccinia; each of these patients were treated and released. Of these 36 
patients, nine were hospitalized. These hospitalizations were 
attributed to providers who were seeing smallpox vaccinated patients 
for the first time being overly cautious. Each of these patients were 
treated and returned to duty. A single service member developed 
erythema multiforme major after receiving multiple vaccines. This was 
seen as a possible reaction to the replication-competent smallpox 
vaccine.\80\
---------------------------------------------------------------------------

    \80\ John D. Grabenstein and William Winkenwerder, ``US Military 
smallpox vaccination program experience.'' Journal of the American 
Medical Association 289(24) (June 25, 2003): 3280.
---------------------------------------------------------------------------

    A revaccination program that occurred in Israel in 2002 and 2003 
provided replication-competent smallpox vaccinations to 21,000 first 
responders and utilized a different vaccine strain than the one used in 
the U.S. Many of the vaccine recipients experienced local swelling and 
pain. However, only one individual was hospitalized with a diagnosis of 
cellulitis at the injection site.\81\
---------------------------------------------------------------------------

    \81\ Emilia Anis et al. ``Smallpox revaccination of 21,000 first 
responders in Israel: lessons learned.'' International Journal of 
Infectious Disease 13 (August 6, 2009): 406.
---------------------------------------------------------------------------

    The severity of adverse reactions following vaccination can vary 
based upon factors such as the immune status of the individual and a 
positive or negative history of past exposure to the smallpox vaccine. 
Typically, those with a potentially higher level of immunity, because 
of previous exposure to the vaccine, may develop a reduced response to 
revaccination. Vaccination site lesions generally resolve with the 
separation of the overlaying scab within 21 days post-vaccination.\82\ 
This 21-day period is the expected timeframe of a normal immune 
response and the time in which reactions associated with the vaccine 
should have occurred and been resolved.\83\
---------------------------------------------------------------------------

    \82\ Lane et al. ``Adverse Events.'' 190.
    \83\ Kennedy et al. ``Smallpox and vaccinia.'' 730.
---------------------------------------------------------------------------

    Skin reactions that occur because of receiving the replication-
competent smallpox vaccine are generally self-limiting and resolve 
without intervention. Minor scarring or minor local reactions do not 
constitute a Table injury. A robust take does not constitute a Table 
injury.
    Based on a review of the medical and scientific literature, the 
Program's evidence standard has been met, and significant local skin 
reactions are serious physical injuries that may be directly caused by 
the use of the replication-competent smallpox vaccine. As explained 
above, the expected time interval between exposure and onset of injury 
for the first symptom or manifestation is 1-21 days.\84\
---------------------------------------------------------------------------

    \84\ Kennedy et al. ``Smallpox and vaccinia.'' 730.
---------------------------------------------------------------------------

    A Table injury in a recipient requires sufficient evidence in the 
medical records of the occurrence of a significant local skin reaction 
at the vaccination or inoculation site. The presence of a scar 
resulting from the significant local skin reaction would not be 
considered a Table injury unless the scar is of sufficient severity to 
warrant hospitalization or lead to a significant loss of function or 
disability.
2. SJS/TEN
    SJS and TEN, are acute hypersensitivity reactions that affect skin, 
mucus membranes, and sometimes internal organs (systemic toxicity). As 
mentioned in the previous section, the terms Erythema Multiforme (EM) 
and SJS have been historically linked to TEN and are often confused by 
clinicians even today. It is now recognized that EM is a different 
disease from SJS and TEN.\102\ Although SJS and TEN were once thought 
to be separate conditions, they are now considered part of a continuum. 
SJS is on the less severe end of the spectrum and TEN represents the 
more severe end.\85\ SJS/TEN is the most commonly used term to refer to 
the spectrum of conditions that include SJS, SJS/TEN overlap, and TEN. 
The difference between SJS, SJS/TEN overlap, and TEN is defined by the 
degree of skin detachment. SJS is defined as skin involvement of less 
than 10 percent. TEN is defined as skin involvement of greater than 30 
percent. SJS/TEN is defined as overlap of 10-30 percent skin 
involvement.\86\ For the purposes of the Table, the term SJS/TEN will 
be used to refer to the SJS and TEN disease spectrum, consistent with 
its use in recent scientific articles.87 88 89 SJS/TEN is a 
rare condition that affects 1-2 people per million, per year. SJS/TEN 
is most commonly triggered by medication, but it is also seen in 
individuals experiencing infections with Mycoplasma pneumoniae and 
cytomegalovirus. In many cases, no cause of SJS/TEN is ever 
identified.\90\ Although rare, generalized hypersensitivity reactions 
have been documented with the use of live attenuated vaccines, such as 
the replication-competent smallpox vaccine, as the body reacts to the 
presence of an identified foreign protein.91 92 93
---------------------------------------------------------------------------

    \85\ National Institutes of Health, U.S. National Library of 
Medicine, ``Steven-Johnsons syndrome/toxic epidermal necrolysis.'' 
(September 10, 2019): 1-2.
    \86\ Marianne Lerch et al. ``Current Perspectives on Stevens-
Johnson syndrome and Toxic Epidermal Necrolysis.'' Clinical Reviews 
in Allergy & Immunology. Feb 2018;54(1):147-176.
    \87\ Roni P. Dodiuk-Gad et al. ``Stevens-Johnson syndrome and 
Toxic Epidermal Necrolysis: An Update.'' American Journal of 
Clinical Dermatology. Dec 2015:16(6):475-493.
    \88\ National Institutes of Health, U.S. National Library of 
Medicine, ``Stevens-Johnson syndrome.'' 1.
    \89\ Lerch et al. ``Current Perspectives on Stevens-Johnson 
syndrome and Toxic Epidermal Necrolysis.'' 147-176.
    \90\ National Institutes of Health, U.S. National Library of 
Medicine, ``Stevens-Johnson syndrome.''1.
    \91\ Adena E. Rosenblatt and Sarah L. Stein, ``Cutaneous 
reactions to vaccines.'' Clinics in Dermatology 33(3). (2015): 327.
    \92\ J. Michael Lane et al. ``Deaths attributed to smallpox 
vaccinations, 1959 to 1966, and 1968.'' Journal of the American 
Medical Association 212(3) (April 20, 1970): 441.
    \93\ Ashish Chopra et al. ``Stevens-Johnson syndrome after 
immunization with smallpox, anthrax and tetanus vaccines.'' Mayo 
Clinic Proceedings 79(9) (September 2004): 1193.
---------------------------------------------------------------------------

    SJS/TEN frequently begins with flu-like symptoms. Shortly 
thereafter, the skin begins to blister and peel creating painful open 
areas on the skin, mouth, airways, and potentially the urinary tract 
and genitals. In SJS/TEN, mucosal involvement generally predominates. 
Mucosal lesions generally occur at more than one location and manifest 
as painful lesions in sites, such as the mouth or eyes. Skin rash or 
lesions in SJS/TEN usually consist of red raised areas, blisters, and 
ulcerations. Open areas created by SJS/TEN can lead to fluid loss and 
make the person susceptible to infection. Because of the damage that 
occurs to the skin and mucus membranes, SJS/TEN is considered a life 
threatening condition. Serious complications of SJS/TEN include 
pneumonia, sepsis, shock, multiple organ failure, and death. 
Approximately 10 percent of individuals with SJS/TEN will die from the 
condition.\94\ For those who survive SJS/TEN, the potential long-term 
complications include skin color changes, skin and mucosal dryness, 
excessive sweating, hair loss, impaired taste, difficulty urinating, 
and genital abnormalities. Some individuals develop chronic dry eye 
leading to photophobia (light sensitivity) and vision impairment.\95\
---------------------------------------------------------------------------

    \94\ National Institutes of Health, U.S. National Library of 
Medicine, ``Stevens-Johnson syndrome.'' 1.
    \95\ National Institutes of Health, U.S. National Library of 
Medicine, ``Stevens-Johnson syndrome.'' 1.
---------------------------------------------------------------------------

    A 1968 survey identified 48 cases of EM among 572 patients 
identified with

[[Page 65322]]

adverse reactions to the replication-competent smallpox vaccine; 
however, it was noted that this may actually be an under representation 
of the actual total number of SJS cases.\96\ At the time of the study, 
EM and SJS were considered synonyms for the same condition or 
conditions on the same spectrum of disease. The United States Armed 
Forces vaccinated 450,293 of its members from December 2002, to May 
2003, and reported one case of severe EM, defined as SJS, during this 
period.\97\
---------------------------------------------------------------------------

    \96\ J Michael Lane et al. ``Complications of smallpox 
vaccination, 1968* National Surveillance in the United States.'' The 
New England Journal of Medicine 281 (22) (November 27, 1969): 1205.
    \97\ Chopra et al. ``Stevens-Johnson syndrome.'' 1196.
---------------------------------------------------------------------------

    Based on a review of the medical and scientific literature, the 
Program's evidence standard has been met, and SJS/TEN is a serious 
physical injury that may be directly caused by the use of the 
replication-competent smallpox vaccine.\98\ For SJS/TEN to be a Table 
injury, both skin and mucus membrane rash or lesions must be present. 
Two or more mucosal sites must be involved and the distribution of the 
rash must be widespread.99 100 The proposed onset interval 
for the first symptom or manifestation is 4-28 days after vaccination. 
The earliest time of onset, 4 days post-vaccination, is consistent with 
other conditions that cause SJS/TEN.101 102 The 28-day mark 
represents the point at which any immune response in the form of SJS/
TEN would have occurred.103 104 105
---------------------------------------------------------------------------

    \98\ Rosenblatt et al. ``Cutaneous Reactions to Vaccinations,'' 
327.
    \99\ Chopra et al. ``Stevens-Johnson Syndrome after Immunization 
with Smallpox, Anthrax, and Tetanus Vaccines.'' 1195.
    \100\ Heng et al. ``Epidermal necrolysis: 60 years of errors and 
advances.'' 1252.
    \101\ Dodiuk-Gad et al. ``Stevens-Johnson syndrome and Toxic 
Epidermal Necrolysis: An Update.'' 475, 477.
    \102\ Maja Mockenhaupt, Cecile Viboud, Ariane Dunant, Luigi 
Naldi, Sima Halevy, Jan Nico Bouwes Bavinck, Alexis Sidoroff, Jurgen 
Schneck, Jean-Claude Roujeau and Antoine Flahault. Stevens-Johnson 
syndrome and Toxic Epidermal Necrolysis: Assessment of Medication 
Risks with Emphasis on Recently Marketed Drugs. The Euro SCAR Study. 
Journal of Investigative Dermatology. January 2008; 128(1):35-44.
    \103\ Dodiuk-Gad et al. ``Stevens-Johnson syndrome and Toxic 
Epidermal Necrolysis: An Update.''477.
    \104\ B. Sassolas, C. Haddad, M. Mockenhaupt, A. Dunant, Y. 
Liss, K. Bork, UF Haustein, D. Vieluf, JC Roujeau and H. Le Louet. 
``ALDEN, an Algorithm for Assessment of Drug Causality in Stevens-
Johnson syndrome and Toxic Epidermal Necrolysis: Comparison with 
Case-Control Analysis'' Nature. July 2010;88(1): 60-68.
    \105\ Cono et al. ``Smallpox Vaccination and Adverse 
Reactions.'' 3.
---------------------------------------------------------------------------

3. Inadvertent Autoinoculation (IA) (Self-Inoculation)
    Unintentional transfer of replication-competent vaccinia virus, 
which includes transfer from the vaccination site to elsewhere on the 
vaccine recipient's body, is called inadvertent autoinoculation (IA) or 
self-inoculation. IA is the most common adverse event associated with 
the smallpox vaccine.\106\
---------------------------------------------------------------------------

    \106\ Kennedy et al. ``Smallpox and vaccinia.'' 738.
---------------------------------------------------------------------------

    Smallpox vaccine recipients or contacts can transfer replication-
competent vaccinia virus to their hands or fomites (inanimate objects 
that carry infection), which become a source for infection elsewhere on 
the body. The Program does not cover injuries caused by the transfer of 
the vaccinia virus to individuals who are not primary vaccine 
recipients. Other than ocular (eyes), the most common sites are the 
face, nose, mouth, lips, genitalia, and anus.\107\ Lesions at IA sites 
progress through the same stages (e.g., papular, vesicular, pustular, 
crusting, and scab) as the vaccination site. When IA occurs greater 
than 5 days post-vaccination, the developing immune response might 
reduce the lesions and their progression. Persons at highest risk for 
IA are children ages 1-4 years and those with disruption of the 
epidermis, such as abrasions and burns.\108\
---------------------------------------------------------------------------

    \107\ Lane et al. ``Adverse Events.'' 191.
    \108\ Kennedy et al. ``Smallpox and vaccinia.'' 741.
---------------------------------------------------------------------------

    Ocular vaccinia infections result from the transfer of vaccinia 
from the vaccine site or other lesion containing vaccinia to or near 
the eye. Infections can be clinically mild to severe and can lead to 
vision loss. 109 110
---------------------------------------------------------------------------

    \109\ Frederick Ruben and J. Michael Lane, ``Ocular vaccinia: an 
epidemiologic analysis of 348 cases.'' Archives of Ophthalmology 84 
(July 1970): 47.
    \110\ Danielle M. Tack et al. ``Unintentional transfer of 
vaccinia virus associated with smallpox vaccines.'' Human Vaccines & 
Immunotherapeutics 9:7 (July 2013): 1491.
---------------------------------------------------------------------------

    IA was a frequently reported complication of early smallpox 
vaccination programs. Proper adherence to aseptic technique with 
dressing changes, hand washing, and the use of hand sanitizers with 
greater than 60 percent alcohol content help to reduce the frequency of 
IA, but it still remains a complication of replication-competent 
smallpox vaccines. Treatment is based on the number of transfer sites 
or the size of the resulting lesions.\111\
---------------------------------------------------------------------------

    \111\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 256.
---------------------------------------------------------------------------

    During the 2002-2004 HHS and DoD smallpox vaccination program, 101 
of the 770,000 individuals vaccinated reported cases of IA. This number 
represents both ocular and non-ocular forms of IA. The study did not 
provide information regarding the rate of hospitalization.\112\
---------------------------------------------------------------------------

    \112\ Poland et al. ``The US smallpox vaccination program: a 
review.'' 2079.
---------------------------------------------------------------------------

    In the 2002-2003 Israeli replication-competent smallpox 
immunization effort to revaccinate 21,000 first responders, there were 
221 identified cases of IA. This represents a 1 percent incident rate 
within this group of vaccine recipients. The study did not provide 
details regarding the extent of the IA, and although some individuals 
were hospitalized as a result of receiving vaccines, the article does 
not make clear if these hospitalizations were the result of IA or other 
causes.\113\
---------------------------------------------------------------------------

    \113\ Anis et al. ``Smallpox revaccination of 21,000.'' 406.
---------------------------------------------------------------------------

    Based on a review of the medical and scientific literature, the 
Program's evidence standard has been met, and IA is a serious physical 
injury that may be directly caused by the use of the replication-
competent smallpox vaccine. Therefore, IA is proposed to be added to 
the Table with an onset interval for the first symptom or manifestation 
of onset of 1-21 days for the first symptom or manifestation to occur 
after vaccination since the live vaccinia virus can be transferred from 
the vaccination site to another location on the vaccine recipient's 
body at any time during this period. By day 21 post-vaccination, the 
vaccination site should be healed, and the scab should have become 
dislodged and fallen off.114 115 116 117 For the purpose of 
this regulation, the inadvertent or intentional inoculation of other 
persons by the vaccine recipient is not considered a covered injury. 
Only individuals who were administered the smallpox vaccine will be 
eligible for benefits.\118\
---------------------------------------------------------------------------

    \114\ Cono et al. ``Smallpox Vaccination and Adverse 
Reactions.'' 3.
    \115\ Lane et al. ``Adverse Events.'' 191.
    \116\ Kennedy et al. ``Smallpox and vaccinia.'' 738.
    \117\ Wertheimer et al. ``Contract transmission of vaccinia 
virus.'' 985.
    \118\ See sections 319F-4(b)(4), (e)(2), and (e)(5) of the PHS 
Act (42 U.S.C. 247d-6e(b)(4), (e)(2), and (e)(5)).
---------------------------------------------------------------------------

4. Generalized Vaccinia
    Generalized vaccinia (GV) is caused by the systemic spread of 
replication-competent vaccinia from the site of vaccination with the 
smallpox vaccine.\119\ It presents as a disseminated vesicular or 
pustular rash and is usually benign and self-limited among 
immunocompetent hosts. GV may be accompanied by fever and can produce 
skin lesions anywhere on the body. GV can also appear as a regional 
form characterized by extensive vesiculation

[[Page 65323]]

around the vaccination site or as an eruption localized to a single 
body region (e.g., arm or leg). The skin lesions of GV are thought to 
contain virus spread through the blood stream. First-time vaccinees are 
at higher risk for GV than re-vaccinees. GV is often more severe among 
persons with underlying immunodeficiency who might have been 
inadvertently vaccinated; these patients might benefit from early 
intervention with vaccinia immunoglobulin (VIG). GV should not be 
confused with multiple inadvertent inoculations that might occur in the 
presence of acute or chronic exfoliative, erosive, or blistering skin 
disease. GV is different from eczema vaccinatum (EV), which typically 
occurs in persons with a history of atopic dermatitis and is often 
associated with systemic illness.\120\
---------------------------------------------------------------------------

    \119\ Kennedy et al. ``Smallpox and vaccinia.'' 738.
    \120\ Cono et al. ``Smallpox Vaccination and Adverse 
Reactions.'' 2.
---------------------------------------------------------------------------

    In GV, the initial lesions usually appear approximately a week 
after immunization on unimmunized skin. These new lesions have a 
similar appearance to the initial immunization but are generally 
smaller and heal quickly to a scar (within 5-6 days). In extremely rare 
cases, lesions have been seen to reoccur at 4 to 6 week intervals for 
up to 1 year unless treatment with VIG stops the recurrence.\121\
---------------------------------------------------------------------------

    \121\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II. 261.
---------------------------------------------------------------------------

    In the U.S., from January 24 through August 8, 2003, 38,257 
civilian health care workers received the smallpox vaccination using 
replication-competent smallpox vaccine. During this period, HHS 
reported there were two suspected cases and one confirmed case of GV 
within the group of vaccine recipients.\122\
---------------------------------------------------------------------------

    \122\ Centers for Disease Control and Prevention. ``Update: 
Adverse events following civilian smallpox vaccination, United 
States, 2003.'' Morbidity and Mortality Weekly Report 52(34) (August 
29, 2003): 819.
---------------------------------------------------------------------------

    In the DoD smallpox vaccination program (770,000 vaccinated), as of 
January 4, 2005, there were 35 suspected cases of GV. All of these 
cases were described in the literature as mild, and all individuals 
made a full recovery.\123\
---------------------------------------------------------------------------

    \123\ Poland et al. ``The US smallpox vaccination program.'' 
2079-2080.
---------------------------------------------------------------------------

    GV is a known, but rare, complication of receiving the replication-
competent smallpox vaccine, and its level of severity varies from 
person to person. The literature indicates the risk of developing GV is 
significantly reduced with obtaining a complete history and excluding 
individuals at risk for developing the condition. It is presently not 
possible to predict completely who may develop GV, but Smallpox 
(Vaccinia) Vaccine Live is contraindicated for use in individuals with 
severe immunodeficiency.\124\ The treatment of GV may require 
hospitalization and the use of vaccinia immunoglobulin intravenous 
(VIGIV).
---------------------------------------------------------------------------

    \124\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 261.
---------------------------------------------------------------------------

    Based on a review of the medical and scientific literature, the 
Program's evidence standard has been met, and GV is a serious physical 
injury that may be directly caused by the administration or use of the 
replication-competent smallpox vaccine.125 126 127 128 129 
Therefore, GV is proposed to be added to the Table with an onset 
interval of 6-9 days for the first symptom or manifestation to occur 
after vaccination as supported by the compelling, reliable and valid 
medical and scientific literature.\130\ The literature supports this 
timeframe as the first symptoms of GV generally occur approximately one 
week after immunization. Because GV entails the systemic spread of 
vaccinia virus throughout the body causing an immune response and then 
the subsequent development of satellite lesions on unvaccinated skin, 
the onset of symptoms typically does not occur prior to 6 days post 
vaccination. Cases of GV with an onset occurring outside this timeframe 
will be considered as non-Table injuries and evaluated on a case-by-
case basis based on the Program's evidence standard.
---------------------------------------------------------------------------

    \125\ Cono et al. ``Smallpox Vaccination and Adverse 
Reactions.'' 12-13.
    \126\ Rosenblatt et al. ``Cutaneous Reactions to Vaccinations.'' 
328.
    \127\ Kennedy et al. ``Smallpox and vaccinia.'' 738.
    \128\ Poland et al. ``The US smallpox vaccination program.'' 
2079.
    \129\ Claudia Vellozzi et al. ``Generalized vaccinia progressive 
vaccinia, and eczema vaccinatum are rare following smallpox 
(vaccinia) vaccination: United States surveillance, 2003.'' Clinical 
Infectious Disease 41(5) (September 1, 2005): 689.
    \130\ Cono et al. ``Smallpox Vaccination and Adverse 
Reactions.'' 12.
---------------------------------------------------------------------------

5. Eczema Vaccinatum (EV)
    Eczema vaccinatum (EV) is the acute onset of widespread painful 
vesicles and pustules that occur in individuals who receive the 
smallpox vaccine and who have a history of atopic dermatitis. Persons 
with a history of atopic dermatitis are at highest risk for eczema 
vaccinatum. However, not all individuals who have a history of atopic 
dermatitis and are vaccinated against smallpox with a replication-
competent vaccine will go on to develop EV. This phenomenon is well 
documented in the medical literature, but is not completely 
understood.\131\
---------------------------------------------------------------------------

    \131\ Jennifer L. Reed, Dorothy E. Scott, and Mike Bray. 
``Eczema vaccinatum.'' Clinical Infectious Disease 54(6) (March 15, 
2012): 834.
---------------------------------------------------------------------------

    EV may occur as the result of implantation of the vaccinia virus 
into broken or diseased skin. After implantation, the virus spreads 
from cell to cell creating extensive lesions. The amount of spread is 
dependent on the amount of abnormal skin and the individual's immune 
system.\132\ Once viremia is established, lesions can develop in 
unbroken skin.\133\ Positive viral cultures of the lesions are 
diagnostic of EV.\134\ Cases of EV have also been reported in 
individuals with a history of atopic dermatitis but whose condition 
appeared to resolve over time and who had intact skin at the time of 
vaccination.135 136
---------------------------------------------------------------------------

    \132\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II. 256-258.
    \133\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II. 256-258.
    \134\ Rosenblatt et al. ``Cutaneous Reactions to Vaccinations.'' 
328.
    \135\ Reed et al. ``Eczema vaccinatum.'' 835.
    \136\ Vincent Fulginiti et al. ``Smallpox vaccination: a review, 
Part I. Background, vaccination technique, normal vaccination and 
revaccination, and expected normal reactions.'' Clinical Infectious 
Disease 37. (July 15, 2003): 244.
---------------------------------------------------------------------------

    Onset of the characteristic lesions can occur concurrently or 
shortly after the occurrence of the reaction at the vaccination site. 
There is generally no visible reaction at the vaccination site before 
day 3 or 4 post vaccination. On approximately day 3 to 4, a papule 
forms, which progresses to a vesicle by day 5 to 6, which forms a 
pustule by day 7 to 9.\137\ In EV, these lesions occur in areas away 
from the primary vaccination site, often initially on non-intact skin, 
and they may progress to areas of intact skin. EV lesions follow the 
same Jennerian progression (progression of dermatological lesions 
through the various stages of development and resolution) as the 
vaccination site in a vaccine recipient. Confluent (flowing together) 
or erosive (wearing away) lesions can occur. The rash is often 
accompanied by fever and lymphadenopathy and affected persons are 
frequently systemically ill. EV tends to be most severe among first-
time replication-competent vaccine recipients, unvaccinated close 
contacts of vaccine recipients, and young children.\138\
---------------------------------------------------------------------------

    \137\ Fulginiti et al. ``Smallpox vaccination: a review Part 
I.'' 248.
    \138\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 258.
---------------------------------------------------------------------------

    Early diagnosis of EV and the administration of VIGIV, within 1 or 
2 days of diagnosis, is helpful in reducing the associated morbidity 
and

[[Page 65324]]

mortality.139 140 The fatality rate for those experiencing 
EV ranges from 5 to 40 percent both with and without treatment, 
respectively.141 142 Complications of EV include secondary 
infections caused by fungus and bacteria, septic shock, and fluid and 
electrolyte imbalances.\143\ Historical reports from the era of 
universal vaccination for smallpox showed greater rates for developing 
EV with varying severity.\144\ In the most recent DoD and HHS smallpox 
vaccination programs, there were no documented cases of EV in primary 
vaccine recipients.\145\ This is attributed to improved pre-screening 
of potential smallpox vaccine recipients and excluding those thought to 
be at risk of developing EV. Attenuated smallpox vaccine may reduce the 
risk of developing EV in those individuals with a history of atopic 
dermatitis. However, the potential of developing EV from receiving the 
smallpox vaccine must be weighed against the potential of being exposed 
to the smallpox virus and then developing smallpox infection.\146\
---------------------------------------------------------------------------

    \139\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 13.
    \140\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 256-258.
    \141\ Rosenblatt et al. ``Cutaneous reactions to vaccinations.'' 
328.
    \142\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 256.
    \143\ Rosenblatt et al. ``Cutaneous reactions to vaccinations.'' 
328.
    \144\ Reed et al. ``Eczema vaccinatum.'' 832.
    \145\ Poland et al. ``The US smallpox vaccination program.'' 
2079.
    \146\ Reed et al. ``Eczema vaccinatum.'' 838.
---------------------------------------------------------------------------

    Based on a review of the medical and scientific literature, the 
Program's evidence standard has been met, and EV is a serious physical 
injury that may be directly caused by the administration or use of the 
replication-competent smallpox vaccine.147 148 149 EV is 
proposed to be added to the Table with an onset interval for the first 
symptom or manifestation of onset of 3-21 days after vaccination. Three 
days would be the minimum time to mount an immune response and develop 
symptoms. With treatment, using VIGIV, no additional lesions should 
occur after 21 days.
---------------------------------------------------------------------------

    \147\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 13.
    \148\ Rosenblatt et al. ``Cutaneous reactions to vaccinations.'' 
328.
    \149\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 256-258.
---------------------------------------------------------------------------

    Although EV can occur as the result of inadvertent transfer of the 
vaccinia virus to non-vaccinia vaccine recipients,\150\ for the purpose 
of this regulation, the inadvertent or intentional inoculation of other 
persons by the vaccine recipient and the subsequent development of EV 
is not considered a covered injury. Only those individuals who actually 
were administered the smallpox vaccine will be eligible for 
benefits.\151\
---------------------------------------------------------------------------

    \150\ Lane et al. ``Adverse events.'' 191.
    \151\ 42 CFR part 110.
---------------------------------------------------------------------------

6. Progressive Vaccinia
    Progressive vaccinia (PV) also known as vaccinia necrosum, vaccinia 
gangrenosa or disseminated vaccinia, is a rare, severe, and potentially 
fatal complication of receiving replication-competent smallpox vaccine. 
Its frequency of occurrence is estimated to be 3 to 5 cases per million 
vaccinated.\152\ PV results when a vaccination site fails to heal after 
14 to 21 days in the presence of a minimal inflammatory response and 
when vaccinia virus replication persists.\153\ Of all of the adverse 
skin conditions associated with smallpox vaccine, PV is the most severe 
and life threatening.\154\ PV occurs as the result of a T-cell 
deficiency within the immune system of the vaccine recipient while the 
``B'' cell function remains intact. As a result, the progression and 
manifestation of this condition are limited to the skin without viremic 
spread.\155\ The skin surrounding the vaccination site becomes vaccinia 
infected due to cell-to-cell spread, the primary lesion (vaccination 
site) becomes larger in diameter, and secondary metastatic vaccinia 
lesions can occur in areas away from the primary immunization site. As 
the lesions increase in size, they leave dead skin behind the leading 
edge of the expanding lesion.
---------------------------------------------------------------------------

    \152\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 253.
    \153\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 263.
    \154\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 263.
    \155\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 263.
---------------------------------------------------------------------------

    The onset of symptoms and rate of progress are based on the 
individual level of T-cell deficiency, but with an expected onset of 3 
to 21 days after vaccination.\156\ Primary lesions that fail to heal by 
day 21 post-vaccination should be suspicious for PV.\157\
---------------------------------------------------------------------------

    \156\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 263.
    \157\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 263.
---------------------------------------------------------------------------

    Lesions can appear necrotic (dead), fungated (ulcerated), piled-up, 
or well demarcated (clear margins). Concomitant bacterial 
superinfection can also occur. Fungal and parasitic infections have 
also been documented in patients diagnosed with PV. Progression of PV 
can lead to toxic or septic shock and disseminated intravascular 
coagulation (DIC), a blood clotting disorder, generally ending with 
death.\158\ A diagnosis of PV is made by the appearance and progression 
of the lesions at the primary vaccination site and other subsequent 
satellite lesions.\159\ Management of PV should include aggressive 
therapy with VIGIV. Cidofovir has been included in some recommendations 
as a potential second-line agent that might be used under an 
investigational protocol if the patient does not respond to VIGIV or if 
supplies of VIGIV are exhausted. In addition, case management should 
include intensive monitoring, and tertiary-level supportive care.\160\ 
More recently, recommendations \161\ have been posted suggesting 
tecovirimat (recently approved as a smallpox treatment) brincidofovir, 
and cidofovir as antivirals that might be used under certain 
circumstances to treat certain vaccine complications if treatment with 
VIGIV alone is inadequate or if VIGIV is not readily available. 
Tecovirimat and brincidofovir were used as part of multifactorial 
interventions in a case of PV though the contribution of any one 
intervention to the patient's outcome could not be assessed.\162\
---------------------------------------------------------------------------

    \158\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 263.
    \159\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 265.
    \160\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 14.
    \161\ https://www.cdc.gov/smallpox/clinicians/vaccine-medical-management6.html.
    \162\ E. Lederman et al. ``Progressive vaccinia: Case 
description and laboratory-guided therapy with vaccinia immune 
globulin, ST-246, and CMX001.'' Journal of Infectious Disease, 206 
(November 1, 2012) 1372-1385.
---------------------------------------------------------------------------

    During the most recent DoD and HHS smallpox vaccination program 
where approximately 770,000 individuals were vaccinated, using 
replication-competent vaccines, there were no documented cases of PV. 
The study results indicate improved screening techniques prior to 
delivering the vaccine and withholding vaccinations from those at 
greatest risk of developing an adverse event contributed to this 
result.\163\
---------------------------------------------------------------------------

    \163\ Poland et al. ``The US smallpox vaccination program.'' 
2079.
---------------------------------------------------------------------------

    Based on a review of the medical and scientific literature, the 
Program's evidence standard has been met, and PV is a serious physical 
injury that may be directly caused by the administration or use of the 
replication-competent smallpox vaccine.164 165 166 167 PV is 
proposed to be added to the Table with an onset interval for the first 
symptom

[[Page 65325]]

or manifestation of onset of 3-21 days after vaccination.
---------------------------------------------------------------------------

    \164\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 13.
    \165\ Lane et al. ``Adverse Events.'' 191.
    \166\ Rosenblatt et al. ``Cutaneous reactions to vaccinations.'' 
328.
    \167\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 263.
---------------------------------------------------------------------------

B. The Post-Vaccinial Encephalopathy (PVE), Encephalitis, and 
Encephalomyelitis Spectrum (PVEM)
    PVEM is a spectrum of overlapping conditions that includes post-
vaccinial encephalopathy, encephalitis, and encephalomyelitis, and, for 
the purposes of this NPRM, is treated as one injury. Encephalopathy, 
encephalitis, and encephalomyelitis are inflammations of the parenchyma 
(the functional tissue of an organ) of the central nervous system, the 
brain and spinal cord generally due to an infectious or post-infectious 
etiology. These conditions have been reported after receiving the 
replication-competent smallpox vaccine and have been causally 
associated with the replication-competent smallpox vaccine.\168\ In 
addition to the replication-competent smallpox vaccine, more than one 
hundred viruses have been identified as causing encephalitis, and there 
are no known predictors for those individuals who will go on to develop 
encephalitis.\169\ Of the conditions on the PVEM spectrum, the 
literature discusses PVE in depth.
---------------------------------------------------------------------------

    \168\ Cornelius Van Dam et al. ``Severe post vaccinia 
encephalitis with acute disseminated encephalomyelitis: recovery 
with early intravenous immunoglobulin, high-dose steroids, and 
vaccinia immunoglobulin.'' Clinical Infectious Disease 48(4) 
(February 15, 2009): e47.
    \169\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 267.
---------------------------------------------------------------------------

    In early vaccination campaigns in Great Britain, Europe, and the 
United States, cases of PVE were reported after receipt of the smallpox 
vaccine with varying rates of occurrence based on the type of vaccine 
used by each country.170 171 The Great Britain incidence of 
PVE decreased when they changed the type of replication-competent 
smallpox vaccine they were using to the Lister 
strain.172 173 Rates for PVE in Dutch military recruits were 
as high as 1 in 4,000 vaccinated, whereas in U.S. military recruits, 
the rate was estimated to be 1 in 100,000 vaccinated.\174\ Statistics 
from the 1960s in the U.S. suggest the rates of PVE could range from 9 
to 59 in 1 million vaccinated.\175\ Among the more than 700,000 DoD 
vaccine recipients, three cases of PVE occurred.\176\ Complications 
from vaccination were much less frequent in previously vaccinated 
individuals than those who were vaccinia-na[iuml]ve.
---------------------------------------------------------------------------

    \170\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 267.
    \171\ Kennedy et al. ``Smallpox and vaccinia.'' 738.
    \172\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 267.
    \173\ Kennedy et al. ``Smallpox and vaccinia.'' 738.
    \174\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 267.
    \175\ Van Dam et al. ``Severe post vaccinia encephalitis.'' e47.
    \176\ Van Dam et al. ``Severe post vaccinia encephalitis.'' e47.
---------------------------------------------------------------------------

    Literature indicates there are two subtypes of PVE associated with 
the smallpox vaccine. First, microglial encephalitis results in the 
demyelination of the subcortical white matter and clinically resembles 
acute disseminated encephalomyelitis (ADEM). Second, the cytotoxic form 
presents with cerebral edema (swelling of the brain), infiltration of 
white blood cells into the meningeal tissues and hemorrhages around the 
small blood vessels of the brain.177 178
---------------------------------------------------------------------------

    \177\ Van Dam et al. ``Severe post vaccinia encephalitis.'' e47.
    \178\ James J. Sejvar et al. ``Neurologic adverse events 
associated with smallpox vaccination in the United States, 2002-
2004.'' Journal of the American Medical Association 294(21) 
(December 7, 2005): 2744.
---------------------------------------------------------------------------

    A confirmed diagnosis of PVE requires demonstration of CNS 
inflammation by histopathology or neuroimaging. A suspected diagnosis 
is made by clinical features alone.179 180 The clinical 
symptoms of PVE generally begin 7 to 14 days post-vaccination. 
Clinically significant findings may be identified on magnetic resonance 
imaging (MRI) as early as day 5 post-vaccination with multifocal 
lesions noted throughout the white matter. Cerebral spinal fluid may be 
positive for vaccinia virus, but this does not universally occur. The 
initial symptoms of PVE may include headache, vomiting, drowsiness, and 
fever in mild cases. Severe cases may include these same symptoms, as 
well as paralysis, incontinence, urinary retention, coma, and seizures. 
There is no effective treatment for PVE, only supportive care. 
Approximately 25 percent of patients with PVE will die, and \1/3\ of 
the survivors will experience a broad spectrum of residual neurological 
conditions that include mental impairment and 
paralysis.181 182
---------------------------------------------------------------------------

    \179\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 15.
    \180\ Stuart N. Isaacs and Harvey M. Friedman, ``Vaccinia virus 
as the smallpox vaccine.'' UpToDate (June 03, 2015): 5.
    \181\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 267.
    \182\ Kennedy et al. ``Smallpox vaccines for biodefense.'' 738.
---------------------------------------------------------------------------

    The pathophysiology of CNS adverse reactions attributed to 
replication-competent smallpox vaccination is not completely 
understood, but it is thought to represent some type of autoimmune 
process involving the white matter of the CNS.\183\ Direct infection of 
the CNS by vaccinia virus may result in acute cytotoxic neuronal damage 
and inflammation. However, laboratory evidence of virus replication is 
often lacking; inflammatory changes are attributed instead to immune 
response mechanisms.
---------------------------------------------------------------------------

    \183\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 268.
---------------------------------------------------------------------------

    Histopathological findings of PVE are often similar to those found 
with acute disseminated encephalomyelitis (or post-infectious 
encephalomyelitis). However, a diagnosis of acute disseminated 
encephalomyelitis is characterized by a longer interval of onset after 
immunization and by MRI findings suggesting acute demyelination.\184\ 
Demyelination occurs as the result of an immune response in which the 
membrane that covers the nerves begins to breakdown. Demyelination 
interferes with nerve signal transmission.
---------------------------------------------------------------------------

    \184\ John Neff et al. ``Monitoring the safety of a smallpox 
vaccination program in the United States: report of the joint 
smallpox vaccine safety working group of the advisory committee on 
immunization practices and the armed forces epidemiological board.'' 
Clinical Infectious Disease 46 (Supplement 3) (2008): S261.
---------------------------------------------------------------------------

    PVE is diagnosed by excluding other causes of the symptoms prior to 
associating them with the vaccine.\185\ Cerebral spinal fluid 
examination may show an increased number of white blood cells and 
increased protein, but this is not always the case.\186\
---------------------------------------------------------------------------

    \185\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 15.
    \186\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 14.
---------------------------------------------------------------------------

    Based on a review of the medical and scientific literature, the 
Program's evidence standard has been met, and PVEM (including PVE, 
encephalitis, and encephalomyelitis) are serious physical injuries that 
may be directly caused by the administration or use of the replication-
competent smallpox vaccine. The expected onset interval for the first 
symptom or manifestation is 5-14 days after 
vaccination.187 188
---------------------------------------------------------------------------

    \187\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 14.
    \188\ Fulginiti et al. ``Smallpox vaccination: a review, Part 
II.'' 267.
---------------------------------------------------------------------------

C. Vaccinial Myocarditis, Pericarditis or Myopericarditis (MP)
    For purposes of the NPRM, MP is vaccinial myocarditis, 
pericarditis, or myopericarditis. Myocarditis is an inflammation of the 
heart muscle without blockage of the coronary arteries, and 
pericarditis is an inflammation of the fibrous sack surrounding the 
heart muscle. Myopericarditis is the term used when the two conditions 
occur

[[Page 65326]]

simultaneously. Severe cases of myopericarditis can result in dilated 
cardiomyopathy (DCM) characterized by an enlarged and weakened heart 
muscle. Myocarditis and pericarditis can cause palpitations, shortness 
of breath, fever, sweats, or chest pain and can be diagnosed by an 
abnormal electrocardiogram (ECG), imaging studies (echocardiogram), 
histopathology, or elevated cardiac enzymes. Myocardial dysfunction in 
cases of myopericarditis may result from direct viral injury or from a 
triggered immune response that targets the myocardium or pericardium. 
In mouse models of infectious myocarditis, the virus is only rarely 
isolated from the myocardium. The absence of direct infection of the 
myocardium suggests immune-mediated injury as the predominant 
pathogenic mechanism.
    Inflammatory processes can be caused by a number of viral 
infections and autoimmune disorders and have sequelae ranging from 
self-limiting asymptomatic disease to DCM, resulting in fulminant 
(severe and sudden) congestive heart failure and possibly death. 
Myocarditis is blamed for causing up to 20 percent of all cases of 
sudden death among military recruits. Although cardiac events after the 
administration or use of replication-competent smallpox vaccine were 
reported in the literature before 2003, they were largely unrecognized 
during the worldwide eradication campaign and were thought to occur 
very rarely. Only six cases of cardiac complications after replication-
competent smallpox vaccination with the New York City Board of Health 
(NYCBH) strain of vaccinia were reported in the United States before 
2003.\189\ In the past decade, cardiac complications following live 
vaccinia vaccination have been detected more often due to the 
availability of more sophisticated diagnostic techniques. Cardiac 
complications resulting from live vaccinia vaccination range in 
severity from mild to fatal and include myocarditis, pericarditis, 
arrhythmias, and DCM.\190\
---------------------------------------------------------------------------

    \189\ Juliette Morgan et al. ``Myocarditis, pericarditis, and 
dilated cardiomyopathy after smallpox vaccination among civilians in 
the United States, January-October 2003.'' Clinical Infectious 
Disease 46 Supplement 3 (2008): S242.
    \190\ Nalca et al. ``ACAM200\TM\: The New Smallpox vaccine.'' 
76.
---------------------------------------------------------------------------

    Of 730,580 U.S. Armed Forces personnel vaccinated with the 
discontinued vaccine, Dryvax, 86 cases of myopericarditis with moderate 
or severe clinical presentation occurred in otherwise healthy vaccine 
recipients.\191\ The single fatal case of myocarditis was in a female. 
The report calculated a rate of myopericarditis 7.5-fold higher than 
the expected background rate among 347,516 primary vaccine recipients 
with the expected rate being 2.16 per 100,000 vaccinated as opposed to 
the observed rate of 16.11 per 100,000 vaccinated.\192\
---------------------------------------------------------------------------

    \191\ Poland et al. ``The US smallpox vaccination program.'' 
2079.
    \192\ Poland et al. ``The US smallpox vaccination program.'' 
2079.
---------------------------------------------------------------------------

    Of 37,901 HHS vaccine recipients, 21 civilians were diagnosed with 
mild cases of myopericarditis (at a rate of 554 per million), all of 
which resolved without further complication.\193\ Additionally, four 
DoD and three HHS cases of DCM occurred among previously healthy 
subjects, with two requiring heart transplants.\194\
---------------------------------------------------------------------------

    \193\ Morgan et al. ``Myocarditis, pericarditis, and dilated 
cardiomyopathy.'' S246.
    \194\ Neff et al. ``Monitoring the safety of a smallpox 
vaccination program.'' S262.
---------------------------------------------------------------------------

    The occurrence of the vast majority of cardiac adverse events 
within 30 days of the smallpox vaccination, and clustering within 7-12 
days post-vaccination, provides compelling, reliable, valid, medical 
and scientific evidence of a direct link between vaccination with live 
vaccinia virus and incidence of vaccinia associated cardiac 
complications consisting of vaccinial myocarditis, pericarditis and 
myopericarditis (MP). Based on a review of the medical and scientific 
literature, the Program's evidence standard has been met, and MP is a 
serious physical injury that may be directly caused by the 
administration or use of the replication-competent smallpox vaccine. 
Therefore, MP is proposed to be added to the Table with an onset 
interval for the first symptom or manifestation of 0-21 days after 
vaccination.195 196 Although clustering occurs 7-12 days 
post-vaccination, symptoms may begin within 24 hours of 
vaccination.\197\ The literature does not indicate that cardiac 
manifestations have occurred beyond 21 days post-vaccination based on 
immune response.\198\
---------------------------------------------------------------------------

    \195\ Centers for Disease Control and Prevention, ``Cardiac 
adverse events following smallpox vaccination--United States, 
2003.'' Morbidity and Mortality Weekly Report 52(12) (March 28, 
2003): 250.
    \196\ Dimitri C. Cassimatis et al. ``Smallpox vaccination and 
myopericarditis: a clinical review.'' Journal of the American 
College of Cardiology 43(9) (May 5, 2004): 1505.
    \197\ Centers for Disease Control and Prevention, ``Cardiac 
adverse.'' 3.
    \198\ Lane et al. ``Adverse events.'' 190.
---------------------------------------------------------------------------

    Anecdotal reports of ischemic heart disease, such as angina 
pectoris or myocardial infarction (heart attacks), occurring in a few 
individuals following receipt of the smallpox vaccine have been 
published in the literature.\199\ However, these reports are not 
compelling, reliable, valid, medical and scientific evidence 
demonstrating that the replication-competent smallpox vaccine directly 
causes ischemic heart disease. Therefore, the Secretary does not 
propose to add ischemic heart disease to the Table, and claims for this 
injury will be considered non-Table injuries and evaluated on a case-
by-case basis based on the Program's evidence standard.
---------------------------------------------------------------------------

    \199\ Centers for Disease Control and Prevention, ``Cardiac 
adverse.'' 2.
---------------------------------------------------------------------------

Other Conditions of Special Interest to Smallpox Vaccination
    Although the conditions listed below may be of special interest to 
the public and are being monitored by HHS, the Secretary does not 
propose including them on the Table at this time because compelling, 
reliable, valid, medical and scientific evidence of causation does not 
currently exist. The conditions include the following:
A. Secondary Infection
    Secondary infections resulting from loss of skin integrity because 
of receiving a replication-competent vaccine are common. All instances 
of secondary infection will be considered non-Table injuries and 
evaluated on a case-by-case basis based on the Program's evidence 
standard.
B. Serum Sickness
    Serum sickness is a systemic, immune complex-mediated 
hypersensitivity vasculitis classically attributed to the therapeutic 
administration of foreign serum proteins. It is a classic example of a 
type III hypersensitivity reaction caused by antigen-antibody 
complexes. The symptoms of serum sickness generally begin 7-12 days 
after injection of the foreign material, but may appear as late as 3 
weeks afterward. Immune complexes involving heterologous (animal) serum 
proteins and complement activation are important pathogenic mechanisms 
in serum sickness. Reactions originally described as serum sickness--
like are now attributed to drug allergy, triggered in particular by 
antibiotics (e.g., penicillin, cefaclor), and, rarely, to other agents, 
such as human immune globulin, humanized monoclonal antibodies, and 
insect venom. The Program is not aware of compelling, reliable, valid, 
medical and scientific evidence in literature demonstrating the 
smallpox vaccine directly causes serum sickness. Therefore, the 
Secretary does not propose to add serum sickness to the

[[Page 65327]]

Table, and claims for this injury will be considered non-Table injuries 
and evaluated on a case-by-case basis based on the Program's evidence 
standard.
C. Shoulder Injury Related to Vaccine Administration (SIRVA)
    Shoulder Injury Related to Vaccine Administration (SIRVA) manifests 
as shoulder pain and limited range of motion occurring after the 
administration of a vaccine intended for intramuscular administration 
in the upper arm. The symptoms occur in the arm in which the vaccine 
was administered because of unintended injection of vaccine antigen or 
trauma from the needle into and around the underlying bursa of the 
shoulder resulting in an inflammatory reaction. SIRVA is not a 
neurological injury.
    The smallpox vaccine is administered via a bifurcated (two-pronged) 
needle into the deep epidermis when administering Smallpox (Vaccinia) 
Vaccine Live, replication-competent or, in the case of Smallpox and 
Monkeypox Vaccine, Live, Non-replicating replication-deficient, via a 
subcutaneous (under the skin) injection. Both injections generally take 
place over the deltoid or triceps muscles. As the smallpox vaccine is 
administered in a manner other than an intramuscular injection and 
neither the vaccine nor the needle reaches the internal structures of 
the shoulder, there is no compelling, reliable, valid, medical and 
scientific evidence of a direct causal association between the smallpox 
vaccination and SIRVA. Therefore, the Secretary does not propose to add 
SIRVA to the Table at this time, and claims for this injury will be 
considered non-Table injuries and evaluated on a case-by-case basis 
based on the Program's evidence standard.
D. Subdeltoid Bursitis
    Subdeltoid bursitis (e.g., deltoid bursitis, subacromial bursitis) 
is an inflammation of the bursa located between the deltoid muscle and 
the capsule of the shoulder joint. A bursa is a closed fluid-containing 
sac that reduces friction between bones and tendons, or bones and skin. 
The bursa extends below the deltoid muscle, and it is possible for a 
deep injection given high in the shoulder to enter the bursa 
inadvertently causing an inflammatory bursitis. Subdeltoid bursitis can 
result in debilitating pain or immobility.
    As stated above, the smallpox vaccine is administered via a 
bifurcated (two-pronged) needle into the deep epidermis or via a 
subcutaneous (under the skin) injection. Both injections generally take 
place over the deltoid or triceps muscles. Since the smallpox vaccine 
is administered in a manner other than an intramuscular injection and 
neither the vaccine nor the needle reaches the subdeltoid space, there 
is no compelling, reliable, valid, medical and scientific evidence of a 
direct causal association between the smallpox vaccination and 
subdeltoid bursitis. Therefore, the Secretary does not propose to add 
subdeltoid bursitis to the Table at this time. However, claims for this 
injury will be considered non-Table injuries and evaluated on a case-
by-case basis based on the Program's evidence standard.
E. EM
    EM is a typically mild and self-limiting mucocutaneous reaction 
characterized by target lesions on the skin and mucous membranes.\200\ 
Historically, EM comprised a disease spectrum that was classified by 
increasing degrees of severity. The spectrum included a minor form (EM 
minor) and a more severe or major form (EM major), SJS. TEN completed 
the spectrum as the most severe form of the disease. The unifying 
clinical features of these diseases that placed them under the EM 
spectrum were target lesions, similar mucosal features and epidermal 
necrosis. However, current evidence suggests that EM, SJS, and TEN are 
not in the same continuum. SJS and TEN are the same disease differing 
only in the area of involvement and severity of systemic findings. EM 
and SJS/TEN differ in their cause, clinical presentation, pathology and 
therapy.\201\
---------------------------------------------------------------------------

    \200\ P. Michele Williams and Robert J. Conklin. ``Erythema 
multiforme: A review and contract from Stevens-Johnson syndrome/
toxic epidermal necrolysis.'' Dental Clinics of North America 2005; 
49: 67-76.
    \201\ Williams et al. ``Erythema multiforme.'' 68.
---------------------------------------------------------------------------

    EM is almost always infectious in origin, with herpes simplex virus 
(HSV) as the infectious agent in 70-80 percent of cases.\202\ Drugs 
have been estimated to induce EM in less than 10 percent of cases. The 
most common precipitators are non-steroidal anti-inflammatory drugs, 
sulfonamides, anti-epileptics and antibiotics.\203\ The interpretation 
of the literature on drug-induced EM is complicated by previous 
classification of SJS/TEN as part of the EM spectrum. This is true for 
studies involving smallpox and EM. A 1968 study noted that EM accounted 
for 13 percent of all complications associated with the replication-
competent smallpox vaccine or a rate of 165 cases of EM per 1 million 
persons vaccinated.\204\ In 1977, an Australian study of 938 adverse 
events related to the replication-competent smallpox vaccine identified 
87 cases of EM, which represented 9.3 percent of all of the reported 
complications.\205\ Neither of these studies specified the severity of 
EM or mentioned SJS/TEN.
---------------------------------------------------------------------------

    \202\ Williams et al. ``Erythema multiforme.'' 68.
    \203\ David Wetter. ``Erythema multiforme: Pathogenesis, 
clinical features and diagnosis.'' 2019 UpToDate.
    \204\ J. Michael Lane et al. ``Complications of smallpox 
vaccination, 1968: Results of ten statewide surveys.'' Journal of 
Infectious Disease 122(4) (October 1, 1970): 305.
    \205\ B.J. Feery, ``Adverse reactions after smallpox 
vaccinations.'' Medical Journal of Australia 2 (August 6, 1977): 
181.
---------------------------------------------------------------------------

    EM most often manifests as both skin and mucosal lesions, but may 
also exhibit skin lesions alone. Occasionally, EM presents only with 
mucous membrane involvement. Skin lesions most commonly appear in a 
symmetrical distribution on the extremities (acral distribution) and 
spread centripetally (toward the center). Skin lesions are usually 
asymptomatic though some patients experience itching and burning. Oral 
mucous lesions are common. Mucosal lesions can also be found in other 
sites (such as genital area and eyes) but are less common.\206\ In most 
patients, EM is a transient condition that spontaneously resolves 
without long-term morbidity. EM lesions usually appear over the course 
of 3 to 5 days and resolve in approximately 2 weeks. Skin lesions do 
not scar, but post-inflammatory hyperpigmentation may remain months 
after resolution. Rarely, patients experience complications, such as 
fluid and electrolyte abnormalities, or those with eye involvement can 
have scarring and visual impairment.\207\
---------------------------------------------------------------------------

    \206\ J. Clark Huff, William Weston, and Marcia Tonnesen. 
``Erythema multiforme: A critical review of characteristics, 
diagnostic criteria and causes.'' Journal of the American Academy of 
Dermatology 8(6) (June 1983): 763-775.
    \207\ Huff et al. Erythema multiforme, 767-768.
---------------------------------------------------------------------------

    Based on a review of the medical and scientific literature, EM is a 
physical injury that may be directly caused by the use of the 
replication-competent smallpox vaccine. However, since EM is typically 
a mild and self-limiting condition, it is not considered a serious 
injury based on the Program's standards. Therefore, the Secretary does 
not propose to add EM to the Table and claims for this injury will be 
considered non-Table injuries and evaluated on a case-by-case basis, 
based on the Program's evidence standard.
Non-Vaccine Countermeasures
    In addition to the smallpox vaccine, there are other potential 
countermeasures that might be used either for smallpox or to treat 
adverse

[[Page 65328]]

events following vaccination including vaccinia immunoglobulin 
intravenous (VIGIV), cidofovir, tecovirimat, and brincidofovir. The 
Secretary proposes to add VIGIV, cidofovir, tecovirimat and 
brincidofovir to the Table as covered countermeasures.
Vaccinia Immunoglobulin Intravenous (VIGIV)
    Vaccinia immunoglobulin intravenous (VIGIV) is a medication that is 
used to treat some of the complications (adverse side effects) of 
receiving the smallpox vaccine. It is not indicated for treatment of 
smallpox infection. Immunoglobulins are a class of medication used to 
treat many autoimmune diseases and primary immune deficiency, 
infections, and complications from the smallpox vaccine. Although the 
clinical use of, and experience with, VIGIV is limited, this product is 
derived in the same way as other types of immunoglobulins and is 
thought to have the same side effects and potential complications. As a 
result, the possible adverse side effects are thought to be similar to 
other immunoglobulins (class effect).
    VIGIV is harvested from the plasma of persons vaccinated with 
vaccinia virus and who have had a sufficient immune response to produce 
antibodies in an effort to prevent smallpox infection. Individuals who 
were vaccinated, as part of their immune response, develop antibodies 
after vaccination, and those antibodies are collected within donated 
plasma. The plasma is processed into VIGIV. VIGIV may help in 
ameliorating some complications of vaccinia immunization including 
eczema vaccinatum, progressive vaccinia, or severe generalized 
vaccinia. It may also be used to treat autoinoculation to the eye or 
eyelid. VIGIV is not thought to be effective in treating PVE. The 
current VIGIV product is administered intravenously.
    The following injuries have been associated with the use of 
immunoglobulins: (a) anaphylaxis, (b) transfusion related acute lung 
injury, (c) acute renal failure, (d) drug-induced aseptic meningitis, 
(e) hemolysis, and (f) thrombosis.\208\
---------------------------------------------------------------------------

    \208\ David J. Hamrock, ``Adverse events associated with 
intravenous immunoglobulin therapy.'' International Immunopharmacol 
6 (2006): 535.
---------------------------------------------------------------------------

A. Anaphylaxis
    A general discussion of anaphylaxis is in the Anaphylaxis section 
under the Smallpox Vaccine heading of this NPRM. Vaccinia immune 
globulin is a product derived from human plasma and as such, it 
contains human proteins and antibodies. According to the literature, 
the use of VIGIV poses a risk of anaphylaxis when used in individuals 
who have an immunoglobulin A (IgA) deficiency and who go on to form 
immunoglobulin E (IgE) antibodies against IgA or who have had a 
previous allergic reaction to human antibody/blood 
products.209 210 211 The number of individuals with IgA 
deficiency varies based on geographic location. Estimates of IgA 
deficiency range from 1 in 400 to 1 in 3,000 within the U.S. 
Approximately 30-40 percent of this population also has anti-IgA 
antibodies. It is possible to reduce the amount of IgA in VIGIV. 
However, it is not possible to eliminate the antibody, and only very 
small amounts are necessary to cause anaphylaxis.\212\
---------------------------------------------------------------------------

    \209\ Centers for Disease Control and Prevention (CDC). 
``Smallpox supplemental fact sheet: Investigational vaccinia immune 
globulin (VIG) information.'' (March 10, 2009): 1.
    \210\ Hamrock, ``Adverse events associated.'' 535.
    \211\ Patrick Cherin et al. ``Management of adverse events in 
the treatment of patients with immunoglobulin therapy: a review of 
evidence.'' Autoimmunity Reviews 15 (September 16, 2015): 75.
    \212\ Hamrock, ``Adverse events associated.'' 539.
---------------------------------------------------------------------------

    Based on the unique nature of the presentation and timing of 
anaphylaxis, the consensus in the medical community regarding causation 
based on IgA antibody reactions, and the existing medical literature, 
anaphylaxis is proposed for inclusion on the Table because it is a 
serious physical injury that may be directly caused by the 
administration or use of VIGIV, as supported by the Program's evidence 
standard. Consistent with the time interval for the first manifestation 
of anaphylaxis after exposure to a foreign protein and as established 
in the 1994 IOM clinical case definition of anaphylaxis \213\, the 
Secretary proposes including anaphylaxis as an injury on the Table with 
an onset interval of 0-4 hours for the first symptom or manifestation 
to occur after the administration or use of VIGIV.\214\ This timeframe 
is consistent with other medications or blood derived products that may 
induce anaphylaxis.\215\
---------------------------------------------------------------------------

    \213\ Institute of Medicine, ``Immunization safety review 
vaccination.'' 5.
    \214\ Ruggeberg et al. ``Anaphylaxis.'' 5677-5678.
    \215\ Ruggeberg et al. ``Anaphylaxis.'' 5677-5678.
---------------------------------------------------------------------------

    In rare cases of acute anaphylaxis, initial symptoms of the 
immediate reaction may present up to 12 hours after exposure. A slow 
evolving late phase hypersensitivity reaction is possible, with an 
onset that usually begins 4-8 hours after the immediate reaction ends. 
The medical literature contains reports of late phase onset up to 72 
hours later.\216\ The late phase reaction results from a different 
immunologic mechanism of action. The late phase reaction is part of a 
biphasic reaction. It is possible for the first immediate 
hypersensitivity reaction to be relatively mild, unrecognized, or not 
observed. There may be unusual cases in which the immediate reaction is 
delayed and/or cases that the immediate reaction is not recognized, 
with the first apparent manifestation occurring in the late phase. 
These unusual cases do not meet the requirements to be considered table 
injuries, and will be evaluated on a case-by-case basis based on the 
Program's evidence standard.
---------------------------------------------------------------------------

    \216\ Ruggeberg et al. ``Anaphylaxis: case definition and 
guidelines.'' 5677.
---------------------------------------------------------------------------

B. Transfusion-Related Acute Lung Injury (TRALI)
    Transfusion-related acute lung injury (TRALI) is defined as the 
onset of respiratory distress within 6 hours after receipt of plasma 
containing blood products in non-critically ill patients. However, in 
critically ill patients, the literature states that it may take as long 
as 72 hours to develop TRALI post-transfusion.\217\ As VIGIV is derived 
from human plasma, VIGIV may precipitate TRALI.
---------------------------------------------------------------------------

    \217\ Alexander P.J. Vlaar and Nicole P. Juffermans, 
``Transfusion-related acute lung injury: a clinical review.'' Lancet 
328 (May 1, 2013): 984.
---------------------------------------------------------------------------

    TRALI is a form of non-cardiac pulmonary edema identified by chest 
x-ray and characterized by severe respiratory distress, pulmonary 
edema, hypoxia (oxygen starvation), and fever in the presence of normal 
left ventricular function.\218\ A patient experiencing TRALI may 
require mechanical ventilation to treat the respiratory distress, 
pulmonary edema, and hypoxia. The use of mechanical ventilation is 
associated with other injuries and complications, such as lung trauma 
and tracheal stenosis. TRALI has been identified as a major cause of 
mortality in those individuals receiving plasma-containing 
transfusions.\219\
---------------------------------------------------------------------------

    \218\ ``Vaccinia immune globulin intravenous (human)'' [package 
insert]. Cangene Corporation, Frederick, MD; (2010): 7.
    \219\ Vlaar et al. ``Transfusion-related acute.'' 984.
---------------------------------------------------------------------------

    Although not completely understood, it is believed that the basis 
of TRALI rests in a host antibody response to receiving blood products 
that contain plasma, via transfusion. The host receives a transfer of 
donor anti-leukocyte antibodies (antibodies that act against the 
patient's white blood cells) within the plasma and then develops a 
reaction causing the activation of the endothelial cells and pulmonary 
neutrophils leading to capillary leakage

[[Page 65329]]

and pulmonary edema (fluid in the lungs).\220\ The patient then goes on 
to develop the classic symptoms of TRALI.\221\
---------------------------------------------------------------------------

    \220\ Vlaar et al. ``Transfusion-related acute.'' 985.
    \221\ Robert S. Makar, Amy Powers and Christopher Stowell, 
``Reducing transfusion-related acute lung injury risk: evidence for 
and approaches to transfusion-related acute lung injury 
mitigation.'' Transfusion Medicine Reviews 26(4) (October 2012): 
305.
---------------------------------------------------------------------------

    Based on the unique nature of the presentation and timing of TRALI 
together with consensus in the medical community regarding causation, 
and the existing scientific and medical literature, the Program's 
evidence standard has been met, and TRALI is as a serious physical 
injury proposed to be added to the Table. The Secretary proposes 
including TRALI as an injury on the Table with an onset interval of 0-
72 hours for the first symptom or manifestation to occur after the 
administration or use of VIGIV.\222\
---------------------------------------------------------------------------

    \222\ Vlaar et al. ``Transfusion-related acute.'' 984.
---------------------------------------------------------------------------

C. Acute Renal Failure
    Acute renal failure (ARF) is the sudden inability of the kidneys to 
filter waste products from the blood stream. This leads to the build-up 
of waste products and fluid in the body and can lead to a metabolic 
derangement (chemical imbalance), fluid overload, and death, if not 
identified and treated early. Acute renal failure can occur over a 
matter of hours or days and can generally be treated and reversed if 
diagnosed early. The use of immunoglobulin has been identified as a 
factor leading to the development of ARF. Between 1985 and 1998, the 
FDA received 120 reports of patients developing ARF associated with the 
use of immunoglobulins.\223\ The majority of cases of renal failure 
were associated with the use of immunoglobulins that contained sucrose 
as a stabilizing agent. The sucrose caused swelling within the kidney 
and the loss of renal function.\224\ VIGIV does not contain sucrose, 
but rather maltose, which may decrease the incidents of ARF but not 
eliminate the risk of developing the condition completely.\225\
---------------------------------------------------------------------------

    \223\ M. Jennifer Cheng and Colleen Christmas, ``Special 
consideration with the use of intravenous immunoglobulin in older 
persons.'' Drugs Aging 28(9) (2011): 732.
    \224\ Hamrock, ``Adverse events associated.'' 538.
    \225\ Hamrock, ``Adverse events associated.'' 538.
---------------------------------------------------------------------------

    The factors that may contribute to or precipitate ARF when using 
VIGIV include: (1) Pre-existing renal insufficiency or use of VIGIV in 
patients at risk of developing renal insufficiency due to diabetes; (2) 
age older than 65 years; (3) volume depletion (dehydration); (4) 
paraproteinemia (high amount of paraprotein in the blood); (5) sepsis; 
(6) a faster rate of immunoglobulin infusion; and (7) the concomitant 
use of nephrotoxic (kidney toxic) drugs.226 227 228
---------------------------------------------------------------------------

    \226\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 18.
    \227\ Vaccinia immune globulin intravenous package insert.
    \228\ Hamrock, ``Adverse events associated.'' 538.
---------------------------------------------------------------------------

    Based on existing scientific and medical literature, the Program's 
evidence standard has been met, and ARF is as a serious physical injury 
proposed to be added to the Table. The onset of ARF with the use of 
VIGIV begins with the onset of renal insufficiency, progressing to 
renal failure, and occurs within 0-10 days after receiving VIGIV. 
Therefore, the Secretary proposes adding ARF to the Table as an injury 
associated with the use of VIGIV with a time of onset within 10 days 
for the first symptom or manifestation to occur after the 
administration or use of VIGIV.229 230 231 232 233
---------------------------------------------------------------------------

    \229\ H.I.A. Sati, R. Ahya and H.G. Watson, ``Incidence and 
associations of acute renal failure complicating high-dose 
intravenous immunoglobulin therapy.'' British Journal of Haematology 
113 (January 4, 2001): 557.
    \230\ Doreen Bianchi-Winward and Mary T. Brophy, ``Acute renal 
failure after administration of intravenous immunoglobulin: review 
of the literature and case report.'' Pharmacotherapy 15(6) (1995): 
766.
    \231\ Yelena M. Itkin and Toby C. Trujillo, ``Intravenous 
immunoglobulin-associated acute renal failure: case series and 
literature review.'' Pharmacotherapy 25(6) (2005): 889.
    \232\ N. Gupta et al. ``Intravenous gammaglobulin-associated 
acute renal failure.'' American Journal of Hematology 66 (2001): 
1552.
    \233\ Thomas G. Cantu et al. ``Acute renal failure associated 
with immunoglobulin therapy.'' American Journal of Kidney Disease 
25(2) (February 1995): 228.
---------------------------------------------------------------------------

D. Drug-Induced Aseptic Meningitis
    Drug-induced aseptic meningitis (DIAM) is an inflammation of the 
linings of the brain (meninges) that is not caused by a bacteria or 
virus, but by a drug or medication. The symptoms of meningitis include 
severe headache, nuchal (neck) rigidity, drowsiness, fever, photophobia 
(light sensitivity), painful eye movements, nausea, and vomiting. 
Discontinuation of the medication leads to a resolution of the 
symptoms. It is postulated that DIAM occurs because of an immunological 
hypersensitivity reaction to a specific medication.\234\ In the case of 
immunoglobulins, DIAM may be precipitated by the immunologically active 
components within the plasma or because of the stabilizers used within 
the product.\235\ The symptoms of DIAM may reoccur with another 
exposure to the offending agent. Drugs that can cause DIAM include 
immunoglobulins, non-steroidal anti-inflammatory drugs (NSAIDs), drugs 
delivered via the intrathecal route (into the spinal canal) and 
antibiotics.236 237
---------------------------------------------------------------------------

    \234\ Stephen Jolles, W.A. Carrock-Sewell and Carol Leighton, 
``Drug-induced aseptic meningitis.'' Drug Safety 3 (March 2000): 
216.
    \235\ Jolles et al. ``Drug-induced.'' 221.
    \236\ German Moris and Juan Carlos Garcia-Monoco, ``The 
challenge of drug-induced aseptic meningitis revisited.'' Journal of 
the American Medical Association 174(9) (September 2004): 1511.
    \237\ Jolles et al. ``Drug-induced.'' 217.
---------------------------------------------------------------------------

    The incidence of DIAM is estimated to occur in approximately 1 
percent of patients receiving immunoglobulins. Most patients who 
experience immunoglobulin-associated DIAM recover completely within 5 
days of stopping the medication and without sequelae or permanent 
injury.\238\ It appears that individuals with a history of migraine 
headaches have an increased risk for developing immunoglobulin 
associated DIAM.\239\ In addition, the dose delivered may contribute to 
the development of DIAM. Doses of immunoglobulin given at 2 g/kg/cycle 
appeared to precipitate aseptic meningitis when compared to smaller 
doses.\240\
---------------------------------------------------------------------------

    \238\ Cherin et al. ``Management of adverse events.'' 75.
    \239\ Hamrock, ``Adverse events associated.'' 537.
    \240\ Hamrock, ``Adverse events associated.'' 537.
---------------------------------------------------------------------------

    Based on existing scientific and medical literature, the Program's 
evidence standard has been met, and DIAM is a serious physical injury 
proposed to be added to the Table. As noted by Jolles et al., the 
anticipated time of onset for the first symptom or manifestation to 
occur is within 48 hours after the administration or use of the first 
dose of VIGIV and no more than 48 hours after the administration or use 
of the last dose of VIGIV.\241\ Therefore, the Secretary proposes 
adding DIAM within this time of onset interval as a Table injury.
---------------------------------------------------------------------------

    \241\ Jolles et al. ``Drug-induced.'' 221.
---------------------------------------------------------------------------

E. Hemolysis
    Hemolysis is the physical breakdown of red blood cells (RBCs) 
either through natural attrition or as caused by external factors. An 
RBC's natural life cycle ranges from 110 to 120 days. This cycle 
coincides with the production of RBCs within the bone marrow, which 
maintains homeostasis (steady state). The RBC's function is to 
transport oxygen throughout the body in the hemoglobin contained within 
the RBCs. Additionally, the RBCs contain the majority of the body's 
potassium stores. When RBCs break down faster than their natural life 
cycle, the bone marrow

[[Page 65330]]

cannot produce new cells fast enough to maintain RBC levels, resulting 
in anemia. The body is unable to transport oxygen effectively, and the 
person develops hypoxia (oxygen starvation). Additionally, the rapid 
breakdown of the cell releases large amounts of potassium into the 
blood stream, which can cause abnormal heart rhythms. Breakdown of RBCs 
also releases large amounts of hemoglobin which may result in renal 
damage. In severe cases of hemolysis, a blood transfusion may be 
required to correct the resulting anemia.\242\
---------------------------------------------------------------------------

    \242\ Cherin et al. ``Management of adverse events.'' 78.
---------------------------------------------------------------------------

    Conditions that contribute to hemolysis include immune reactions, 
infections, toxins, poisons, hemodialysis, and medications. 
Immunoglobulins cause hemolysis in certain individuals due to blood 
group antibodies. These antibodies cause RBCs to be coated with immune 
globulin, which leads to an anti-globulin reaction and hemolysis.\243\ 
Individuals with non-group O type blood may be more susceptible to 
hemolysis in conjunction with the use of immunoglobulin.\244\ There may 
also be a relationship between hemolysis and the total accumulative 
amount of immunoglobulin received by an individual. Individuals who 
have received a larger accumulative dose of immunoglobulin had a 
greater likelihood of developing hemolysis.\245\
---------------------------------------------------------------------------

    \243\ Vaccinia immune globulin intravenous package insert.
    \244\ Cherin et al. ``Management of adverse events.'' 78.
    \245\ Cherin et al. ``Management of adverse events.'' 78.
---------------------------------------------------------------------------

    Based on existing scientific and medical literature, the Program's 
evidence standard has been met, and development of hemolysis after the 
use or administration of VIGIV is a serious physical injury proposed to 
be added to the Table. As noted by Berg, et al., the onset of hemolysis 
associated with the use of VIGIV is anticipated to develop between 12 
hours and 14 days from the administration of VIGIV.246 247 
Therefore, the Secretary proposes adding hemolysis as a Table injury 
with a time of onset from 12 hours to 14 days for the first symptom or 
manifestation to occur after the administration or use after of 
VIGIV.\248\
---------------------------------------------------------------------------

    \246\ Zohra Daw et al. ``Hemolytic transfusion reactions after 
administration of intravenous immune (gamma) globulin: a case series 
analysis.'' Transfusion 48(8) (August 2008): 1598.
    \247\ Scott Winiecki et al. ``Complementary use of passive 
surveillance and mini-sentinel of better characterize hemolysis 
after immune globulin.'' Transfusion 55 (July 2015): s30.
    \248\ Roger Berg et al. ``Hemolytic events associated with 
intravenous immune globulin therapy: a qualitative analysis of 263 
cases reported to four manufacturers between 2003 and 2012.'' 
Transfusion 55 (July 2015): S40.
---------------------------------------------------------------------------

Other Conditions of Special Interest to VIGIV
A. Thrombotic Events
    A thrombotic event involves the formation of a blood clot within a 
blood vessel. This clot restricts flow of blood back to the heart and 
lungs in the area distal to (behind) the clot. Once formed the clot 
poses a risk of dislodging, becoming an embolism, floating to a smaller 
blood vessel in the brain, lung, or heart and causing tissue death in 
one of these areas resulting in a stroke, pulmonary embolism, or heart 
attack, respectively. People with a history of atherosclerosis (blood 
vessel disease), multiple cardiovascular risk factors, advanced age, 
impaired cardiac output, hypercoagulable disorders (blood clotting 
disorders), prolonged periods of immobilization and known or suspected 
hyperviscosity (thickening of the blood) are at increased risk of 
thrombus formation.249 250 251 252 253 Additional risk 
factors for forming a thrombus include smoking, obesity, pregnancy, and 
the use of oral contraceptives.\254\
---------------------------------------------------------------------------

    \249\ Cangene Corporation, ``Vaccinia immune globulin 
intravenous package insert.'' (2005): 6.
    \250\ Hamrock, ``Adverse events associated.'' 538-539.
    \251\ Cherin et al. ``Management of adverse events.'' 76-77.
    \252\ Gregory W. Daniel et al. ``Immune globulins and thrombotic 
adverse events as recorded in a large administrative database in 
2008 through 2010.'' Transfusion 52 (October 2012): 2117.
    \253\ Cheng et al. ``Special considerations with the use.'' 733.
    \254\ Mayo Clinic, ``Diseases and conditions-Deep vein 
thrombosis (DVT). (August 10, 2018). Available from https://www.mayoclinic.org/diseases-conditions/deep-vein-thrombosis/symptoms-causes/syc-20352557.
---------------------------------------------------------------------------

    Medical and scientific literature supports an association between 
the use of VIGIV and thrombotic events. There are a number of 
predisposing factors, which may increase an individual's risk of 
developing a thrombus in association with the use of immunoglobulins. 
Since multiple external factors play a role in the development of a 
thrombus, a timeframe for the onset of a thrombotic event after the use 
of VIGIV that meets the Program's evidence standard cannot be 
determined. Therefore, claims for thrombotic events associated with the 
use of VIGIV will be considered a non-table injury and evaluated on a 
case-by-case basis based on the Program's evidence standard.
B. Interference With Blood Glucose Testing
    As noted above, VIGIV uses maltose, a disaccharide or sugar, in its 
composition. Some forms of blood glucose monitoring equipment may 
falsely identify the presence of maltose as an elevated blood glucose 
level. Treating this false reading by providing supplemental insulin 
could result in hypoglycemia (low blood sugar) in patients receiving 
VIGIV.\255\
---------------------------------------------------------------------------

    \255\ Cangene Corporation, ``Vaccinia immune globulin 
intravenous package insert.'' (2005): 6.
---------------------------------------------------------------------------

    There is compelling, reliable, valid, medical and scientific 
evidence that the use of VIGIV may lead to false measurements of 
elevated blood glucose levels if the appropriate testing methods are 
not used. However, these falsely elevated blood glucose levels in and 
of themselves are not harmful unless treated inappropriately. Since 
false test results alone do not meet the Program's definition of a 
serious injury, the Secretary does not propose adding interference with 
blood glucose testing as a Table injury with the use of VIGIV. However, 
claims of hypoglycemia resulting from the treatment of falsely elevated 
blood glucose levels will be considered a non-Table injury and will be 
evaluated on a case-by-case basis based on the Program's evidence 
standard.
C. Infectious Contamination
    As immunoglobulins generally and VIGIV specifically are products 
derived from human blood plasma, there is a risk, however slight, of 
the product being contaminated with human viruses. Prior to donating 
plasma, all donors are tested for certain infectious diseases. 
Additionally, during the processing of plasma into VIGIV, it undergoes 
treatment to remove and or kill infectious organisms. It is possible, 
however, that an individual could potentially obtain a blood-borne 
infection from receiving VIGIV.\256\
---------------------------------------------------------------------------

    \256\ Cangene Corporation, ``Vaccinia immune globulin.'' 7-8.
---------------------------------------------------------------------------

    The medical literature supports the theoretical possibility of 
infectious contamination of VIGIV; however, as there is no compelling, 
reliable, valid, medical or scientific evidence linking VIGIV to a 
specific infection meeting the Program's definition of a serious 
injury, each claim for unintended infections caused by the receipt of 
VIGIV will be considered on a case-by-case basis based on the Program's 
evidence standard.
Cidofovir
    Cidofovir is a medication that is only approved to treat 
cytomegalovirus retinitis in HIV-infected persons. However, it has been 
included in some recommendations as a potential second-line agent that 
might be used under an

[[Page 65331]]

investigational protocol when treatment with VIGIV is not sufficient or 
not available to treat adverse events related to the smallpox vaccine, 
based on studies in animals.\257\ It might sometimes be used 
(preferably under an IND protocol) for serious vaccine adverse events, 
such as eczema vaccinatum or progressive vaccinia, if other potential 
countermeasures are not available or not working. Reports indicate some 
activity in the laboratory against vaccinia and variola viruses, but 
there is currently no human data showing efficacy against any poxvirus 
infection. Cidofovir is injected through a needle into the vein. The 
co-administration of intravenous fluids (fluids given through the vein) 
and probenecid have been shown to decrease the renal side effects of 
cidofovir. Cidofovir is a pregnancy category ``C'' meaning that can 
cause severe birth defects in pregnant women. Cidofovir is excreted in 
breast milk, therefore, nursing mothers should not receive cidofovir or 
discontinue nursing.\258\
---------------------------------------------------------------------------

    \257\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 14.
    \258\ Mylan Institutional LLC. Cidofovir package insert. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=56541229-8c1a-4550-8951-2415ed08e7e9.
---------------------------------------------------------------------------

    The major adverse events associated with the use of cidofovir are 
kidney injury that can lead to kidney failure and a decreased number of 
white blood cells, which may in turn lead to increased susceptibility 
to infections. Additionally, the following have been reported with the 
use of cidofovir: Decreased pressure in the eye, swelling and 
tenderness of the eye, and buildup of acid in the body that can result 
in liver abnormalities and inflammation of the pancreas that can result 
in death. Other symptoms include fever, infection, pneumonia, shortness 
of breath, and nausea with vomiting.
    At this time, the Secretary is not proposing to add any injuries to 
the Table related to the use of cidofovir. Claims of injuries 
associated with the use of cidofovir will be considered as a non-Table 
injury and evaluated on a case-by-case basis based on the Program's 
evidence standard.
Conditions of Special Interest to Cidofovir
Acute Renal Failure
    Acute renal failure (ARF), associated with the use of cidofovir, 
can occur after as few as one or two doses and in some cases has been 
reported as resulting in dialysis or contributing to death. It is 
believed that cidofovir is toxic to the epithelial cells of the kidney, 
and this combined with other factors can lead to the development of 
ARF.\259\ The factors that may contribute to, or precipitate, ARF when 
using cidofovir include: (1) Pre-existing renal insufficiency or use of 
cidofovir in patients at risk of developing renal insufficiency; (2) 
increased baseline serum creatinine concentration greater than 1.5 mg/
dL, baseline creatinine clearance less than 55mL/min; (3) baseline 
urine protein concentration greater than 100 mg/dL, 2+ proteinuria 
(protein in the urine); or (4) glycosuria (glucose or sugar in the 
urine) and concomitant use of nephrotoxic drugs.\260\
---------------------------------------------------------------------------

    \259\ Hassane Izzedine, Vincent Launay-Vacher and Gilbert Deray, 
``Antiviral drug-induced nephrotoxicity.'' American Journal of 
Kidney Diseases 45(5) (May 2005): 804.
    \260\ Mylan Institutional LLC. Cidofovir package insert.
---------------------------------------------------------------------------

    The compelling, reliable, valid, medical and scientific evidence, 
regarding the clinical use of this medication in treating the 
complications of smallpox vaccination, and other types of infections, 
indicates that there is an increased risk of developing ARF with the 
use of cidofovir. However, the literature does not establish an exact 
time of onset for the possible development of ARF after using 
cidofovir. The increased risk of developing ARF is individually based 
and may be influenced by the patient's age, fluid status, baseline 
renal function, and the level of infection at the time the medication 
is administered. Because an exact timeframe for the onset of ARF with 
the use of cidofovir cannot be established by compelling, reliable, and 
valid medical and scientific evidence, the Secretary does not propose 
including ARF after the use of cidofovir as a Table injury. Claims for 
ARF associated with the use of cidofovir will be considered a non-Table 
injury and evaluated on a case-by-case basis based on the Program's 
evidence standard.
Other Conditions
    The following injuries have been associated with the use of 
cidofovir: neutropenia (abnormally low concentration of the white blood 
cells, neutrophils), decreased intraocular pressure and metabolic 
acidosis (an imbalance of the acid/base balance within the body).\261\ 
Although documented in medical case studies, most of these data were 
collected from patients with significant co-morbidities, including 
organ transplants, and/or who were taking other medications, such as 
immunosuppressants. There is insufficient compelling, reliable, valid, 
medical and scientific evidence that these injuries are directly caused 
by cidofovir. Therefore, the Secretary does not propose to add these 
injuries to the Table at this time. Claims for these injuries 
associated with cidofovir will be considered on a case-by-case basis as 
non-Table injuries.
---------------------------------------------------------------------------

    \261\ Cono et al. ``Smallpox vaccination and adverse 
reactions.'' 19-20.
---------------------------------------------------------------------------

Tecovirimat
    Tecovirimat is a small-molecule antiviral oral drug that has been 
approved for the treatment of smallpox under the Animal Rule \262\ 
which in certain instances allows for approval based on adequate and 
well-controlled animal efficacy studies. An intravenous formulation is 
presently under development. Although extensively tested in animal 
models, the drug has had no efficacy testing in humans due to the 
eradication of naturally occurring smallpox, but an acceptable safety 
profile has been demonstrated in healthy human volunteers. It is also 
possible that it would be used as an investigational treatment for 
certain serious vaccinia vaccine adverse events. In a clinical trial 
with 359 participants receiving tecovirimat, 21 individuals reported 
minor adverse side effects.\263\ Due to the limited information 
regarding possible adverse reactions associated with tecovirimat, there 
is presently no compelling, reliable, valid, medical and scientific 
evidence of any injury directly caused by tecovirimat. Therefore, the 
Secretary does not propose to add any injuries to the Table as 
associated with tecovirimat at this time, and claims for injuries 
associated with it will be considered a non-Table injury and evaluated 
on a case-by-case basis based on the Program's evidence standard.
---------------------------------------------------------------------------

    \262\ See 21 CFR part 314 Subpart I.
    \263\ U.S. Food and Drug Administration. ``Drug Trial Snapshot: 
TPOXX.'' (July 13, 2018): 1-2.
---------------------------------------------------------------------------

Brincidofovir
    Brincidofovir is a broad-spectrum antiviral agent, which has 
activity in the laboratory against a number of double stranded DNA 
(dsDNA) viruses and has been under investigation for its potential 
clinical utility. It might be used as an investigational treatment of 
some serious vaccinia vaccine complications and is under development 
for possible use against smallpox, but its role in treating any of 
these infections has not been established. Brincidofovir is a 
nucleotide analog of the drug, cidofovir; however, brincidofovir is 
likely to demonstrate a different spectrum of

[[Page 65332]]

toxicity when compared to cidofovir.\264\ Specifically, 
gastrointestinal toxicity (including severe diarrhea) and 
hepatotoxicity have been observed in clinical trials of brincidofovir; 
however, most of these data were collected from patients with 
significant co-morbidities, including patients' post-stem cell or solid 
organ transplantation who were taking other medications, such as 
immunosuppressants.\265\
---------------------------------------------------------------------------

    \264\ Lawrence C. Trost et al. ``The efficacy and 
pharmacokinetics of brincidofovir for the treatment of lethal 
rabbitpox virus infection: A model of smallpox disease.'' Antiviral 
Research 117 (2015): 115.
    \265\ Francisco Marty et al. ``A randomized, double-blind, 
placebo-controlled phase 3 trial of oral brincidofovir for 
cytomegalovirus prophylaxis in allogeneic hematopoietic cell 
transplantation.'' Biology of Blood and Marrow Transplant 25(2019) 
369-381.
---------------------------------------------------------------------------

    Due to the challenges inherent in evaluating the available safety 
data regarding possible adverse reactions associated with 
brincidofovir, there is no compelling, reliable, valid, medical and 
scientific evidence of any injury directly caused by brincidofovir. 
Therefore, the Secretary does not propose to add any injuries to the 
Table as associated with brincidofovir at this time, and claims for 
injuries associated with it will be considered a non-Table injury and 
evaluated on a case-by-case basis based on the Program's evidence 
standard.
Smallpox Infection Diagnostic Testing Devices
    Presently, there is no compelling, reliable, valid, medical and 
scientific evidence demonstrating a causal association between smallpox 
infection diagnostic testing devices and any serious injuries. 
Therefore, the Secretary does not propose to add any injuries to the 
Table as associated with diagnostic testing devices at this time. Any 
claims of injury from the use or administration of smallpox infection 
diagnostic testing devices will be considered as non-Table injuries and 
evaluated on a case-by-case basis based on the Program's evidence 
standard.
    The Program will not compensate claims merely because a diagnostic 
test provides inaccurate results, such as failure to diagnose the 
presence of a smallpox infection or yielding a positive result of a 
smallpox infection that is not present. The Program also cannot 
compensate for injuries that are the direct result of the covered 
condition or disease for which the countermeasure was administered or 
used, and that are not the direct result of the administration or use 
of the covered countermeasure (for example, if the covered 
countermeasure is ineffective).\266\
---------------------------------------------------------------------------

    \266\ See 42 CFR 110.20(d).
---------------------------------------------------------------------------

Other Proposed Changes to Section 42 CFR 110.100
    In light of the proposed additions related to the inclusion of the 
Smallpox Countermeasure Injury Table, this NPRM also proposes changes 
to section 110.100. First, revisions are proposed to the introductory 
text of paragraph (b). These revisions are intended to clarify that 
paragraph (b) relates to the Pandemic Influenza Countermeasure Injury 
Table in paragraph (a). The NPRM also proposes to revise paragraph (c) 
by deleting the current language and replacing it with the proposed 
Smallpox Countermeasures Injury Table. The language in current 
paragraph (c) indicates that the Secretary publishes information about 
certain covered countermeasures in the Federal Register. The Secretary 
proposes to delete the current language in paragraph (c) because it is 
unnecessary and for accuracy as, when declarations are updated, the 
language becomes out of date. Finally, the NPRM proposes to add 
paragraph (d) to include the Smallpox Countermeasures Injury Table's 
qualifications and aids to interpretation (table definitions and 
requirements).
Impact on Family Well-Being
    This NPRM will not adversely affect the following elements of 
family well-being: family safety, family stability, marital commitment; 
parental rights in the education, nurture, and supervision of their 
children; family functioning, disposable income, or poverty; or the 
behavior and personal responsibility of youth, as determined under 
section 654(c) of the Treasury and General Government Appropriations 
Act of 1999. In fact, this NPRM may have a positive impact on the 
disposable income and poverty elements of family well-being to the 
extent that injured persons or their families may receive medical, lost 
employment income, and/or death benefits paid under this part without 
imposing a corresponding burden on them.

IV. Statutory and Regulatory Requirements

A. Executive Orders 12866, 13563, and 13771: Regulatory Planning and 
Review

    HHS examined the impact of this proposed rule as required by 
Executive Order 12866 on Regulatory Planning and Review (September 30, 
1993), Executive Order 13563 on Improving Regulation and Regulatory 
Review (January 18, 2011), the Congressional Review Act (5 U.S.C. 
804(2)), the Regulatory Flexibility Act (RFA) (September 19, 1980, Pub. 
L. 96-354), section 202 of the Unfunded Mandates Reform Act of 1995 
(March 2, 1995; Pub. L. 104-4), section 654(c) of the Treasury and 
General Government Appropriations Act of 1999, and Executive Order 
13132 on Federalism (August 4, 1999).
    Executive Order 12866 requires all regulations reflect 
consideration of alternatives, costs, benefits, incentives, equity, and 
available information. Regulations must meet certain standards, such as 
avoiding an unnecessary burden. Regulations that are ``significant'' 
because of cost, adverse effects on the economy, inconsistency with 
other agency actions, effects on the budget, or novel legal or policy 
issues, require special analysis. In 2011, President Obama supplemented 
and reaffirmed Executive Order 12866.
    Executive Order 13563 provides that, to the extent feasible and 
permitted by law, the public must be given a meaningful opportunity to 
comment on any proposed regulations, with at least a 60-day comment 
period. In addition, to the extent feasible and permitted by law, 
agencies must provide timely online access to both proposed and final 
rules of the rulemaking docket on https://www.regulations.gov/, 
including relevant scientific and technical findings, in an open format 
that can be searched and downloaded. Federal agencies must consider 
approaches to maintain the freedom of choice and flexibility, including 
disclosure of relevant information to the public. Objective scientific 
evidence guides regulations and should be easy to understand, 
consistent, and written in plain language. Furthermore, federal 
agencies must attempt to coordinate, simplify, and harmonize 
regulations to reduce costs and promote certainty for the public.
    Executive Order 13771 (January 30, 2017) requires that the costs 
associated with significant new regulations ``to the extent permitted 
by law, be offset by the elimination of existing costs associated with 
at least two prior regulations.'' The designation of this rule, if 
finalized, will be informed by public comments received; however, if 
finalized as proposed, this rule would be neither regulatory nor 
deregulatory for purposes of E.O. 13771. There are no additional costs; 
the proposed rule, if finalized, will only change how HRSA expends the 
appropriated funds.
Summary of Impacts
    In this NPRM, the Secretary proposes a Table identifying serious 
physical

[[Page 65333]]

injuries that shall be presumed to result from the administration or 
use of the covered countermeasures, and the time interval in which the 
onset of the first symptom or manifestation of each such serious 
physical injury must manifest in order for such presumption to apply. 
The Secretary is also proposing Table definitions and requirements. 
This proposed rule would have the effect of affording certain persons a 
presumption that particular serious physical injuries occurred as the 
result of the administration or use of covered countermeasures. The 
Table, if implemented, will establish a presumption of causation and 
relieve requesters of the burden of demonstrating causation for covered 
injuries listed on the Table. However, this presumption is rebuttable 
based on the Secretary's review of the evidence. This Table also may 
afford some requesters a new filing deadline.
    Rather than showing that a serious physical injury or death 
directly resulted from an injury included on the Table, individuals 
may, in the alternative, receive compensation if they can show that a 
covered countermeasure caused an injury or death. This NPRM is based 
upon legal authority.
    The Secretary has determined that minimal resources are required to 
implement the provisions included in this NPRM. Therefore, in 
accordance with the Regulatory Flexibility Act of 1980 (RFA) and the 
Small Business Regulatory Enforcement Fairness Act of 1996, which 
amended the RFA, the Secretary certifies that this NPRM will not have a 
significant impact on a substantial number of small entities.
    The Secretary also determined that this NPRM does not meet the 
criteria for a major rule as defined by Executive Order 12866 and would 
have no major effect on the economy or federal expenditures. The 
Secretary determined that this NPRM is not a ``major rule'' within the 
meaning of the statute providing for Congressional Review of Agency 
Rulemaking, 5 U.S.C. 801.
    This rule is not being treated as a ``significant regulatory 
action'' under section 3(f) of Executive Order 12866. Accordingly, the 
rule has not been reviewed by the Office of Management and Budget.

B. Unfunded Mandates Reform Act of 1995

    The Secretary determined that this NPRM will not have effects on 
state, local, or tribal governments or on the private sector such as to 
require consultation under the Unfunded Mandates Reform Act of 1995. 
This NPRM comports with the 2011 supplemental requirements.

C. Executive Order 13132--Federalism

    The Secretary also reviewed this NPRM in accordance with Executive 
Order 13132 regarding federalism, and has determined that it does not 
have ``federalism implications.'' This NPRM, if implemented, would not 
``have substantial direct effects on the states, or on the relationship 
between the national government and the states, or on the distribution 
of power and responsibilities among the various levels of government.''

D. Collection of Information

    This NPRM has no information collection requirements.

List of Subjects in 42 CFR Part 110

    Biologics, Immunization.

    Dated: August 24, 2020.
Thomas J. Engels,
Administrator, Health Resources and Services Administration.
    Approved: September 14, 2020.
Alex M. Azar II,
Secretary, Department of Health and Human Services.
    Therefore, for the reasons stated in the preamble, the Department 
of Health and Human Services proposes to amend 42 CFR part 110 as 
follows:

PART 110--COUNTERMEASURES INJURY COMPENSATION PROGRAM

0
1. The authority citation for part 110 continues to read as follows:

    Authority:  42 U.S.C. 247d-6e.
0
2. Amend Sec.  110.100 by revising paragraph (b) introductory text and 
paragraph (c), and adding paragraph (d) to read as follows:


Sec.  110.100  Injury Tables.

* * * * *
    (b) Qualifications and aids to interpretation (table definitions 
and requirements). The following definitions and requirements shall 
apply to the table set forth in paragraph (a) of this section and only 
apply for purposes of this subpart.
* * * * *
    (c) Smallpox countermeasures injury table.
    Table 1 to paragraph (c)

------------------------------------------------------------------------
                                                     Time interval (for
                                                      first symptom or
                                                      manifestation of
                                Serious physical       onset of injury
   Covered countermeasures      injury (illness,    after administration
     under declarations        disability, injury,    or use of covered
                                or condition) \1\      countermeasure,
                                                      unless otherwise
                                                         specified)
------------------------------------------------------------------------
I. Smallpox Vaccines          A. Anaphylaxis......  A. 0-4 hours.
 Replication-Deficient.       B. Vasovagal Syncope  B. 0-1 hour.
II. Smallpox Vaccines         A. Anaphylaxis......  A. 0-4 hours.
 Replication-Competent.
                              B. Vasovagal Syncope  B. 0-1 hour.
                              C. Significant Local  C. 1-21 days.
                               Skin Reaction.
                              D. Stevens-Johnson    D. 4-28 days.
                               Syndrome/Toxic
                               Epidermal
                               Necrolysis.
                              E. Inadvertent        E. 1-21 days.
                               Autoinoculation.
                              F. Generalized        F. 6-9 days.
                               Vaccinia.
                              G. Eczema Vaccinatum  G. 3-21 days.
                              H. Progressive        H. 3-21 days.
                               Vaccinia.
                              I. Post-vaccinial     I. 5-14 days.
                               Encephalopathy,
                               Encephalitis or
                               Encephalomyelitis
                               (PVEM).
                              J. Vaccinial          J. 0-21 days.
                               Myocarditis,
                               Pericarditis, or
                               Myopericarditis
                               (MP).
III. Vaccinia Immunoglobulin  A. Anaphylaxis......  A. 0-4 hours.
 Intravenous (VIGIV).
                              B. Transfusion-       B. 0-72 hours.
                               Related Acute Lung
                               Injury (TRALI).
                              C. Acute Renal        C. 0-10 days.
                               Failure (ARF).
                              D. Drug-Induced       D. Within 48 hours
                               Aseptic Meningitis    after the first
                               (DIAM).               dose and up to 48
                                                     hours after the
                                                     last dose of VIGIV.

[[Page 65334]]

 
                              E. Hemolysis........  E. 12 hours to 14
                                                     days.
IV. Cidofovir...............  A. No Condition       A. Not Applicable.
                               Covered \2\.
V. Tecovirimat..............  A. No Condition       A. Not Applicable.
                               Covered \2\.
VI. Brincidofovir...........  A. No Condition       A. Not Applicable.
                               Covered \2\.
VII. Smallpox Infection       A. No Condition       A. Not Applicable.
 Diagnostic Testing Devices.   Covered \2\.
------------------------------------------------------------------------
\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 interpretation (table definitions 
and requirements). The following definitions and requirements shall 
apply to the Table set forth in paragraph (c) of this section and only 
apply for purposes of this subpart.
    (1) Anaphylaxis. Anaphylaxis is an acute, severe, and potentially 
lethal systemic reaction that occurs as a single discrete event with 
simultaneous involvement of two or more organ systems. Most cases 
resolve without sequelae. Signs and symptoms begin within minutes to a 
few hours after exposure. Death, if it occurs, usually results from 
airway obstruction caused by laryngeal edema or bronchospasm and may be 
associated with cardiovascular collapse. Other significant clinical 
signs and symptoms may include the following: Cyanosis, hypotension, 
bradycardia, tachycardia, arrhythmia, edema of the pharynx and/or 
trachea and/or larynx with stridor and dyspnea. There are no specific 
pathological findings to confirm a diagnosis of anaphylaxis.
    (2) Vasovagal syncope. Vasovagal syncope (also sometimes called 
neurocardiogenic syncope) means loss of consciousness (fainting) and 
loss of postural tone caused by a transient decrease in blood flow to 
the brain occurring after the administration of an injected 
countermeasure. Vasovagal syncope is usually a benign condition, but 
may result in falling and injury with significant sequelae. Vasovagal 
syncope may be preceded by symptoms, such as nausea, lightheadedness, 
diaphoresis (sweating), and/or pallor. Vasovagal syncope may be 
associated with transient seizure-like activity, but recovery of 
orientation and consciousness generally occurs simultaneously. Loss of 
consciousness resulting from the following conditions will not be 
considered vasovagal syncope: Organic heart disease, cardiac 
arrhythmias, transient ischemic attacks, hyperventilation, metabolic 
conditions, neurological conditions, psychiatric conditions, seizures, 
trauma, and situational as can occur with urination, defecation, or 
cough. This list is not complete as other conditions that are not 
associated with the vaccine also may cause loss of consciousness. 
Episodes of recurrent syncope occurring after the applicable timeframe 
are not considered to be sequelae of an episode of syncope meeting the 
Table requirements.
    (3) Significant local skin reaction. Significant local skin 
reaction is an unexpected and extreme response at the vaccination or 
inoculation site that results in a significant scar that is serious 
enough to require surgical intervention. The onset of this injury is 
the initial skin lesion at the vaccination site that generally occurs 
with replication-competent smallpox vaccinations. Minor scarring or 
minor local reactions do not constitute a Table injury. A robust take, 
defined as an area of redness at the vaccination site that exceeds 7.5 
cm in diameter with associated swelling, warmth and pain, is generally 
considered an expected response to the vaccination or inoculation. A 
robust take, in itself, does not constitute a Table injury, even when 
the redness and swelling involves the entire upper arm with associated 
enlargement and tenderness of the glands (lymph nodes) in the underarm 
(axilla).
    (4) Stevens-Johnson syndrome/Toxic Epidermal Necrolysis (SJS/TEN). 
SJS/TEN is a spectrum of acute hypersensitivity reactions that affects 
skin, mucous membranes, and sometimes, internal organs (systemic 
toxicity) associated with the use or administration of replication-
competent smallpox vaccines. For purposes of the Table, both skin and 
mucous membrane rash or lesions must be present. Rash or lesion 
distribution must be widespread. Rash must not have a symmetric acral 
distribution (affecting arms, hands, legs or feet). Two or more mucosal 
sites must be involved. Mucosal lesions generally manifest as painful 
lesions in sites, such as the mouth or eyes. Skin rash or lesions in 
SJS/TEN usually consist of red or purple raised areas (erythematous 
macules), blisters, and ulcerations.
    (5) Inadvertent Autoinoculation (IA). IA is the spread of vaccinia 
virus from an existing vaccination site to a second location usually by 
scratching the vaccination site and subsequently spreading the virus, 
which produces a new vaccinial lesion on the same person who received 
the vaccination. IA is the most common adverse event associated with 
the replication-competent smallpox vaccine.
    (6) Generalized Vaccinia (GV). GV is a vaccinial infection that 
occurs from the spread of vaccinia from an existing vaccination or 
inoculation site, with the use or administration of a replication-
competent smallpox vaccine, to otherwise normal skin, resulting in 
multiple new areas of vaccinial rash or lesions. The vaccinia is 
believed to be spread through the blood. The rash or lesions, 
characterized by multiple blisters (vesicles or pustules) generally 
evolve in a similar sequence or manner as the original vaccination 
site.
    (7) Eczema Vaccinatum (EV). EV is the transmission or the spread of 
vaccinia virus from a vaccination site, after the use or administration 
of a replication-competent smallpox vaccine, to skin that has been 
affected by, or is currently affected with, eczema or atopic 
dermatitis. EV is characterized by lesions that include multiple 
blisters (vesicles or pustules), which generally evolve in a similar 
sequence or manner as the original vaccination site. The lesions may 
come together to form larger lesions. Lesions may also spread to 
patches of skin that have never been involved with eczema or atopic 
dermatitis. The new lesions, if cultured, will be positive for vaccinia 
virus. A person with EV may become severely ill with signs and symptoms 
that involve the whole body (systemic illness), such

[[Page 65335]]

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

[[Page 65336]]

body's potassium stores. With hemolysis, the body is unable to 
transport oxygen effectively, and the person develops hypoxia. 
Additionally, the rapid breakdown of the cell releases large amounts of 
potassium into the blood stream, which can cause abnormal heart rhythms 
and cardiac arrest. In severe cases of hemolysis, a blood transfusion 
may be required to correct the resulting anemia. A Table injury for 
hemolysis has occurred if there is sufficient evidence in the medical 
record of an occurrence of hemolysis, and the patient received the 
associated countermeasure (VIGIV). Hemolysis occurring in the absence 
of the use of VIGIV and outside of the timeframe of 12 hours to 14 days 
after receiving VIGIV is not a Table injury. Hemolysis occurring from a 
more likely alternative diagnosis, such as infections, toxins, poisons, 
hemodialysis, or medications, is not a Table injury. This list of 
conditions that can cause hemolysis, not associated with VIGIV, is not 
exhaustive, and all additional diagnoses within the medical 
documentation will be evaluated.

[FR Doc. 2020-20806 Filed 10-14-20; 8:45 am]
BILLING CODE 4165-15-P