[Federal Register Volume 60, Number 40 (Wednesday, March 1, 1995)]
[Notices]
[Pages 11284-11287]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4961]
[[Page 11283]]
_______________________________________________________________________
Part XIII
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Guideline on Clinical Safety
Data Management; Notice
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 /
Notices
[[Page 11284]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 93D-0203]
International Conference on Harmonisation; Guideline on Clinical
Safety Data Management: Definitions and Standards for Expedited
Reporting; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a final
guideline entitled ``Clinical Safety Data Management: Definitions and
Standards for Expedited Reporting.'' This guideline was prepared under
the auspices of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH). The guideline provides standard definitions and terms for
key aspects of clinical safety reporting. The guideline also discusses
mechanisms for expedited reporting. This guideline is intended to help
harmonize methods for gathering and evaluating clinical safety data.
DATES: Effective March 1, 1995. Submit written comments at any time.
ADDRESSES: Submit written comments on the guideline to the Dockets
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,
12420 Parklawn Dr., Rockville, MD 20857. Copies of the guideline are
available from CDER Executive Secretariat Staff (HFD-8), Center for
Drug Evaluation and Research, Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855.
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Murray M. Lumpkin, Center for Drug
Evaluation and Research (HFD-2), Food and Drug Administration, 1451
Rockville Pike, Rockville, MD 20852, 301-594-6740.
Regarding ICH: Janet J. Showalter, Office of Health Affairs (HFY-
20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, 301-443-1382.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote international harmonization of regulatory
requirements. FDA has participated in many meetings designed to enhance
harmonization and is committed to seeking scientifically based
harmonized technical procedures for pharmaceutical development. One of
the goals of harmonization is to identify and then reduce differences
in technical requirements for drug development among regulatory
agencies.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. ICH is concerned with
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission; the European Federation of Pharmaceutical Industry
Associations; the Japanese Ministry of Health and Welfare; the Japanese
Pharmaceutical Manufacturers Association; the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA; and
the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Association (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and IFPMA, as well as observers from the World Health
Organization, the Canadian Health Protection Branch, and the European
Free Trade Area.
Harmonization of clinical safety data management was selected as a
priority topic during the early stages of the ICH initiative. In the
Federal Register of July 9, 1993 (58 FR 37408), FDA published a draft
tripartite guideline entitled, ``Clinical Safety Data Management:
Definitions and Standards for Expedited Reporting.'' The notice gave
interested persons an opportunity to submit comments by August 9, 1993.
After consideration of the comments received and revisions to the
guideline, a final draft of the guideline was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies at the ICH meeting held in October 1994.
The guideline defines basic terms, such as ``adverse event,''
``adverse drug reaction,'' and ``unexpected adverse drug reaction.''
The guideline also provides guidance on determining whether an adverse
drug reaction is ``expected,'' and contains standards for expedited
reporting, describing what information should be reported, recommending
reporting timeframes and the use of the CIOMS-I form for reporting
information or, alternatively, suggesting that basic information or
data elements be used. The guideline also discusses: Whether and when
the blind should be broken for a patient; reporting reactions
associated with comparison drug or placebo treatments; products with
more than one dosage form, route of administration, or use; and adverse
events that occur after the patient has completed the clinical study.
In the past, guidelines have generally been issued under
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of
guidelines to state procedures or standards of general applicability
that are not legal requirements but are acceptable to FDA. The agency
is now in the process of revising Sec. 10.90(b). Therefore, this
guideline is not being issued under the authority of Sec. 10.90(b), and
it does not create or confer any rights, privileges, or benefits for or
on any person, nor does it operate to bind FDA in any way.
As with all of FDA's guidelines, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guideline. The comments in the docket will be periodically
reviewed, and, where appropriate, the guideline will be amended. The
public will be notified of any such amendments through a notice in the
Federal Register.
Interested persons may, at any time, submit written comments on the
guideline to the Dockets Management Branch (address above). Two copies
of any comments are to be submitted, except that individuals may submit
one copy. Comments are to be identified with the docket number found in
brackets in the heading of this document. The guideline and received
comments may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday.
The text of the guideline follows:
Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting
I. Introduction
It is important to harmonize the way to gather and, if
necessary, to take action on important clinical safety information
arising during clinical development. Thus, agreed definitions and
terminology, as well as procedures, will ensure uniform Good
Clinical Practice standards in this area. The initiatives already
undertaken for marketed medicines through the CIOMS-1 and CIOMS-2
Working Groups on expedited (alert) reports and periodic safety
update reporting, respectively, are important precedents and models.
However, there are special circumstances involving medicinal
products under development, especially in the early stages and
before any marketing [[Page 11285]] experience is available.
Conversely, it must be recognized that a medicinal product will be
under various stages of development and/or marketing in different
countries, and safety data from marketing experience will ordinarily
be of interest to regulators in countries where the medicinal
product is still under investigational only (Phase 1, 2, or 3)
status. For this reason, it is both practical and well-advised to
regard premarketing and postmarketing clinical safety reporting
concepts and practices as interdependent, while recognizing that
responsibility for clinical safety within regulatory bodies and
companies may reside with different departments, depending on the
status of the product (investigational versus marketed).
There are two issues within the broad subject of clinical safety
data management that are appropriate for harmonization at this time:
(1) The development of standard definitions and terminology for
key aspects of clinical safety reporting, and
(2) The appropriate mechanism for handling expedited (rapid)
reporting, in the investigational (i.e., preapproval) phase.
The provisions of this guideline should be used in conjunction
with other ICH Good Clinical Practice guidelines.
II. Definitions and Terminology Associated with Clinical Safety
Experience
A. Basic Terms
Definitions for the terms adverse event (or experience), adverse
reaction, and unexpected adverse reaction have previously been
agreed to by consensus of the more than 30 Collaborating Centers of
the WHO International Drug Monitoring Centre (Uppsala, Sweden).
(Edwards, I. R., et al., ``Harmonisation in Pharmacovigilance,''
Drug Safety, 10(2): 93-102, 1994.) Although those definitions can
pertain to situations involving clinical investigations, some minor
modifications are necessary, especially to accommodate the
preapproval, development environment.
The following definitions, with input from the WHO Collaborative
Centre, have been agreed.
1. Adverse Event (or Adverse Experience).
Any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product and
which does not necessarily have to have a causal relationship with
this treatment.
An adverse event (AE) can therefore be any unfavorable and
unintended sign (including an abnormal laboratory finding, for
example), symptom, or disease temporally associated with the use of
a medicinal product, whether or not considered related to the
medicinal product.
2. Adverse Drug Reaction (ADR).
In the preapproval clinical experience with a new medicinal
product or its new usages, particularly as the therapeutic dose(s)
may not be established:
All noxious and unintended responses to a medicinal product
related to any dose should be considered adverse drug reactions.
The phrase ``responses to medicinal products'' means that a
causal relationship between a medicinal product and an adverse event
is at least a reasonable possibility, i.e., the relationship cannot
be ruled out.
Regarding marketed medicinal products, a well-accepted
definition of an adverse drug reaction in the postmarketing setting
is found in WHO Technical Report 498 (1972) and reads as follows:
``A response to a drug which is noxious and unintended and which
occurs at doses normally used in man for prophylaxis, diagnosis, or
therapy of disease or for modification of physiological function.''
The old term ``side effect'' has been used in various ways in
the past, usually to describe negative (unfavorable) effects, but
also positive (favorable) effects. It is recommended that this term
no longer be used and particularly should not be regarded as
synonymous with adverse event or adverse reaction.
3. Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not
consistent with the applicable product information (e.g.,
Investigator's Brochure for an unapproved investigational medicinal
product). See III. C.
B. Serious Adverse Event Or Adverse Drug Reaction
During clinical investigations, adverse events may occur which,
if suspected to be medicinal product-related (adverse drug
reactions), might be significant enough to lead to important changes
in the way the medicinal product is developed (e.g., change in dose,
population, needed monitoring, consent forms). This is particularly
true for reactions which, in their most severe forms, threaten life
or function. Such reactions should be reported promptly to
regulators.
Therefore, special medical or administrative criteria are needed
to define reactions that, either due to their nature (``serious'')
or due to the significant, unexpected information they provide,
justify expedited reporting.
To ensure that no confusion or misunderstanding exist of the
difference between the terms ``serious'' and ``severe,'' which are
not synonymous, the following note of clarification is provided:
The term ``severe'' is often used to describe the intensity
(severity) of a specific event (as in mild, moderate, or severe
myocardial infarction); the event itself, however, may be of
relatively minor medical significance (such as severe headache).
This is not the same as ``serious,'' which is based on patient/event
outcome or action criteria usually associated with events that pose
a threat to a patient's life or functioning. Seriousness (not
severity) serves as a guide for defining regulatory reporting
obligations.
After reviewing the various regulatory and other definitions in
use or under discussion elsewhere, the following definition is
believed to encompass the spirit and meaning of them all:
A serious adverse event (experience) or reaction is any untoward
medical occurrence that at any dose:
Results in death,
Is life-threatening,
(NOTE: The term ``life-threatening'' in the definition of
``serious'' refers to an event in which the patient was at risk of
death at the time of the event; it does not refer to an event which
hypothetically might have caused death if it were more severe.)
Requires inpatient hospitalization or prolongation of
existing hospitalization,
Results in persistent or significant disability/
incapacity, or
Is a congenital anomaly/birth defect.
Medical and scientific judgment should be exercised in deciding
whether expedited reporting is appropriate in other situations, such
as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize
the patient or may require intervention to prevent one of the other
outcomes listed in the definition above. These should also usually
be considered serious.
Examples of such events are intensive treatment in an emergency
room or at home for allergic bronchospasm; blood dyscrasias or
convulsions that do not result in hospitalization; or development of
drug dependency or drug abuse.
C. Expectedness of an Adverse Drug Reaction
The purpose of expedited reporting is to make regulators,
investigators, and other appropriate people aware of new, important
information on serious reactions. Therefore, such reporting will
generally involve events previously unobserved or undocumented, and
a guideline is needed on how to define an event as ``unexpected'' or
``expected'' (expected/unexpected from the perspective of previously
observed, not on the basis of what might be anticipated from the
pharmacological properties of a medicinal product).
As stated in the definition (II.A.3.), an ``unexpected'' adverse
reaction is one, the nature or severity of which is not consistent
with information in the relevant source document(s). Until source
documents are amended, expedited reporting is required for
additional occurrences of the reaction.
The following documents or circumstances will be used to
determine whether an adverse event/reaction is expected:
1. For a medicinal product not yet approved for marketing in a
country, a company's Investigator's Brochure will serve as the
source document in that country. See III.F. and ICH Guideline for
the Investigator's Brochure.
2. Reports which add significant information on specificity or
severity of a known, already documented serious ADR constitute
unexpected events. For example, an event more specific or more
severe than described in the Investigator's Brochure would be
considered ``unexpected.'' Specific examples would be (a) acute
renal failure as a labeled ADR with a subsequent new report of
interstitial nephritis and (b) hepatitis with a first report of
fulminant hepatitis.
III. Standards for Expedited Reporting
A. What Should Be Reported?
1. Single Cases of Serious, Unexpected ADR's
All ADR's that are both serious and unexpected are subject to
expedited reporting. This applies to reports from spontaneous
sources and from any type of [[Page 11286]] clinical or
epidemiological investigation, independent of design or purpose. It
also applies to cases not reported directly to a sponsor or
manufacturer (for example, those found in regulatory authority
generated ADR registries or in publications). The source of a report
(investigation, spontaneous, other) should always be specified.
Expedited reporting of reactions that are serious but expected
will ordinarily be inappropriate. Expedited reporting is also
inappropriate for serious events from clinical investigations that
are considered not related to study product, whether the event is
expected or not. Similarly, nonserious adverse reactions, whether
expected or not, will ordinarily not be subject to expedited
reporting.
Information obtained by a sponsor or manufacturer on serious,
unexpected reports from any source should be submitted on an
expedited basis to appropriate regulatory authorities if the minimum
criteria for expedited reporting can be met. See section III.B.
Causality assessment is required for clinical investigation
cases. All cases judged by either the reporting health care
professional or the sponsor as having a reasonable suspected causal
relationship to the medicinal product qualify as ADR's. For purposes
of reporting, adverse event reports associated with marketed drugs
(spontaneous reports) usually imply causality.
Many terms and scales are in use to describe the degree of
causality (attributability) between a medicinal product and an
event, such as certainly, definitely, probably, possibly, or likely
related or not related. Phrases such as ``plausible relationship,''
``suspected causality,'' or ``causal relationship cannot be ruled
out'' are also invoked to describe cause and effect. However, there
is currently no standard international nomenclature. The expression
``reasonable causal relationship'' is meant to convey in general
that there are facts (evidence) or arguments to suggest a causal
relationship.
2. Other Observations
There are situations in addition to single case reports of
``serious'' adverse events or reactions that may necessitate rapid
communication to regulatory authorities; appropriate medical and
scientific judgment should be applied for each situation. In
general, information that might materially influence the benefit-
risk assessment of a medicinal product or that would be sufficient
to consider changes in medicinal product administration or in the
overall conduct of a clinical investigation represents such
situations. Examples include:
a. For an ``expected, serious ADR, an increase in the rate of
occurrence which is judged to be clinically important.
b. A significant hazard to the patient population, such as lack
of efficacy with a medicinal product used in treating life-
threatening disease.
c. A major safety finding from a newly completed animal study
(such as carcinogenicity).
B. Reporting Time Frames
1. Fatal Or Life-Threatening Unexpected ADR's
Certain ADR's may be sufficiently alarming so as to require very
rapid notification to regulators in countries where the medicinal
product or indication, formulation, or population for the medicinal
product are still not approved for marketing, because such reports
may lead to consideration of suspension of, or other limitations to,
a clinical investigation program. Fatal or life-threatening,
unexpected ADR's occurring in clinical investigations qualify for
very rapid reporting. Regulatory agencies should be notified (e.g.,
by telephone, facsimile transmission, or in writing) as soon as
possible but no later than 7 calendar days after first knowledge by
the sponsor that a case qualifies, followed by as complete a report
as possible within 8 additional calendar days. This report should
include an assessment of the importance and implication of the
findings, including relevant previous experience with the same or
similar medicinal products.
2. All Other Serious, Unexpected ADR's
Serious, unexpected reactions (ADR's) that are not fatal or
life-threatening should be filed as soon as possible but no later
than 15 calendar days after first knowledge by the sponsor that the
case meets the minimum criteria for expedited reporting.
3. Minimum Criteria for Reporting
Information for final description and evaluation of a case
report may not be available within the required timeframes for
reporting outlined above. Nevertheless, for regulatory purposes,
initial reports should be submitted within the prescribed time as
long as the following minimum criteria are met: An identifiable
patient; a suspect medicinal product; an identifiable reporting
source; and an event or outcome that can be identified as serious
and unexpected, and for which, in clinical investigation cases,
there is a reasonable suspected causal relationship. Followup
information should be actively sought and submitted as it becomes
available.
C. How To Report
The CIOMS-I form has been a widely accepted standard for
expedited adverse event reporting. However, no matter what the form
or format used, it is important that certain basic information/data
elements, when available, be included with any expedited report,
whether in a tabular or narrative presentation. The listing in
Attachment 1 addresses those data elements regarded as desirable; if
all are not available at the time of expedited reporting, efforts
should be made to obtain them. See III.B.
All reports must be sent to those regulators or other official
parties requiring them (as appropriate for the local situation) in
countries where the drug is under development.
D. Managing Blinded Therapy Cases
When the sponsor and investigator are blinded to individual
patient treatment (as in a double-blind study), the occurrence of a
serious event requires a decision on whether to open (break) the
code for the specific patient. If the investigator breaks the blind,
then it is assumed the sponsor will also know the assigned treatment
for that patient. Although it is advantageous to retain the blind
for all patients prior to final study analysis, when a serious
adverse reaction is judged reportable on an expedited basis, it is
recommended that the blind be broken only for that specific patient
by the sponsor even if the investigator has not broken the blind. It
is also recommended that, when possible and appropriate, the blind
be maintained for those persons, such as biometrics personnel,
responsible for analysis and interpretation of results at the
study's conclusion.
There are several disadvantages to maintaining the blind under
the circumstances described which outweigh the advantages. By
retaining the blind, placebo and comparator (usually a marketed
product) cases are filed unnecessarily. When the blind is eventually
opened, which may be many weeks or months after reporting to
regulators, it must be ensured that company and regulatory data
bases are revised. If the event is serious, new, and possibly
related to the medicinal product, then if the Investigator's
Brochure is updated, notifying relevant parties of the new
information in a blinded fashion is inappropriate and possibly
misleading. Moreover, breaking the blind for a single patient
usually has little or no significant implications for the conduct of
the clinical investigation or on the analysis of the final clinical
investigation data.
However, when a fatal or other ``serious'' outcome is the
primary efficacy endpoint in a clinical investigation, the integrity
of the clinical investigation may be compromised if the blind is
broken. Under these and similar circumstances, it may be appropriate
to reach agreement with regulatory authorities in advance concerning
serious events that would be treated as disease-related and not
subject to routine expedited reporting.
E. Miscellaneous Issues
1. Reactions Associated With Active Comparator or Placebo
Treatment
It is the sponsor's responsibility to decide whether active
comparator drug reactions should be reported to the other
manufacturer and/or directly to appropriate regulatory agencies.
Sponsors should report such events to either the manufacturer of the
active control or to appropriate regulatory agencies. Events
associated with placebo will usually not satisfy the criteria for an
ADR and, therefore, for expedited reporting.
2. Products With More Than One Presentation or Use
To avoid ambiguities and uncertainties, an ADR that qualifies
for expedited reporting with one presentation of a product (e.g., a
dosage form, formulation, delivery system) or product use (e.g., for
an indication or population) should be reported or referenced to
regulatory filings across other product presentations and uses.
It is not uncommon that more than one dosage form, formulation,
or delivery system (oral, IM, IV, topical, etc.) of the
pharmacologically active compound(s) is under study or marketed; for
these different presentations there may be some marked differences
in the clinical safety profile. The same may apply for a given
product used in different indications or populations (single dose
versus chronic administration, for example). Thus, ``expectedness''
may be [[Page 11287]] product or product-use specific, and separate
Investigator's Brochures may be used accordingly. However, such
documents are expected to cover ADR information that applies to all
affected product presentations and uses. When relevant, separate
discussions of pertinent product-specific or use-specific safety
information will also be included.
It is recommended that any adverse drug reactions that qualify
for expedited reporting observed with one product dosage form or use
be cross referenced to regulatory records for all other dosage forms
and uses for that product. This may result in a certain amount of
overreporting or unnecessary reporting in obvious situations (for
example, a report of phlebitis on IV injection sent to authorities
in a country where only an oral dosage form is studied or marketed).
However, underreporting is completely avoided.
3. Poststudy Events
Although such information is not routinely sought or collected
by the sponsor, serious adverse events that occurred after the
patient had completed a clinical study (including any protocol
required posttreatment followup) will possibly be reported by an
investigator to the sponsor. Such cases should be regarded for
expedited reporting purposes as though they were study reports.
Therefore, a causality assessment and determination of expectedness
are needed for a decision on whether or not expedited reporting is
required.
F. Informing Investigators and Ethics Committees/Institutional
Review Boards of New Safety Information
International standards regarding such communication are
discussed within the ICH GCP Guidelines, including the addendum on
``Guideline for the Investigator's Brochure.'' In general, the
sponsor of a study should amend the Investigator's Brochure as
needed, and in accord with any local regulatory requirements, so as
to keep the description of safety information updated.
Attachment 1
Key Data Elements for Inclusion in Expedited Reports of Serious Adverse
Drug Reactions
The following list of items has its foundation in several
established precedents, including those of CIOMS-I, the WHO
International Drug Monitoring Centre, and various regulatory
authority forms and guidelines. Some items may not be relevant
depending on the circumstances. The minimum information required for
expedited reporting purposes is: an identifiable patient, the name
of a suspect medicinal product, an identifiable reporting source,
and an event or outcome that can be identified as serious and
unexpected and for which, in clinical investigation cases, there is
a reasonable suspected causal relationship. Attempts should be made
to obtain followup information on as many other listed items
pertinent to the case.
1. Patient Details:
Initials,
Other relevant identifier (clinical investigation
number, for example),
Gender,
Age and/or date of birth,
Weight,
Height.
2. Suspected Medicinal Product(s):
Brand name as reported,
International Nonproprietary Name (INN),
Batch number,
Indication(s) for which suspect medicinal product was
prescribed or tested,
Dosage form and strength,
Daily dose and regimen (specify units--e.g., mg, mL,
mg/kg)
Route of administration,
Starting date and time of day,
Stopping date and time, or duration of treatment.
3. Other Treatment(s):
For concomitant medicinal products (including
nonprescription/OTC medicinal products) and nonmedicinal product
therapies, provide the same information as for the suspected
product.
4. Details Of Suspected Adverse Drug Reaction(s)
Full description of reaction(s) including body site and
severity, as well as the criterion (or criteria) for regarding the
report as serious should be given. In addition to a description of
the reported signs and symptoms, whenever possible, attempts should
be made to establish a specific diagnosis for the reaction.
Start date (and time) of onset of reaction,
Stop date (and time) or duration of reaction,
Dechallenge and rechallenge information,
Setting (e.g., hospital, out-patient clinic, home,
nursing home),
Outcome: Information on recovery and any sequelae; what
specific tests and/or treatment may have been required and their
results; for a fatal outcome, cause of death and a comment on its
possible relationship to the suspected reaction should be provided.
Any autopsy or other post-mortem findings (including a coroner's
report) should also be provided when available. Other information:
anything relevant to facilitate assessment of the case, such as
medical history, including allergy, drug or alcohol abuse; family
history; findings from special investigations.
5. Details on Reporter of Event (Suspected ADR):
Name,
Address,
Telephone number,
Profession (specialty).
6. Administrative and Sponsor/Company Details:
Source of report: was it spontaneous, from a clinical
investigation (provide details), from the literature (provide copy),
other?
Date event report was first received by sponsor/
manufacturer,
Country in which event occurred,
Type of report filed to authorities: initial or
followup (first, second, etc.).
Name and address of sponsor/manufacturer/company,
Name, address, telephone number, and FAX number of
contact person in reporting company or institution,
Identifying regulatory code or number for marketing
authorization dossier or clinical investigation process for the
suspected product (for example, IND or CTX number, NDA number).
Sponsor/manufacturer's identification number for the
case. (This number should be the same for the initial and followup
reports on the same case.)
Dated: February 23, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-4961 Filed 2-28-95; 8:45 am]
BILLING CODE 4160-01-F
