[Federal Register: June 26, 2009 (Volume 74, Number 122)]
[Notices]
[Page 30577-30584]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26jn09-77]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2009-N-0264]
Amended Authorization of Emergency Use of Doxycycline Hyclate
Tablet Emergency Kits for Eligible United States Postal Service
Participants in the Cities Readiness Initiative and Their Household
Members; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing an
amendment to the Emergency Use Authorization (EUA) (the Authorization)
for doxycycline hyclate tablet emergency kits for eligible U.S. Postal
Service (USPS) participants in the Cities Readiness Initiative (CRI)
and their household members issued on October 3, 2008, under the
Federal Food, Drug, and Cosmetic Act (the act), as requested by the
Biomedical Advanced Research and Development Authority (BARDA), Office
of the Assistant Secretary for Preparedness and Response (ASPR),
[[Page 30578]]
Health and Human Services (HHS). Following issuance of FDA's October 3,
2008, Authorization letter, on February 19, 2009, BARDA submitted a
request on behalf of ASPR, to amend the Authorization. In response to
BARDA's request, FDA amended the Authorization letter and reissued the
Authorization letter in its entirety on February 25, 2009. The
Authorization, as amended and reissued in its entirety, is reprinted in
this document.
DATES: The amended Authorization is effective as of February 25, 2009.
ADDRESSES: Submit written requests for single copies of the EUA to the
Office of Counterterrorism and Emerging Threats (HF-29), Food and Drug
Administration, 5600 Fishers Lane, rm. 14C-26, Rockville, MD 20857.
Send one self-addressed adhesive label to assist that office in
processing your request or include a fax number to which the
Authorization may be sent. See the SUPPLEMENTARY INFORMATION section
for electronic access to the Authorization.
FOR FURTHER INFORMATION CONTACT: Boris Lushniak, Office of
Counterterrorism and Emerging Threats (HF-29), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-4067.
SUPPLEMENTARY INFORMATION:
I. Amendment to the October 3, 2008, Authorization for Doxycycline
Hyclate in Emergency Kits
On September 23, 2008, under section 564(b)(1)(A) of the the act
(21 U.S.C. 360bbb-3(b)(1)(A)), as amended by the Project BioShield Act
of 2004 (Public Law 108-276), the Secretary of Homeland Security
determined that there is a significant potential for a domestic
emergency, involving a heightened risk of attack with a specified
biological, chemical, radiological, or nuclear agent or agents--in this
case, Bacillus anthracis. On October 1, 2008, under section 564(b) of
the act, and on the basis of such determination, the Secretary of HHS,
Michael O. Leavitt, declared an emergency justifying the authorization
of the emergency use of doxycycline hyclate tablets accompanied by
emergency use information subject to the terms of any authorization
issued under 21 U.S.C. 360bbb-3(a). Notice of the determination of the
Secretary of Homeland Security and the declaration of the Secretary of
HHS was published in the Federal Register on October 6, 2008 (73 FR
58242).
On October 1, 2008, BARDA requested an EUA for doxycycline hyclate
tablet emergency kits for eligible USPS participants in CRI and their
household members. As required under section 564(h)(1) of the act, on
October 21, 2008, FDA published in the Federal Register notice of the
Authorization for doxycycline hyclate tablet emergency kits for
eligible USPS participants in the CRI and their household members,
including an explanation of the reasons for its issuance (73 FR 62057,
October 21, 2008). On February 19, 2009, BARDA submitted a request on
behalf of ASPR to amend the Authorization to make certain changes to
the written information authorized to accompany the doxycycline hyclate
tablets and to the roles and responsibilities provided for in the
Authorization. On February 25, 2009, in response to BARDA's request,
FDA amended the Authorization letter and reissued the Authorization
letter in its entirety.
II. Electronic Access
An electronic version of this notice and the full text of the
Authorization are available on the Internet at http://
www.regulations.gov.
III. The Authorization
After having consulted with the National Institutes of Health (NIH)
and the Centers for Disease Control and Prevention (CDC) and having
concluded that the criteria for issuance of this Authorization under
section 564(c) of the act were met, on October 3, 2008, FDA authorized
the emergency use of doxycycline hyclate tablet emergency kits for
eligible USPS participants in the CRI and their household members. The
letter of authorization in its entirety, as amended on February 25,
2009, follows:
February 25, 2009
Robin Robinson, Ph.D.
Director
Biomedical Advanced Research and Development Authority (BARDA)
330 Independence Avenue SW
Room G640
Washington, DC 20201
Dear Dr. Robinson:
This letter is in response to BARDA's October 1, 2008
submission, as amended,\1\ requesting that the Food and Drug
Administration (FDA) issue an Emergency Use Authorization (EUA) for
the pre-event provision and potential use of doxycycline hyclate
tablet emergency kits\2\ for inhalational anthrax, pursuant to
section 564 of the Federal Food, Drug, and Cosmetic Act (the Act).
Your request is specifically for eligible\3\ United States Postal
Service (USPS) participants in the Cities Readiness Initiative (CRI)
(hereinafter USPS participants) and their household members.\4\
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\1\ BARDA submitted an amendment on October 3, 2008. Following
issuance of FDA's October 3, 2008, authorization letter, BARDA
submitted a request on behalf of the Office of the Assistant
Secretary for Preparedness and Response (ASPR) on February 19, 2009,
to further amend the authorization. This amended authorization
letter responds to that request.
\2\ Your submissions refer to a Household Antibiotic Kit (HAK),
which would be stored in an eligible United States Postal Service
(USPS) participant's home and would contain unit-of-use bottles of
doxycycline hyclate tablets (100 mg) and both emergency use
instructions and home preparation instructions. Your submissions
also refer to an individual Household Antibiotic Kit (iHAK), which
would be stored at an eligible USPS participant's workplace and
would contain only one unit-of-use bottle of doxycycline hyclate
tablets (100 mg) and emergency use instructions. For ease of
reference, this letter of authorization will use the term
``doxycycline hyclate tablet emergency kit(s)'' to refer to both
types of kits, unless otherwise specified. When referring to the
kits separately, this letter will use the term ``household
doxycycline hyclate tablet emergency kit'' to refer to the HAK and
the term ``individual doxycycline hyclate tablet emergency kit'' to
refer to the iHAK.
\3\ The term ``eligible'' refers to USPS participants who have
agreed in writing to participate in the Postal Module of CRI, have
been screened for fitness to receive OSHA-required personal
protective equipment, have (including household members) been
medically screened for contraindications based on completed health
assessment forms, have (including household members) been given a
valid prescription, and have (including household members) not
otherwise been determined to be ineligible to receive doxycycline
hyclate tablet emergency kits.
\4\ Your submissions define ``household member'' as ``anyone
that considers that address as his or her permanent place of
residence.''
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On September 23, 2008, pursuant to section 564(b)(1)(A) of the
Act, 21 U.S.C. Sec. 360bbb-3(b)(1)(A), the Secretary of the
Department of Homeland Security determined that there is a
significant potential for a domestic emergency, involving a
heightened risk of attack with a specified biological, chemical,
radiological, or nuclear agent or agents--in this case, Bacillus
anthracis.\5\ On October 1, 2008, pursuant to section 564(b) of the
Act, and on
[[Page 30579]]
the basis of such determination, the Secretary of the Department of
Health and Human Services declared an emergency justifying the
authorization of the emergency use of doxycycline hyclate tablets
accompanied by emergency use information subject to the terms of any
authorization issued under 21 U.S.C. Sec. 360bbb-3(a).\6,7\ Having
consulted with the National Institutes of Health (NIH) and the
Centers for Disease Control and Prevention (CDC), and having
concluded that the criteria for issuance of this authorization under
section 564(c) of the Act are met, I am authorizing the emergency
use of doxycycline hyclate tablet emergency kits for the post-
exposure prophylaxis of inhalational anthrax for eligible USPS
participants and their household members,\8\ subject to the terms of
this authorization.
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\5\ Memorandum from Michael Chertoff to Michael O. Leavitt,
Determination Pursuant to Sec. 564 of the Federal Food, Drug, and
Cosmetic Act (Sept. 23, 2008).
\6\ Declaration of Emergency Pursuant to Section 564 of the
Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 360bbb-3(b) (Oct. 1,
2008).
\7\ The doxycycline hyclate tablet emergency kits for eligible
USPS participants and their household members referenced and
authorized in this letter fall within the scope of the Secretary of
the Department of Health and Human Services' declaration.
\8\ Doxycycline hyclate tablets are indicated for treatment of
infections caused by ``Anthrax due to Bacillus anthracis, including
inhalational anthrax (post-exposure): to reduce the incidence or
progression of disease following exposure to aerosolized Bacillus
anthracis.'' This indication generally means that drug
administration is expected to start after a known or suspected
exposure to aerosolized Bacillus anthracis spores, but before
clinical symptoms of the disease develop. The indication includes
presumed exposure, since it is often difficult to know whether and
when exposure has actually occurred. The indication also encompasses
instances where Bacillus anthracis exposure via inhalation is
expected and will be imminent. In such cases, the first few doses of
prophylaxis may be taken pre-exposure, but the remainder of the
course would be taken post-exposure. The indication is commonly
referred to as ``post-exposure prophylaxis of inhalational
anthrax,'' and this term will be used throughout this letter for
ease of reference.
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The remainder of this letter is organized into four sections:
Background, Criteria for Issuance of Authorization, Scope of
Authorization, Conditions of Authorization, and Duration of
Authorization.
I. Background
CRI involves 72 major metropolitan areas and all 50 states. The
primary goal of CRI is to develop the ability to provide mass
prophylaxis to 100% of the identified population within 48 hours of
notification to do so.
On February 18, 2004, the Secretary of the Department of Health
and Human Services (HHS), the Secretary of the Department of
Homeland Security (DHS), and the Postmaster General signed a
Memorandum of Agreement to explore how the resources of the USPS
could be made available to help deliver oral antibiotics in response
to a biological terrorism incident. Subsequently, HHS launched CRI
and asked the USPS to participate in what has been referred to as
the CRI Postal Module (or Postal Plan). The Postal Module involves
the delivery of antibiotics to residential households within pre-
determined zip codes by USPS participants where there may be an
intentional release of Bacillus anthracis in their geographic area.
The CRI Postal Module could be activated and executed while the
municipality is establishing its points-of-dispensing (POD) network
for the remainder of the emergency response which, in the case of a
wide-area anthrax event, could continue for 1-2 months. The postal
carriers' role is voluntary because emergency response is neither
part of the basic mission of USPS nor a provision of the contracts
between USPS and the unions representing the carriers. USPS has made
its participation in the CRI Postal Module contingent on the pre-
event provision of prescription antibiotic countermeasures to USPS
participants and their household members.
Your request relates to a potential EUA for the pre-event
provision and potential use of doxycycline hyclate tablets (100 mg)
in the form of emergency kit(s) for eligible USPS participants and
their household members. Although doxycycline hyclate tablets are
approved for the post-exposure prophylaxis of inhalational anthrax,
the emergency kits you describe in your submissions would require an
EUA because they would include certain written information that is
not currently part of the approved new drug applications (NDAs) or
abbreviated new drug applications (ANDAs) for doxycycline hyclate
tablets (100 mg). Specifically, you indicated that the following
pieces of written information would accompany the doxycycline
hyclate tablets:
Fact Sheet for Recipients
For the household doxycycline hyclate tablet emergency
kit, home preparation instructions for recipients who cannot swallow
pills (hereinafter home preparation instructions)
Information placard (unless the bag is pre-printed with
placard information)
MedWatch Form 3500 for the reporting of any adverse
events associated with the doxycycline hyclate tablet emergency kit
In addition, a Fact Sheet for Health Care Providers would be
distributed to health care providers and authorized dispensers of
the doxycycline hyclate tablet emergency kits.
You propose to use doxycycline hyclate tablets (100 mg) that
were manufactured by West-Ward Pharmaceutical Corp., and repackaged
by PD-Rx Pharmaceuticals into unit-of-use bottles containing 20 oral
tablets each, a 10-day supply.\9\
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\9\ We note that the full course of doxycycline hyclate tablets
for adults for the post-exposure prophylaxis of inhalational anthrax
is 100 mg twice daily for 60 days. The corresponding oral dosing
regimen for children under 100 pounds is 1 mg per pound of body
weight twice daily for 60 days.
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The doxycycline hyclate tablet emergency kit(s) that are the
subject of your request would come in two forms. The first, which
you describe as a Household Antibiotic Kit (HAK), would contain a
unit-of-use bottle of doxycycline hyclate tablets for each eligible
USPS participant and each eligible household member, as well as the
Fact Sheet for Recipients, home preparation instructions, MedWatch
Form 3500, and information placard (unless bag is pre-printed with
placard information) described above. All of these items would be
placed in one tamper-evident, clear plastic bag for home storage.
The second, which you describe as an individual Household Antibiotic
Kit (iHAK), would contain one unit-of-use bottle of doxycycline
hyclate tablets for the eligible USPS participant and the Fact Sheet
for Recipients, MedWatch Form 3500, and information placard (unless
the bag is pre-printed with placard information) described above.
All of these items would be placed in a separate tamper-evident,
clear plastic bag for secure storage at the USPS participant's
workplace, should the USPS participant need to deploy emergently.
II. Criteria for Issuance of Authorization
Having considered the September 23, 2008 determination by the
Secretary of the Department of Homeland Security that there is a
significant potential for a domestic emergency, involving a
heightened risk of attack with a biological, chemical, radiological,
or nuclear agent or agents--in this case, Bacillus anthracis, and
the October 1, 2008 declaration of emergency by the Secretary of
Health and Human Services, and having consulted with NIH and CDC, I
have concluded that the emergency use of doxycycline hyclate tablet
emergency kits for the post-exposure prophylaxis of inhalational
anthrax for eligible USPS participants and their household members
meets the criteria for issuance of an authorization under section
564(c) of the Act, because I have concluded that:
(1) Bacillus anthracis can cause anthrax, a serious or life-
threatening disease or condition;
(2) based on the totality of scientific evidence available to
FDA, it is reasonable to believe that doxycycline hyclate tablet
emergency kits may be effective for post-exposure prophylaxis of
inhalational anthrax,\10\ and that the known and potential benefits
of doxycycline hyclate tablet emergency kits, when used for the
post-exposure prophylaxis of inhalational anthrax in the specified
population, outweigh the known and potential risks of the product;
and
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\10\ The Act uses the terms ``diagnosing, treating, or
preventing'' in Section 564(c)(2)(A). Post-exposure prophylaxis is
encompassed by these statutory terms.
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(3) there is no adequate, approved, and available alternative to
doxycycline hyclate tablet emergency kits for the post-exposure
prophylaxis of inhalational anthrax.\11\
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\11\ No other criteria of issuance have been prescribed by
regulation under section 564(c)(4) of the Act.
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Specifically, I have concluded, pursuant to section 564(c)(1) of
the Act, that Bacillus anthracis can cause inhalational anthrax,
which is a serious or life-threatening disease or condition. The
fatality rate for inhalational anthrax in the United States is
estimated to be approximately 45 percent to 90 percent. From 1900 to
October 2001, there were 18 identified cases of inhalational anthrax
in the United States, the latest of which was reported in 1976, with
an 89 percent (16/18) mortality rate. Most of these exposures
occurred in industrial settings, i.e., textile mills. From October
4, 2001, to December 5, 2001, a total of 11 cases of inhalational
anthrax linked to intentional dissemination of Bacillus anthracis
spores were identified in the United States. Five of these cases
were fatal. These fatalities occurred despite aggressive medical
care, including treatment with antimicrobial drugs.
I have also concluded that, based on the totality of the
scientific evidence available to FDA, including data supporting the
safe and effective use of doxycycline hyclate tablets (100 mg) for
the post-exposure prophylaxis of inhalational anthrax, the results
of CDC's home MedKit study, and information associated with the
development of the home preparation instructions, it is reasonable
to believe that doxycycline hyclate tablet emergency kits may be
effective for the post-exposure prophylaxis of inhalational anthrax
pursuant to section 564(c)(2)(A) of the Act.
The above conclusion is largely based on the fact that FDA has
previously approved a number of NDAs and ANDAs for doxycycline
hyclate tablets for the treatment and post-exposure prophylaxis of
inhalational anthrax, as summarized below.
In November 2001, as part of a public health response to the use
of anthrax spores
[[Page 30580]]
as a bioterrorism agent, the Agency published a notice in the
Federal Register that clarified the dosing recommendations for,
among others, doxycycline hyclate products, in the management of
patients with inhalational anthrax who had been exposed to spores of
Bacillus anthracis, but who did not manifest clinical disease.\12\
In that notice, FDA announced that it had determined that the
language in the labeling of certain drug products, including those
containing doxycycline hyclate, is intended to, and does, cover all
forms of anthrax, including inhalational anthrax (post-exposure): to
reduce the incidence or progression of disease exposure to
aerosolized B. anthracis. FDA also announced that the appropriate
dosing regimen for adults is 100 mg of doxycycline, taken orally
twice daily for 60 days; and the corresponding oral dosing regimen
for children under 100 pounds is 1 mg per pound (1 mg/lb) of body
weight (2.2 mg/kilogram (kg)), given twice daily for 60 days.\13\
FDA based these conclusions on the following:
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\12\ See 66 Fed. Reg. 55679 (Nov. 2, 2001); Docket 01N-0494.
\13\ Id. The Federal Register notice further requested that
applicants for these products submit labeling supplements to update
their package inserts with this information.
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Effectiveness was supported by minimal inhibitory
concentration (MIC) data for the tetracycline class and Bacillus
anthracis, pharmacokinetic data, data from the Sverdlovsk incident,
and the outcome data from a study of inhalational exposure to
Bacillus anthracis in rhesus monkeys.
With respect to safety, FDA noted that doxycycline drug
products have been used for over 30 years and the literature on the
products is voluminous. FDA previously reviewed the literature
dealing with the long-term administration of doxycycline for
treatment of diseases other than anthrax. Several articles reported
the results of studies involving the administration of doxycycline
in amounts comparable to the recommended doses. They also involved
administration of doxycycline for 60 days and periods approaching
and exceeding 60 days. FDA also reviewed data from the Adverse Event
Reporting System (AERS). Analysis of these articles and data
indicated no pattern of unlabeled adverse events associated with the
long-term use of doxycycline.
FDA also noted that doxycycline and other members of
the tetracycline class of antibiotics are not generally indicated
for the treatment of any patients under the age of 8 years.
Tetracyclines are known to be associated with teeth discoloration
and enamel hypoplasia in children and delays in bone development in
premature infants after prolonged use. FDA balanced the nature of
the effect on teeth and the fact that this delay in bone development
is apparently reversible against the lethality of inhalational
anthrax, and concluded that doxycycline drug products can be labeled
with a pediatric dosing regimen for inhalational anthrax (post-
exposure).
As noted above, FDA has approved, under section 505(j) of the
Act, a number of abbreviated new drug applications (ANDAs),
including West-Ward's ANDA (65-095) for doxycycline hyclate
tablets (100 mg) for treatment and post-exposure prophylaxis of
inhalational anthrax on July 2, 2003. West-Ward's doxycycline
hyclate tablets (100 mg), which have been repackaged and re-labeled
by PD-Rx Pharmaceuticals, are the subject of this emergency use
authorization. This product is the same as the reference listed
drug, Vibra-Tabs (doxycycline hyclate tablets, 100 mg; NDA
50-333), within the meaning of section 505(j) of the Act.
I have also considered CDC's home MedKit study and information
associated with the development of the home preparation instructions
as part of the totality of the scientific evidence available to FDA,
and have determined that this information helps to support the
conclusion that it is reasonable to believe that doxycycline hyclate
tablet emergency kits may be effective for post-exposure prophylaxis
of inhalational anthrax, as summarized below.
The CDC study evaluated the ability of study participants to
receive what was referred to as a MedKit -- doxycycline\14\ with
certain written information, including emergency use instructions
and home preparation instructions similar to those being authorized
here. A convenience sample of 4,250 St. Louis area households,
divided among three cohorts, was enrolled in the study after medical
screening and informed consent. The primary outcomes for this
evaluation were to determine the extent to which participants would
follow instructions for appropriately keeping the MedKits intact and
reserving them for emergency use until directed by a local
government official. Although this study had a number of limitations
as explained below, approximately 97% of all study respondents
returned the MedKits upon completion of the study.
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\14\ In this study, participants who were allergic to
doxycycline or for whom doxycycline was otherwise contraindicated
received ciprofloxacin.
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Finally, FDA considered information associated with the
development of the home preparation instructions for doxycycline
hyclate tablets. FDA had previously developed home preparation
instructions and these instructions were tested by the Chicago
Department of Public Health, which provided its results to FDA. The
Agency revised the home preparation instructions based on these
findings and performed additional laboratory tests and limited
palatability testing. FDA also worked with CDC to improve the
readability of the instructions.
Although FDA has approved a number of NDAs and ANDAs for
doxycycline hyclate tablets (100 mg) for the treatment and post-
exposure prophylaxis of inhalational anthrax, these products are not
approved with emergency use instructions and home preparation
instructions. The amount and nature of the scientific evidence
regarding the ability to use emergency use instructions and home
preparation instructions is more limited than the scientific
evidence supporting the approval of doxycycline hyclate tablets for
the post-exposure prophylaxis of inhalational anthrax. However,
taking into consideration the potentially fatal nature of anthrax
disease, the CDC home MedKit study and the information associated
with the development of the home preparation instructions also helps
to support a conclusion that it is reasonable to believe that
doxycycline hyclate tablet emergency kits may be effective for the
post-exposure prophylaxis of inhalational anthrax. Accordingly,
based on the totality of the scientific evidence available to FDA,
it is reasonable to believe that doxycycline hyclate tablet
emergency kits may be effective for the post-exposure prophylaxis of
inhalational anthrax.
I have also concluded, pursuant to section 564(c)(2)(B) of the
Act, that it is reasonable to believe that the known and potential
benefits of doxycycline hyclate tablet emergency kits outweigh the
known and potential risks of the product for USPS participants and
their household members. The available scientific evidence that
supports this conclusion is summarized below.
We have already concluded, as evidenced by the previous NDA and
ANDA approvals discussed above, that the known and potential
benefits of the approved doxycycline hyclate tablets (100 mg) for
post-exposure prophylaxis of inhalational anthrax outweigh the known
and potential risks of the product. Under this EUA, doxycycline
hyclate tablets will be packaged with additional written information
(including emergency use instructions and home preparation
instructions) that has not been approved by FDA as part of a new
drug application. CDC's home MedKit study and the process by which
home preparation instructions were developed, as discussed above,
help to further inform the requisite risk-benefit analysis under
section 564(c)(2)(B).
The CDC home MedKit study was somewhat limited in its ability to
address certain questions about home storage and use since the
participants were not required to follow any directions for
preparation or use of doxycycline hyclate tablets in an actual
emergency. The effect of the actual storage conditions on the stored
drug product was not tested and the instructions for storage did not
provide the temperature conditions for storage on the outside of the
bag. Despite the limitations of the CDC home MedKit study, it is
important to note that approximately 97% of all study respondents
returned the MedKits upon completion of the study.
As described above, the development of the home preparation
instructions has been informed by limited testing and input from
CDC. However, the current version of the home preparation
instructions has not been subjected to formal independent testing
procedures for an assessment of an individual's understanding or
his/her ability to follow the directions.
Because of the limitations of the CDC study and the lack of
formal independent testing on the home preparation instructions, FDA
cannot conclude without further testing and
[[Page 30581]]
information that the emergency use instructions and home preparation
instructions pose no additional risks to eligible USPS participants
and their household members. Inappropriate use and the development
of doxycycline resistant microorganisms could be a potential issue
if a considerable number of eligible USPS participants take the
product for an unintended purpose.
The known and potential risks of eligible USPS participants and
their household members not being able to store, prepare, and use
doxycycline hyclate tablets in accordance with the emergency use
instructions and home preparation instructions, and of experiencing
adverse reactions, is outweighed by the known and potential benefits
of using doxycycline hyclate tablets as a safe and effective
treatment against an otherwise potentially fatal aerosolized anthrax
attack. For the foregoing reasons, it is reasonable to believe that
the known and potential benefits of the doxycycline hyclate tablet
emergency kits (including emergency instructions and home
preparation instructions as authorized) for the post-exposure
prophylaxis of inhalational anthrax in the specified population
outweigh the known and potential risks of the product under the
terms of this letter of authorization.\15\
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\15\ The terms of this letter of authorization, including its
scope and conditions, are integral to the conclusions regarding the
known and potential risks and benefits of the emergency use of this
product in eligible USPS participants and their household members.
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I have also concluded, pursuant to section 564(c)(3) of the Act,
that there is no adequate, approved, and available alternative to
the doxycycline hyclate tablet emergency kits for post-exposure
prophylaxis of inhalational anthrax in the specified population.
Although doxycycline hyclate is approved for treatment and post-
exposure prophylaxis of inhalational anthrax, the emergency use
instructions and home preparation instructions included here as part
of the doxycycline hyclate tablet emergency kits are not approved by
FDA.
Other products approved for treatment and post-exposure
prophylaxis of inhalational anthrax include penicillin G procaine,
ciprofloxacin, and levofloxacin. However, none of these products is
approved with emergency use instructions. In addition, penicillin G
procaine is administered by injection and fluoroquinolones
(ciprofloxacin and levofloxacin) have additional significant adverse
events reported following their use, including adverse tendon
effects and rupture, peripheral neuropathy, and central nervous
system disorders.
Further, Biothrax (Anthrax Vaccine Adsorbed) is indicated for
the active immunization against Bacillus anthracis of individuals
between 18 and 65 years of age who come in contact with animal
products such as hides, hair or bones that come from anthrax endemic
areas, and that may be contaminated with Bacillus anthracis spores.
This product is not considered an ``adequate, approved, and
available'' alternative for several reasons including: (1) the
license for Biothrax does not extend to post exposure use; (2) the
immunization consists of three subcutaneous injections given 2 weeks
apart followed by three additional subcutaneous injections given at
6, 12 and 18 months; and (3) following the initial injections, time
is needed to develop the antibodies. Therefore, I have concluded
that there is no adequate, approved, and available alternative to
doxycycline hyclate tablet emergency kits for the post-exposure
prophylaxis of inhalational anthrax for the specified population.
III. Scope of Authorization
Pursuant to section 564(d)(1) of the Act, this authorization is
limited to the use of doxycycline hyclate tablet emergency kits for
the post-exposure prophylaxis of inhalational anthrax\16\ for
eligible\17\ USPS participants in the Postal Module of CRI and their
household members.
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\16\ See footnote 8.
\17\ See footnote 3.
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The doxycycline hyclate tablets authorized under this EUA were
manufactured by West-Ward Pharmaceutical Corp. and have been
repackaged into unit-of-use bottles containing 20 tablets (a 10-day
supply) by PD-Rx Pharmaceuticals, consistent with current Good
Manufacturing Practice (CGMP) and the Draft Guidance entitled
``Expiration Dating of Unit-Dose Repackaged Drugs; Compliance Policy
Guide.'' The product has been stored under conditions consistent
with the manufacturer's labeled storage conditions and CGMP and is
within its labeled expiration date. Once doxycycline hyclate tablets
covered by this EUA have passed their expiration date, they are
outside the scope of this EUA.
ASPR will determine whether to initiate distribution of product
under this EUA to particular CRI locations based on:
(a) whether the municipality has submitted a Strategic Security Plan
acceptable to USPS and ASPR;
(b) whether the municipality, in collaboration with pertinent State
public health officials, local law enforcement agencies, USPS, ASPR,
and other appropriate entities, has developed a mutually acceptable
set of policies and procedures for recruiting USPS participants,
screening them for fitness to receive doxycycline hyclate tablets,
providing the doxycycline hyclate tablet emergency kits to eligible
USPS participants and their household members, and maintaining the
readiness of the participant force. Policies and procedures must
also include screening for fitness to receive OSHA-required personal
protective equipment (PPE) (i.e., N95 masks) and provision of PPE to
eligible USPS participants;\18\
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\18\ The emergency use of unapproved, unlicensed, or uncleared
PPE or the unapproved use of approved, licensed, or cleared PPE is
not authorized as part of this EUA.
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(c) whether ASPR has determined that it has sufficient funds to
cover the costs of CRI Postal Module implementation in that
location.
After the distribution decision has been made by ASPR and
conveyed to FDA, the unit-of-use bottles will be delivered to secure
site(s), where the participating public health authority(ies) will
assume control over them. Under this EUA, the unit-of-use bottles
will be repackaged and relabeled\19\ into doxycycline hyclate tablet
emergency kits by licensed health care providers under the auspices
of the participating public health authority(ies).
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\19\ The term ``repackaged and relabeled'' will be used to refer
to the activity of putting unit-of-use bottles into clear, tamper-
evident bags with the addition of certain written information.
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I have concluded, pursuant to section 564(d)(2) of the Act, that
it is reasonable to believe that the known and potential benefits of
the doxycycline hyclate tablet emergency kits, when used for the
post-exposure prophylaxis of inhalational anthrax, outweigh the
known and potential risks of the product for the population
described above.
I have concluded, pursuant to section 564(d)(3) of the Act,
based on the totality of scientific evidence available to FDA, that
it is reasonable to believe that the doxycycline hyclate tablet
emergency kits may be effective for the post-exposure prophylaxis of
inhalational anthrax pursuant to section 564(c)(2)(A) of the Act.
FDA has reviewed the scientific information available, including the
information described in Section II above, and concludes that the
doxycycline hyclate tablet emergency kits, when used for the post-
exposure prophylaxis of inhalational anthrax in the specified
population, meet the criteria set forth in section 564(c) of the Act
concerning safety and potential effectiveness.
The pre-event distribution and use of doxycycline hyclate tablet
emergency kits under this EUA must conform to and may not exceed the
terms of this letter of authorization, including the scope and the
conditions of authorization set forth below. Subject to the terms of
this EUA and under the circumstances set forth in the Secretary of
Homeland Security's determination under section 564(b)(1)(A)
described above and the Secretary of HHS's corresponding declaration
under section 564(b)(1), doxycycline hyclate tablet emergency kits
are authorized for the post-exposure prophylaxis of inhalational
anthrax for eligible USPS participants and their household members.
This EUA will cease to be effective when the declaration of
emergency is terminated under section 564(b)(2) of the Act or when
the EUA is revoked under section 564(g) of the Act. When the EUA
ceases to be effective, doxycycline hyclate tablet emergency kits
will no longer be authorized for emergency use under this EUA, and
doxycycline hyclate tablet emergency kits that have been distributed
under this EUA must be collected as described in this letter of
authorization.
IV. Conditions of Authorization
Pursuant to section 564 of the Act, I am establishing the
following conditions on this authorization:
A. BARDA will provide to the participating public health
authority(ies) the written materials included in BARDA's October 3,
2008 submission, as amended on February 19, 2009, and authorized
under this EUA.
B. The participating public health authority(ies) will conduct
an educational and information program under appropriate
[[Page 30582]]
conditions designed to ensure that health care providers or other
authorized dispensers (hereinafter health care providers)
distributing doxycycline hyclate tablet emergency kits are informed:
(1) that FDA has authorized the emergency use of doxycycline
hyclate tablet emergency kits for the post-exposure prophylaxis of
inhalational anthrax for eligible USPS participants and their
household members;
(2) of the significant known and potential benefits and risks of
the emergency use of doxycycline hyclate tablet emergency kits, and
of the extent to which such benefits and risks are unknown for
eligible USPS participants and their household members; and
(3) of the alternatives to doxycycline hyclate tablet emergency
kits for eligible USPS participants and their household members, and
of their benefits and risks.
With respect to condition (2) above, relating to provision of
the significant known and potential benefits and risks of the
emergency use of doxycycline hyclate tablet emergency kits, the
participating public health authority(ies) will ensure that the
manufacturer's package insert is provided to all health care
providers who distribute doxycycline hyclate tablet emergency kits
to eligible USPS participants and their household members. With
respect to conditions (1) - (3), the participating public health
authority(ies) will ensure that health care providers are provided
with the authorized Fact Sheet for Health Care Providers. Any
revision to the authorized Fact Sheet for Health Care Providers is
subject to FDA's prior approval. The participating public health
authority(ies) will also ensure that all such health care providers
are provided with the same information as that provided to eligible
recipients described immediately below.
C. The participating public health authority(ies) will conduct
an educational and information program under appropriate conditions
designed to ensure that individuals to whom doxycycline hyclate
tablet emergency kits are distributed are informed:
(1) that FDA has authorized the emergency use of doxycycline
hyclate tablet emergency kits for the post-exposure prophylaxis of
inhalational anthrax for eligible USPS participants and their
household members;
(2) of the significant known and potential benefits and risks of
the emergency use of doxycycline hyclate tablet emergency kits for
eligible USPS participants and their household members, and of the
extent to which such benefits and risks are unknown; and
(3) of the option to accept or refuse administration of
doxycycline hyclate tablet emergency kits, of the consequences, if
any, of refusing administration of the product, and of the
alternatives to the product that are available, and of their
benefits and risks.
As a condition of this authorization, the participating public
health authority(ies) will ensure that, prior to distribution of
doxycycline hyclate tablet emergency kits, the authorized
information that meets the requirements set forth above is provided
to each eligible recipient (i.e., in the case of the household
doxycycline hyclate emergency kit, the Fact Sheet for Recipients,
home preparation instructions, and information placard (or bag pre-
printed with placard information); in the case of the individual
doxycycline hyclate emergency kit, the Fact Sheet for Recipients,
and information placard (or bag pre-printed with placard
information)). Any revision to the authorized information for
potential recipients is subject to FDA's prior approval.
D. The participating public health authority(ies) will
distribute doxycycline hyclate tablet emergency kits to eligible
recipients through health care providers who are qualified and
licensed under applicable state law to dispense prescription drugs.
The health care providers will distribute doxycycline hyclate tablet
emergency kits under conditions that assure that otherwise
eligible\20\ recipients are screened for medical eligibility
(including contraindications) and are issued prescriptions for the
doxycycline hyclate tablet emergency kit. Such conditions shall
include exclusion of a USPS participant if:
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\20\ USPS postal carriers are not eligible to receive a
doxycycline hyclate tablet emergency kit if they have not passed
their N95 mask fit test. See Section III, Scope of Authorization,
above.
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No medical history and Health Assessment Form is
available for the USPS participant or any member of their household;
or
Doxycycline hyclate is contraindicated for the USPS
participant.
The participating public health authority(ies) must ensure
documentation of eligibility or ineligibility to receive doxycycline
hyclate tablet emergency kits. If doxycycline hyclate tablets are
contraindicated for any of the USPS participant's household members,
the USPS participant can still receive the doxycycline hyclate
tablet emergency kit if s/he consents in writing to accept an
incomplete kit and acknowledges that the household member(s) will
have the same dependence on whatever community-based mass
prophylaxis is available to the general public in an emergency.
USPS will be responsible for providing copies of the authorized
Health Assessment Form to potential USPS participants. If they elect
to apply for participation, potential USPS participants and their
household members should complete Health Assessment Forms and mail
them to the participating public health authority(ies) at the
address provided. Qualified health care providers, under the
auspices of the participating public health authority(ies), will be
responsible for reviewing the completed Health Assessment Forms to
determine whether potential recipients are eligible to receive
doxycycline hyclate tablet emergency kits prior to dispensing such
kits to eligible USPS recipients . Any revision of the authorized
Health Assessment Form is subject to FDA's prior approval. A health
care provider will review with each USPS participant his/her Health
Assessment Form and the Health Assessment Form corresponding to each
family member and will comply with applicable state prescribing laws
before authorizing the filling of one unit-of-use bottle for each
eligible USPS participant and household member. See Section D below
for requirements regarding repackaging and relabeling of doxycycline
hyclate tablet emergency kits prior to dispensing to eligible
recipients.
E. Doxycycline hyclate tablet emergency kits must be
manufactured, (re)packaged, (re)labeled, and held according to
applicable good manufacturing practice requirements, except that
with respect to the doxycycline hyclate tablet emergency kits that
will be repackaged and relabeled by participating local public
health authorities using the doxycycline unit-of-use bottles
manufactured by West-Ward Pharmaceutical Corp. and repackaged by PD-
Rx Pharmaceuticals described in this EUA, the Secretary waives good
manufacturing practice requirements applicable to the repackaging
and relabeling of such kits, subject to the following requirements
The participating public health authority(ies) will be
responsible for repackaging and relabeling doxycycline hyclate unit-
of-use bottles into doxycycline hyclate tablet emergency kits
through health care providers qualified and licensed under state law
to dispense prescription drugs.
The packaging and relabeling described below should be
performed in a controlled environment such that there is adequate
space, lighting, and freedom from debris and from other drug
products to prevent mix-ups or cross-contamination.
A health care provider who initially assembles the
doxycycline hyclate tablet emergency kits will do the following:
[cir] The health care provider will determine the number of
authorized individuals in a household eligible to receive the
product using the completed Health Assessment Form. The health care
provider will document the prescription number, lot number, and
expiration date of doxycycline hyclate for each authorized
individual.
[cir] The health care provider will record all prescription
numbers for the household on the Healthcare Provider Quality
Checklist.
[cir] The health care provider will be responsible for
maintaining an inventory/drug accountability record. At a minimum,
this record will contain a running total/balance, the date filled,
household name, and number of unit-of-use bottles dispensed to a
household. The prescription number, lot number, and expiration date
of the doxycycline hyclate tablets for each authorized individual
will also be recorded.
[cir] For the household doxycycline hyclate tablet emergency
kit, the health care provider will place the correct number of unit-
of-use bottles of doxycycline hyclate (corresponding to the
authorized USPS participant and each authorized
[[Page 30583]]
household member) in one clear, tamper-evident plastic bag. Each
unit-of-use bottle will be labeled with the appropriate authorized
individual's name.
[cir] For an individual doxycycline hyclate tablet emergency
kit, the health care provider will place one unit-of-use bottle of
doxycycline hyclate tablets in a separate clear, tamper-evident
plastic bag for the authorized USPS participant for secure storage
by the USPS at work. The unit-of-use bottle will be labeled with the
authorized USPS participant's name.
[cir] For the household doxycycline hyclate tablet emergency
kit, the health care provider will place the Fact Sheet for
Recipients, home preparation instructions, and MedWatch Form 3500
inside and in the outer pocket of the clear, tamper-evident plastic
bag; and, if the bag is not pre-printed with placard information,
the health care provider will place the information placard inside
the bag facing out so the wording is plainly visible.
[cir] For the individual doxycycline hyclate tablet emergency
kit, the health care provider will place the Fact Sheet for
Recipients and MedWatch Form 3500 Form inside and in the outer
pocket of the clear, tamper-evident plastic bag; and, if the bag is
not pre-printed with placard information, the health care provider
will place the information placard inside the bag facing out so the
wording is plainly visible.
[cir] The health care provider will complete the first page of
the Healthcare Provider Quality Checklist, including signature and
date.
[cir] The health care provider will not seal the bag, and will
give it to the identified health care provider to check the contents
of the bags as described below.
Before dispensing, a different health care provider
will check each doxycycline hyclate tablet emergency kit that has
been assembled as follows:
[cir] Review and verify Health Assessment Forms for eligibility
of USPS participant and each household member to receive the
doxycycline hyclate tablet emergency kit.
[cir] Verify that each unit-of-use bottle is labeled with the
authorized individual's name.
[cir] Verify the prescription number, lot number, and expiration
date of the doxycycline hyclate tablets for each authorized
individual on the Health Assessment Forms.
[cir] Verify prescription numbers for each authorized individual
on the Healthcare Provider Quality Checklist.
[cir] For the household doxycycline hyclate tablet emergency
kit, verify that the correct number of unit-of-use bottles of
doxycycline hyclate tablets have been placed in the tamper-evident
bag for that household based on the number of household members
eligible. For the individual doxycycline hyclate tablet emergency
kit, verify that the correct unit-of-use bottle of doxycycline
hyclate tablets has been placed in the tamper-evident bag for the
USPS participant for secure storage by USPS at work.
[cir] Verify that the appropriate written information is inside
the tamper-evident bags.
[cir] Verify that the appropriate written information is in the
outer pocket of the tamper-evident bags.
[cir] If the information placard is not pre-printed on the
outside of the tamper-evident bags, verify that the information
placard is inside the tamper-evident bags and plainly visible.
[cir] Complete the second page of the Healthcare Provider
Quality Checklist, including signature and date.
[cir] Seal the bags.
[cir] Attach the Healthcare Provider Quality Checklist to the
Health Assessment Forms for the household.
[cir] The doxycycline hyclate tablet emergency kits may then be
dispensed to the USPS participant along with review of the
instructions and information.
The authorized Healthcare Provider Quality Checklist and placard
information will be used. Any revision of the authorized Healthcare
Provider Quality Checklist or placard information is subject to
FDA's prior approval.
F. ASPR will record the amount of unit-of-use bottles of
doxycycline hyclate tablets (including lot numbers) shipped under
this EUA to the participating public health authority(ies) for use
by eligible USPS participants and their households. Such records
will be made available to FDA for inspection upon request. However,
the the participating public health authority(ies) responsible for
distributing the doxycycline hyclate tablet emergency kits will
prepare, maintain, and make available records and provide reports as
directed by ASPR/FDA.
G. Once an individual doxycycline hyclate tablet emergency kit
has been dispensed to an eligible USPS participant, USPS will store
the individual doxycycline hyclate tablet emergency kit in a secure
location for the eligible USPS participant.
H. ASPR, USPS, and the participating public health
authority(ies) may only provide written materials as included in
BARDA's October 3, 2008 submission, as amended on February 19, 2009,
and authorized under this EUA. Any revisions or additional written
materials to be provided by ASPR, USPS, or the participating public
health authority(ies) are subject to FDA's prior approval, except
that USPS may provide additional materials for recruitment purposes
to the extent that those materials are consistent with the materials
included in BARDA's October 3, 2008 submission, as amended on
February 19, 2009, that are authorized under this EUA. The
participating public health authority(ies) may evaluate activities
undertaken pursuant to this authorization. To ensure consistency
with this authorization, the participating public health
authority(ies) must consult with FDA before conducting such
evaluations.
I. The participating public health authority(ies) will conduct
an adverse event monitoring and reporting program designed to ensure
that adverse events and medication errors associated with the use of
the doxycycline hyclate tablet emergency kit are documented and
reported within 15 days to MedWatch through www.fda.gov/medwatch, by
submitting MedWatch Form 3500 in hard copy, or by calling 1-800-FDA-
1088; and that any such report identifies the product as
``doxycycline hyclate tablet emergency kit'' and includes in the
description of the event the designation ``USPS-CRI EUA'' or ``USPS-
CRI Emergency Use Authorization.'' As part of this program, health
care providers will be provided copies of MedWatch Form 3500,
recipients will be instructed to report if they take any of the
doxycycline hyclate tablets in their emergency kit and experience an
adverse event or medication error, MedWatch Form 3500 will be
included in each doxycycline hyclate tablet emergency kit, and
recipients will be provided with a toll-free number for contacting a
health care provider if they experience an adverse event or
medication error. The participating public health authority(ies)
will maintain associated records until notified by FDA and will make
such records available to FDA for inspection upon request.
J. The participating public health authority(ies) will
periodically verify and document that any undistributed doxycycline
hyclate is within its labeled expiration date. The participating
public health authority(ies) will maintain any associated records
until notified by FDA and will make such records available to FDA
for inspection upon request. Appropriate local public health
authorities will periodically verify and reconcile drug
accountability records.
K. USPS will be responsible for providing USPS participants
every six months with the Form entitled ``Questions to Determine
Status of Your Household Antibiotic Kit (HAK)'' (Kit Status form) to
document whether (a) they have stored their kits as instructed; (b)
they are able to locate their kits readily; (c) their kits are
intact; and (d) the doxycycline hyclate in their kits has not
expired. USPS participants should complete these forms and mail them
to the participating public health authority(ies) at the address
provided. The participating public health authority(ies) will
ascertain the circumstances surrounding non-compliance for USPS
participants who (a) report loss of a kit; (b) report use of
doxycycline hyclate from the emergency kit in the absence of
instructions to do so; or (c) fail to return a completed Kit Status
Form. Depending on its findings, the participating public health
authority(ies) may disqualify an individual from further
participation. If the doxycycline hyclate emergency kit will expire
before the next 6-month follow-up, a new doxycycline hyclate
emergency kit will be prescribed for eligible participants in
accordance with paragraph D and the other terms of this letter. In
such cases, USPS will be responsible for collecting such kits and
turning them over to the participating public health authority(ies),
which then will be responsible for accounting for them and disposing
ofthem as instructed by ASPR. The participating public health
authority(ies) will maintain drug accountability records. The
participating public health authority(ies) will also
[[Page 30584]]
ascertain whether there have been any adverse events or medication
errors associated with the doxycycline hyclate tablet emergency kit.
If any such adverse events or medication errors have not previously
been reported to FDA as outlined in paragraph H, they must be
reported within 15 days to FDA. FDA has authorized ASPR's Form
entitled ``Questions to Determine Status of Your Household
Antibiotic Kit (HAK)'' (Kit Status form). Any revision of the Kit
Status form is subject to FDA's prior approval. USPS, in conjunction
with appropriate local public health authorities, will be
responsible for ensuring that completed Kit Status forms are
maintained until notified by FDA. A report summarizing the
information collected on Kit Status forms under this paragraph will
be submitted to FDA within 30 days of gathering such information.
Associated records will be made available to FDA for inspection upon
request.
L. USPS will be responsible for collecting any expired
doxycycline hyclate tablet emergency kits and turning them over to
the participating public health authority(ies). The participating
public health authority(ies) will be responsible for disposing of
expired doxycycline hyclate tablet emergency kits as instructed by
ASPR at that time. The participating public health authority(ies)
will ensure that drug accountability records are maintained and
reconciled. Such records shall be made available to FDA for
inspection upon request.
M. USPS and the participating public health authority(ies) will
be responsible for ensuring that completed Health Assessment Forms,
Healthcare Provider Quality Checklists, and any other records
associated with this EUA are maintained until notified by FDA. Such
records will be made available to FDA for inspection upon request.
N. As a condition of this EUA, all advertising and promotional
descriptive printed matter relating to the use of doxycycline
hyclate tablet emergency kits authorized under this EUA shall be
consistent with the Fact Sheets, home preparation instructions, and
placard information, as well as the terms set forth in this EUA and
other requirements set forth in the Act and FDA regulations.
O. Upon termination of the declaration of emergency under
section 564(b)(2) of the Act or upon revocation of this EUA under
section 564(g) of the Act, USPS will be responsible for collecting
all doxycycline hyclate tablet emergency kits and turning them over
to the participating public health authority(ies). The participating
public health authority(ies) will dispose of doxycycline hyclate
emergency kits as instructed by ASPR at that time. The participating
public health authority(ies) will ensure that drug accountability
records are maintained and reconciled. Such records will be made
available to FDA for inspection upon request.
P. HHS will notify FDA of its decision to add a CRI location and
its decision to initiate distribution of doxycycline hyclate tablet
emergency kits under this EUA to particular CRI locations.
The emergency use of doxycycline hyclate tablet emergency kits
as described in this letter of authorization must comply with the
conditions above and all other terms of this authorization.
V. Duration of Authorization
This EUA will be effective until the declaration of emergency is
terminated under section 564(b)(2) of the Act or the EUA is revoked
under section 564(g) of the Act.
Randall W. Lutter, Ph.D.
Deputy Commissioner for Policy
Dated: June 17, 2009.
Randall W. Lutter,
Deputy Commissioner for Policy.
[FR Doc. E9-15044 Filed 6-25-09; 8:45 am]
BILLING CODE 4160-01-S