[Federal Register: January 8, 2008 (Volume 73, Number 5)]
[Rules and Regulations]
[Page 1269-1271]
[DOCID:fr08ja08-2]

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

DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2008-0410; Directorate Identifier 2007-NM-338-AD;
Amendment 39-15325; AD 2008-01-02]
RIN 2120-AA64

Airworthiness Directives; Viking Air Limited Model (Caribou) DHC-
4 and (Caribou) DHC-4A Airplanes

AGENCY: Federal Aviation Administration (FAA), Department of
Transportation (DOT).

ACTION: Final rule; request for comments.

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

SUMMARY: We are adopting a new airworthiness directive (AD) for the
products listed above. This AD results from mandatory continuing
airworthiness information (MCAI) originated by an aviation authority of
another country to identify and correct an unsafe condition on an
aviation product. The MCAI describes the unsafe condition as:

    During a heavy maintenance check on a DHC-4 aircraft, an
operator discovered that both of the upper engine mount bracket
assemblies on one aircraft were cracked. Further inspection of the
operator's fleet confirmed that engine mount bracket assemblies on
five out of ten aircraft were also cracked.

* * * * *
Failure of the upper engine mount bracket assembly could result in
separation of the engine from the airplane. This AD requires actions
that are intended to address the unsafe condition described in the
MCAI.

DATES: This AD becomes effective January 23, 2008.
    The Director of the Federal Register approved the incorporation by
reference of a certain publication, listed in the AD as of January 23,
2008.
    We must receive comments on this AD by February 7, 2008.

ADDRESSES: You may send comments by any of the following methods:
     Federal eRulemaking Portal: Go to http://www.regulations.gov.
 Follow the instructions for submitting comments.

     Fax:<PHONE_NUMBER>.
     Mail: U.S. Department of Transportation, Docket
Operations, M-

30, West Building Ground Floor, Room W12-140, 1200 New Jersey Avenue,
SE., Washington, DC 20590.
     Hand Delivery: U.S. Department of Transportation, Docket
Operations, M-30, West Building Ground Floor, Room W12-40, 1200 New
Jersey Avenue, SE., Washington, DC, between 9 a.m. and 5 p.m., Monday
through Friday, except Federal holidays.

Examining the AD Docket

    You may examine the AD docket on the Internet at http://www.regulations.gov
; or in person at the Docket Operations office

between 9 a.m. and 5 p.m., Monday through Friday, except Federal
holidays. The AD docket contains this AD, the regulatory evaluation,
any comments received, and other information. The street address for
the Docket Operations office (telephone<PHONE_NUMBER>) is in the
ADDRESSES section. Comments will be available in the AD docket shortly
after receipt.

FOR FURTHER INFORMATION CONTACT: George Duckett, Aerospace Engineer,
Airframe and Propulsion Branch, ANE-171, FAA, New York Aircraft
Certification Office, 1600 Stewart Avenue, Suite 410, Westbury, New
York 11590; telephone<PHONE_NUMBER>; fax<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Discussion

    Transport Canada Civil Aviation (TCCA), which is the aviation
authority for Canada, has issued Canadian Airworthiness Directive CF-
2007-26, dated November 7, 2007 (referred to after this as ``the
MCAI''), to correct an unsafe condition for the specified products. The
MCAI states:

    During a heavy maintenance check on a DHC-4 aircraft, an
operator discovered that both of the upper engine mount bracket
assemblies on one aircraft were cracked. Further inspection of the
operator's fleet confirmed that engine mount bracket assemblies on
five out of ten aircraft were also cracked.
    As an interim action to prevent failure of upper engine mount
bracket assemblies, this directive mandates a one-time fluorescent
penetrant inspection. Subsequent corrective action may be
implemented in the future pending results of the investigation.

Failure of the upper engine mount bracket assembly could result in
separation of the engine from the airplane. Corrective actions include
replacing any cracked engine mount bracket assembly with a new
assembly. You may obtain further information by examining the MCAI in
the AD docket.

Relevant Service Information

    Viking Air Limited has issued Alert Service Bulletin V4/0001, dated
November 9, 2007. The actions described in this service information are
intended to correct the unsafe condition identified in the MCAI.

FAA's Determination and Requirements of This AD

    This product has been approved by the aviation authority of another
country, and is approved for operation in the United States. Pursuant
to our bilateral agreement with the State of Design Authority, we have
been notified of the unsafe condition described in the MCAI and service
information referenced above. We are issuing this AD because we
evaluated all pertinent information and determined the unsafe condition
exists and is likely to exist or develop on other products of the same
type design.

Differences Between the AD and the MCAI or Service Information

    We have reviewed the MCAI and related service information and, in
general, agree with their substance. But we might have found it
necessary to use different words from those in the MCAI to ensure the
AD is clear for U.S. operators and is enforceable. In making these
changes, we do not intend to differ substantively from the information
provided in the MCAI and related service information.
    We might also have required different actions in this AD from those
in the MCAI in order to follow FAA policies. Any such differences are
highlighted in a NOTE within the AD.

FAA's Determination of the Effective Date

    An unsafe condition exists that requires the immediate adoption of
this AD. The FAA has found that the risk to the flying public justifies
waiving notice and comment prior to adoption of this rule because
failure of the upper engine mount bracket assembly could lead to
separation of the engine from the airplane. Therefore, we find that
notice and opportunity for prior public comment hereon are
impracticable and that good cause exists for making this amendment
effective in less than 30 days.

Comments Invited

    This AD is a final rule that involves requirements affecting flight
safety, and we did not precede it by notice and opportunity for public
comment. We invite you to send any written relevant data, views, or
arguments about this AD. Send your comments to an address listed under
the ADDRESSES section. Include ``Docket No. FAA-2008-0410; Directorate
Identifier 2007-NM-338-AD'' at the beginning of your comments. We
specifically invite comments on the overall regulatory, economic,
environmental, and energy aspects of this AD. We will consider all
comments received by the closing date and may amend this AD because of
those comments.
    We will post all comments we receive, without change, to http://www.regulations.gov
, including any personal information you provide. We

will also post a report summarizing each substantive verbal contact we
receive about this AD.

Authority for This Rulemaking

    Title 49 of the United States Code specifies the FAA's authority to
issue rules on aviation safety. Subtitle I, section 106, describes the
authority of the FAA Administrator. ``Subtitle VII: Aviation
Programs,'' describes in more detail the scope of the Agency's
authority.
    We are issuing this rulemaking under the authority described in
``Subtitle VII, Part A, Subpart III, Section 44701: General
requirements.'' Under that section, Congress charges the FAA with
promoting safe flight of civil aircraft in air commerce by prescribing
regulations for practices, methods, and procedures the Administrator
finds necessary for safety in air commerce. This regulation is within
the scope of that authority because it addresses an unsafe condition
that is likely to exist or develop on products identified in this
rulemaking action.

Regulatory Findings

    We determined that this AD will not have federalism implications
under Executive Order 13132. This AD will not have a substantial direct
effect on the States, on the relationship between the national
government and the States, or on the distribution of power and
responsibilities among the various levels of government.
    For the reasons discussed above, I certify this AD:
    1. Is not a ``significant regulatory action'' under Executive Order
12866;
    2. Is not a ``significant rule'' under the DOT Regulatory Policies
and Procedures (44 FR 11034, February 26, 1979); and
    3. Will not have a significant economic impact, positive or
negative, on a substantial number of small entities under the criteria
of the Regulatory Flexibility Act.
    We prepared a regulatory evaluation of the estimated costs to
comply with this AD and placed it in the AD docket.

List of Subjects in 14 CFR Part 39

    Air transportation, Aircraft, Aviation safety, Incorporation by
reference, Safety.

Adoption of the Amendment

0
Accordingly, under the authority delegated to me by the Administrator,
the FAA amends 14 CFR part 39 as follows:

PART 39--AIRWORTHINESS DIRECTIVES

0
1. The authority citation for part 39 continues to read as follows:

    Authority: 49 U.S.C. 106(g), 40113, 44701.

Sec.  39.13  [Amended]

0
2. The FAA amends Sec.  39.13 by adding the following new AD:

2008-01-02 Viking Air Limited (Formerly Bombardier, Inc.): Amendment
39-15325. Docket No. FAA-2008-0410; Directorate Identifier 2007-NM-
338-AD.

Effective Date

    (a) This airworthiness directive (AD) becomes effective January
23, 2008.

Affected ADs

    (b) None.

Applicability

    (c) This AD applies to all Viking Air Limited Model (Caribou)
DHC-4 and (Caribou) DHC-4A airplanes, certificated in any category.

Subject

    (d) Air Transport Association (ATA) of America Code 54:
Nacelles/Pylons.

Reason

    (e) The mandatory continued airworthiness information (MCAI)
states:
    ``During a heavy maintenance check on a DHC-4 aircraft, an
operator discovered that both of the upper engine mount bracket
assemblies on one aircraft were cracked. Further inspection of the
operator's fleet confirmed that engine mount bracket assemblies on
five out of ten aircraft were also cracked.
    ``As an interim action to prevent failure of upper engine mount
bracket assemblies, this directive mandates a one-time fluorescent
penetrant inspection. Subsequent corrective action may be
implemented in the future pending results of the investigation.''
    Failure of the upper engine mount bracket assembly could result
in separation of the engine from the airplane. Corrective actions
include replacing any cracked engine mount bracket assembly with a
new assembly.

Actions and Compliance

    (f) Unless already done, do the following actions.
    (1) Within 10 flight hours after the effective date of this AD,
do a fluorescent penetrant inspection (FPI) for cracking of the
upper engine mount bracket assemblies having part numbers C4WM1090-1
and C4WM1090-2, in accordance with the Accomplishment Instructions
of Viking Alert Service Bulletin V4/0001, dated November 9, 2007.
Before further flight, replace any cracked engine mount bracket
assembly with a new engine mount bracket assembly, in accordance
with the Accomplishment Instructions of the alert service bulletin.
    (2) Within 7 days after completing the inspection required by
paragraph (f)(1) of this AD or within 30 days after the effective
date of this AD, whichever occurs later, report any crack found to:
Viking Technical Support, E-mail<EMAIL_ADDRESS>
telephone<PHONE_NUMBER>; toll free 1-800-663-8444; fax<PHONE_NUMBER>.
    (3) Actions done before the effective date of this AD in
accordance with Viking All Operators Message 2007-4-11-02, Revision
A, dated November 5, 2007, are considered acceptable for compliance
with the requirements of this AD.

FAA AD Differences

    Note: This AD differs from the MCAI and/or service information
as follows: No differences.

Other FAA AD Provisions

    (g) The following provisions also apply to this AD:
    (1) Alternative Methods of Compliance (AMOCs): The Manager, New
York Aircraft Certification Office, FAA, has the authority to
approve AMOCs for this AD, if requested using the procedures found
in 14 CFR 39.19. Send information to ATTN: George Duckett, Aerospace
Engineer, Airframe and Propulsion Branch, ANE-171, FAA, New York
Aircraft Certification Office, 1600 Stewart Avenue, Suite 410,
Westbury, New York 11590; telephone<PHONE_NUMBER>; fax (516) 794-
5531. Before using any approved AMOC on any airplane to which the
AMOC applies, notify your appropriate principal inspector (PI) in
the FAA Flight Standards District Office (FSDO), or lacking a PI,
your local FSDO.
    (2) Airworthy Product: For any requirement in this AD to obtain
corrective actions from a manufacturer or other source, use these
actions if they are FAA-approved. Corrective actions are considered
FAA-approved if they are approved by the State of Design Authority
(or their delegated agent). You are required to assure the product
is airworthy before it is returned to service.
    (3) Reporting Requirements: For any reporting requirement in
this AD, under the provisions of the Paperwork Reduction Act, the
Office of Management and Budget (OMB) has approved the information
collection requirements and has assigned OMB Control Number 2120-
0056.

Related Information

    (h) Refer to MCAI Canadian Airworthiness Directive CF-2007-26,
dated November 7, 2007; Viking All Operators Message 2007-4-11-02,
Revision A, dated November 5, 2007; and Viking Alert Service
Bulletin V4/0001, dated November 9, 2007; for related information.

Material Incorporated by Reference

    (i) You must use Viking Alert Service Bulletin V4/0001, dated
November 9, 2007, to do the actions required by this AD, unless the
AD specifies otherwise.
    (1) The Director of the Federal Register approved the
incorporation by reference of this service information under 5
U.S.C. 552(a) and 1 CFR part 51.
    (2) For service information identified in this AD, contact
Viking Air Limited, 9574 Hampden Road, Sidney, British Columbia V8L
5V5, Canada.
    (3) You may review copies at the FAA, Transport Airplane
Directorate, 1601 Lind Avenue, SW., Renton, Washington; or at the
National Archives and Records Administration (NARA). For information
on the availability of this material at NARA, call<PHONE_NUMBER>,
or go to: http://www.archives.gov/federal-register/cfr/ibr-locations.html
.

    Issued in Renton, Washington, on December 20, 2007.
Ali Bahrami,
Manager, Transport Airplane Directorate, Aircraft Certification
Service.
 [FR Doc. E7-25613 Filed 1-7-08; 8:45 am]

BILLING CODE 4910-13-P


Measuring Program Progress Work Group Update September 24, 2002 MPP Work Group ° Bill Adams ° Sue Briggum ° Grant Cope ° Steve Ebert ° Mark Giesfelt ° Robert Hickmont ° Aimee Houghton ° FredKalish ° RayLoehr ° Ed Lorenz ° Dick Stewart ° Mike Tilchin ° Jason White MPP Work Group: Purpose ° Provide review and reaction to initial Agency ideas on measuring progress of the Superfund program ( from the " charge")

° Three performance measures white papers in early development stage:

  Population Risk Reduction Indicators   Ecological Risk Reduction Indicators   Land Reuse Performance Measures MPP Work Group ° Status of Agency's Program Performance White Papers   Population Risk: initial draft provided to MPP work group   Ecological Risk: initial draft under development   Land Reuse: initial draft under development Relationship Between MPP Work Group and the Subcommittee ° MPP work group to provide interim, consultative feedback to Agency in early stage of performance measure development ° Work group committed to " quick turnaround"

( goal to provide work group comments within 6 weeks of receipt of draft white paper)

° Subcommittee charge allows for/ assumes more comprehensive recommendations to Agency on performance measures MPP Work Group: Activities and progress to date ° Developing additional performance measure concepts while white papers under preparation:

  Community and environmental justice   Consistency among cleanups   Cost measures   Institutional controls   Remediation and physical activity   Tribal measures ° Work group drafts ( once developed) to go to full Subcommittee MPP Work Group: Activities and progress to date ° Initial performance measure concepts developed by individual work group members ° Individual concept papers consolidated prior to discussion or editing ° Preliminary work group discussions revealed overlapping themes MPP Work Group: Activities and progress to date ° Structured work group review of concepts just underway ° Work group's critical path is to provide timely feedback on performance measures white papers MPP Work Group Path Forward ° Meeting 9/ 24 to develop MPP work group work plan; integrate with Subcommittee work plan ° Develop work group milestones, define roles and responsibilities ° Continue with conference calls; anticipate work group meeting late October/ early November


[Federal Register Volume 78, Number 206 (Thursday, October 24, 2013)]
[Notices]
[Pages 63479-63481]
[FR Doc No: 2013-24939]

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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-1276]

Meta-Analyses of Randomized Controlled Clinical Trials (RCTs) for
the Evaluation of Risk To Support Regulatory Decisions; Notice of
Public Meeting; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comments.

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

    The Food and Drug Administration (FDA or the Agency) is announcing
a public meeting to obtain input on scientific approaches for the
conduct and assessment of meta-analyses of randomized controlled
clinical trials (RCTs) to evaluate safety risks associated with the use
of human drugs or biological products within the framework of
regulatory decisionmaking. The term meta-analysis refers to the
combining of evidence from independent studies using appropriate
statistical methods. The purpose of the public workshop is to initiate
constructive discussion and information sharing among regulators,
researchers, health care providers, representatives from the
pharmaceutical industry and health care organizations, and others from
the general public, about the use of meta-analyses of randomized trials
as a tool for safety assessment in the regulation of pharmaceutical
products. The format of the meeting consists of a series of
presentations describing and illustrating the methodological issues
that arise in the use of meta-analyses to evaluate safety risks,
followed by a discussion of those issues from invited panelists and
audience members. This meeting satisfies an FDA commitment that is part
of the fifth authorization of the Prescription Drug User Fee Act (PDUFA
V). The input from the meeting will be used to develop a draft guidance
that describes best practices for the conduct of meta-analyses and
FDA's intended approach for the use of meta-analyses in regulatory
decision-making. FDA is also publishing a white paper to facilitate
discussion at the public meeting, which is available online at http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm360080.htm.
The public is invited to comment on this paper through Docket Number
FDA-2013-N-1276 and at the public meeting.
    Date and Time: The meeting will be held on November 25, 2013, from
8:30 a.m. to 4:30 p.m.
    Location: The public meeting will be held at FDA's White Oak
Campus, 10903 New Hampshire Ave., Bldg. 31, rm. 1503, Silver Spring, MD
20993. Entrance for public meeting attendees is through Building 1,
where routine security check procedures will be performed. For parking
and security information, please refer to http://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm.
    Contact: Indira Hills, Food and Drug Administration, Center for
Drug Evaluation and Research, 10903 New Hampshire Ave., Bldg. 21, Rm.
4508, Silver Spring, MD 20993,<PHONE_NUMBER>, FAX:<PHONE_NUMBER>, email:
<EMAIL_ADDRESS>    Registration and Requests for Oral Presentation: The FDA Conference
Center at the White Oak location is a Federal facility with security
procedures and limited seating. Individuals who wish to attend the
public meeting must register on or before November 18, 2013, by
visiting https://www.surveymonkey.com/s/QRKMGNY and contacting Indira
Hills (see Contact Person). Early registration is recommended.
Registration is free and will be on a first-come, first-served basis.
However, FDA may limit the number of participants from each
organization based on space limitations. Onsite registration on the day
of the meeting will be based on space availability.
    Time will be reserved during the meeting for planned presentations
from the audience. If you would like to present at the meeting, please
indicate this in your meeting registration. Time for audience
presentations is limited and will be assigned on a first-come, first-
served basis. Note also that time will be designated throughout the day
for general comments and questions from the audience following the
panel discussions.
    In this Federal Register notice, FDA has included specific issues
that will be addressed by the panel. If you wish to address one or more
of these issues in your presentation, please indicate this at the time
you register so that FDA can consider that in organizing the
presentations. FDA will do its best to accommodate requests to speak,
and will determine the amount of time allotted to each presenter and
the approximate time that each oral presentation is scheduled to begin.
An agenda will be available approximately 2 weeks before the meeting at
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm360080.htm.
    If you need special accommodations because of disability, please
contact Indira Hills (see Contact Person) at least 7 days before the
meeting.
    Streaming Webcast of the Public Meeting: A live webcast of this
meeting will be viewable at https://collaboration.fda.gov/metaanalysis1113/ on the day of the meeting. A video record of the
meeting will be available at the same web address for 1 year.
    Comments: Regardless of attendance at the public meeting,
interested persons may submit either electronic comments regarding this
document to http://www.regulations.gov or written comments to the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD. It is only necessary to
send one set of comments. Identify comments with the docket number
found in brackets in the heading of this document. To ensure
consideration, submit comments by December 16, 2013. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.
    Transcripts: Please be advised that as soon as a transcript is
available, it will be accessible at http://www.regulations.gov. It may
be viewed at the Division of Dockets Management (see Comments). A
transcript will also be available in either hard copy or on CD-ROM,
after submission of a Freedom of Information request. Written requests
are to be sent to the Division of Freedom of Information (ELEM-1029),
Food and Drug Administration,

12420 Parklawn Dr, Element Bldg., Rockville, MD 20857.

SUPPLEMENTARY INFORMATION:

I. Background

    On July 9, 2012, the President signed into law the Food and Drug
Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144).
Title I of FDASIA reauthorizes PDUFA and provides FDA with the user fee
resources necessary to maintain an efficient review process for human
drug and biological products. The reauthorization of PDUFA includes
performance goals and procedures for the Agency that represent FDA's
commitments during fiscal years 2013-2017. These commitments are fully
described in the document entitled ``PDUFA Reauthorization Performance
Goals and Procedures Fiscal Years 2013 through 2017'' (``PDUFA Goals
Letter''), available on FDA's Web site at http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf. Section IX
of the PDUFA Goals Letter, titled ``Enhancing Regulatory Science and
Expediting Drug Development,'' includes an enhancement to advance the
science of meta-analysis methodologies. As part of this enhancement,
FDA committed to hold a public meeting to engage stakeholders in a
discussion of current and emerging scientific approaches and methods
for the conduct of meta-analyses and to facilitate stakeholder input
regarding the use of meta-analyses in FDA's regulatory review process.
The public meeting announced by this notice will fulfill this
commitment.

II. Purpose and Scope of the Meeting

    The objectives of the meeting are to:
    1. Initiate constructive discussion and information-sharing about
best practices in meta-analyses of clinical trial data that can be used
to evaluate potential drug risks while limiting spurious findings,
    2. Share current experience regarding the criteria considered by
FDA to be important in making regulatory decisions when evaluating the
strength and quality of evidence provided by a meta-analysis, and
    3. Obtain input on specific issues identified by FDA on procedures,
methods, and potential sources of bias in the design, conduct and use
of meta-analysis.
    Although many external stakeholders conduct meta-analyses, FDA's
use of meta-analyses and other safety evaluation tools has the
potential to result in consequential regulatory actions, including
market withdrawal or concluding that a safety concern is not supported
by data. As a result, FDA must adopt a rigorous approach to these
analyses and be transparent regarding its evidentiary standards and how
it weighs the evidence of a meta-analysis in arriving at a decision or
regulatory action. The public meeting will focus on meta-analyses
conducted for purposes of safety evaluation using data from RCTs.
    FDA acknowledges that meta-analyses conducted to evaluate a
product's effectiveness, either overall or within specific subgroups,
are occasionally of interest to the Agency, but the primary use of
meta-analyses in the regulatory setting is for the assessment of
product risk. Furthermore, although meta-analyses of non-randomized
studies may be informative for the assessment of certain safety
endpoints, the issues related to such a meta-analysis are not the focus
of the meeting.
    FDA expects that this meeting will build upon prior stakeholder
feedback on the design, conduct, and assessment of meta-analyses
obtained at the ``DIA/FDA Best Practices for Regulatory Information
Synthesis of Randomized Controlled Trials for Product Safety
Evaluation'' workshop held on March 10 and 11, 2011, in Bethesda, MD.
    The public input from the meeting will be used to develop a draft
guidance describing best practices for the conduct and use of meta-
analyses of randomized controlled trials for the evaluation of risks
associated with the use of human drugs or biological products within
the framework of regulatory decisionmaking. The future guidance will be
intended for FDA reviewers, the pharmaceutical industry, and for third-
party entities that prepare or evaluate meta-analyses to assess the
safety of regulated products, as there is currently no FDA guidance in
this area. Specifically, this guidance will describe FDA's view of
various aspects of the criteria considered important when evaluating
the strength and quality of evidence provided by a meta-analysis.
    To facilitate discussions at the public meeting, FDA is publishing
a white paper on considerations in the conduct and use of meta-analyses
of RCTs that are intended to support regulatory decisionmaking about a
product's safety. This document is available on FDA's Web site at
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm360080.htm.

III. Scope of Public Input Requested

    FDA seeks input on a range of topics related to the design and
conduct of meta-analyses and the interpretation of meta-analysis
results when evaluating risk in the regulation of pharmaceutical
products. These include the following:
    1. Potential sources of bias that may arise in designing a meta-
analysis, including:
    a. Advance or prior knowledge of individual study results and their
influence on study selection.
    b. Lack of or inadequate pre-specification of the meta-analysis
hypothesis.
    c. Inclusion of the hypothesis-generating study in the meta-
analysis designed to confirm the hypothesis.
    d. Other sources of bias that may exist but cannot be identified.
    2. Potential for spurious findings because of the examination of
multiple hypotheses, endpoints, and subgroups, and use of data driven
analyses, in a meta-analysis.
    3. Methodological issues in the conduct of the meta-analysis,
including the following:
    a. The use of fixed versus random effects models in evaluating a
meta-analytic hypothesis, especially with regard to individual and
overall study power, study heterogeneity, and generalizability.
    b. The relative value of the use of frequentist versus Bayesian
methods for meta-analyses.
    c. The choice of statistical levels of uncertainty of the results,
including the significance level for the primary and secondary
hypotheses.
    d. The most appropriate methods to incorporate studies with few
events and those with no events.
    4. Issues related to the individual studies constituting a meta-
analysis, including:
    a. Measures of individual study quality, including availability of
protocols and amendments.
    b. Outcome and exposure ascertainment in each study.
    c. The use of patient-level versus study-level data.
    5. Issues related to the overall quality of the meta-analysis,
including the following:
    a. Whether there is adequate documentation of the pre-specification
and proper conduct of a meta-analysis, and more generally, how
researchers should document their methods, including the important
issues of pre-specification, in support of their proper conduct of a
meta-analysis.
    b. Use and pre-specification of the types of sensitivity analyses
to evaluate the impact of various sources of bias (see section III.1)
on the meta-analysis findings.
    c. Evaluating the results of a meta-analysis when one or a few
large studies dominate the findings (often recognized before the
analysis).

    d. The overall framework to evaluate the quality of the meta-
analysis; whether there is a basis for establishing a hierarchy of
evidence for judging the quality of the meta-analysis.

    Dated: October 21, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-24939 Filed 10-23-13; 8:45 am]
BILLING CODE 4160-01-P


EPA Registration Division contact: Sidney Jackson,<PHONE_NUMBER>

<Interregional Research Project #4>

<PP# 8E7341>

<	EPA has received a pesticide petition (PP) 8E7341 from Interregional
Research Project #4 (IR-4) Project Headquarters, 500 College Road East,
Suite 201 W, Princeton, NJ 08540 proposing, pursuant to section 408(d)
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d),
to amend 40 CFR part 180.>

 by establishing a tolerance for the combined residues of cyhalofop
(cyhalofop-butyl,
R-(+)-n-butyl-2-(4(4-cyano-2-fluorophenoxy)-phenoxy)propionate, plus
cyhalofop acid,
R-(+)-2-(4(4-cyano-2-fluorophenoxy)-phenoxy)propionicacid) and the
di-acid metabolite, (2R)-4-[4-(1-carboxyethoxy)phenoxy]-3-fluorobenzoic
acid in or on the raw agricultural commodity Rice, wild, grain at 0.03
parts per million (ppm).  EPA has determined that the petition contains
data or information regarding the elements set forth in section 408
(d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency
of the submitted data at this time or whether the data supports granting
of the petition. Additional data may be needed before EPA rules on the
petition.

<A. Residue Chemistry>

<	1. Plant metabolism. The metabolism of cyhalofop-butyl in plants
(rice) is adequately understood for the purposes of a tolerance in rice.
 Two separate foliar broadcast 14C NOR studies have been conducted.
Results indicated cyhalofop-butyl was metabolized to cyhalofop (acid
form) and then subsequently to the free and conjugated forms of the
di-acid and the FHPBA.  Other minor metabolites were also identified.
In addition, the rotational crop study showed no carryover of
significant cyhalofop-butyl related residues in representative crops.>

<	2. Analytical method. An adequate analytical method is available for
enforcement purposes; the method has been developed and validated to
determine the residues of cyhalofop-butyl, cyhalofop (acid form) and the
diacid metabolite in rice grain, straw and processed products.  The
method was based on capillary gas chromatography with mass selective
detection.>

<	3. Magnitude of residues. This petition for wild rice builds on the
previous registration of cyhalofop-butyl for use in traditional rice.
Both rice (Oryza sativa) and wild rice (Zizania palustris) are members
of the grass (Poaceae) subfamily (Bambusoideae) and tribe (Oryzeae).
Cultural practices and pest problems are similar enough that rice data
can be used for bridging data to wild rice.  Production practices,
growth requirements and physical characteristics are very similar for
rice and wild rice in California.  Because the proposed use pattern is
similar to the representative rice crop and based on previous guidance
from EPA, IR-4 proposes that the tolerance on wild rice be established
based on bridging to the existing residue data for cyhalofop-butyl in
traditional rice.

>

<B. Toxicological Profile The toxicological profile and endpoints for
cyhalofop-butyl which support this petition to establish these
tolerances were previously published in the Federal Register of June 4,
2002 (67 FRL-7178-5).  The relevant information is summarized below.>

<	1. Acute toxicity.  No appropriate endpoint attributable to a single
dose was identified; the EPA has not established an acute RfD for
cyhalofop-butyl.>

<	2. Genotoxicty. No evidence of genetic toxicity was observed when
cyhalofop-butyl was tested in a battery of in vitro and in vivo tests.>

<	3. Reproductive and developmental toxicity. Cyhalofop-butyl did not
have any effects on reproductive parameters at dose levels that induced
treatment-related effects in parental rats.  In addition, not
teratogenic potential was demonstrated in either rats or rabbits at dose
levels that induced maternal toxicity.>

<	4. Subchronic toxicity. Sub-chronic studies on cyhalofop-butyl have
been conducted and reviewed.  No endpoint was established for dermal
exposure because no systemic effects were observed in the 21-day dermal
study in the rat at doses up to 1000 mg/kg/day.  A short-term incidental
NOAEL of 4.3 mg/kg/day was selected as endpoint based on subchronic
feeding study in mice; this endpoint was also designated as conservative
surrogate for inhalation exposures.  However, for the extension of a
tolerance, no short-term oral, dermal or inhalation exposures are
considered.>

<	5. Chronic toxicity. A chronic reference dose (cRfD) of 0.01 mg/kg/day
has been established based on the 18-month feeding study in mice and the
application of an uncertainty factor of 100 (10X for interspecies
extrapolation and 10X for intra-species variation).  A 1X FQPA safety
factor was applied to the chronic endpoint.  Thus in the case of
cyhalofop-butyl, the cPAD = cRfD = 0.01 mg/kg/day.

Cyhalofop-butyl has not been classified in relation to carcinogenicity.
There was no evidence of carcinogenic potential under the conditions of
the mouse feeding study and there were no treatment-related increases in
tumors in the rat study.  However, the agency concluded the dosing was
too low to elicit frank toxicity in the original studies and deemed them
inadequate to assess carcinogenic potential (Federal Register of June 4,
2002 (67 FRL-7178-5).  In 2002, the EPA used a surrogate Q* value of
2.3x10-1 (mg/kg-day)-1 based on the structural analog diclofop-methyl to
assess cancer risk.  The agency stated use of this value was
conservative and protective for exposures to cyhalofop-butyl.
Subsequently, Dow AgroSciences provided the agency with mechanistic
arguments for classification of cyhalofop-butyl as “Not Likely to Be
Carcinogenic to Humans”.  Dow AgroSciences believes no assessment
against the cancer endpoint is required.>

<	6. Animal metabolism. Oral administration of cyhalofop-butyl, results
in rapid absorption, metabolism and excretion in the dog and rat.  The
butyl ester form is rapidly hydrolyzed to the acid form (cyhalofop) with
no significant quantities of unchanged parent in the plasma, tissues or
excreta.>

<	7. Metabolite toxicology. In all matrices (animal, plant,
environmental), cyhalofop-butyl is rapidly metabolized to the acid form,
cyhalofop.  Hence mammalian toxicity studies inherently include the acid
metabolite as part of the study.  Plant studies have identified the
diacid as a major metabolite; the diacid is more polar, and less lipid
soluble and is expected to be less toxic than the parent.>

<	8. Endocrine disruption. No evidence from any of the studies indicates
cyhalofop-butyl is an endocrine disrupter.>

<C. Aggregate Exposure>

<	1. Dietary exposure. Chronic exposure resulting from agricultural use
of cyhalofop-butyl on traditional and wild rice has been assessed for
the US population and sub-populations.  The dietary assessment model
DEEM-FCID version 2.16 was employed.  It estimates US consumption
patterns based on the Continuing Survey of Food Intake by Individuals
(CSFII) and EPA/USDA translation recipes from August 2002.  An estimate
of the residue level in each food (e.g., water or rice) is multiplied by
the average daily consumption estimate for that food.  The resulting
residue consumption estimate for each food is summed to determine the
total estimated exposure.  Exposure estimates are expressed in mg/kg
body weight/day and compared to the cPAD.

>

<	i. Food. For cyhalofop-butyl, a DEEM residue file for a Tier III
dietary assessment was prepared using the average residue value from
field trials (0.0066 ppm) for rice, the 0.03 tolerance for wild rice and
a cPAD = cRfD = 0.01 mg/kg/day.  Marketing data for Clincher* herbicide
treated acres was used to confirm the percent crop treated (PCT) value
used in the DEEM file as the 2nd adjustment factor.  The average number
of planted rice acres over the last 3 year period is 3,214,000 acres.
It is estimated that between % 1 and <5% of the treated fields utilize
the 2 applications of Clincher* herbicide allowed on the label.  The
average of the total treated acreage (Doune Agrotrak 2006) has been
conservatively adjusted by the lower 1% retreatment.  When the PCT is
calculated from the updated numbers there is excellent agreement with
the value originally projected for maturity of sales and used by the
EPA; the 2002 EPA projection was 17.6%, the revised number is 18.4%.  A
rounded value of 18% PCT has been used as the second adjustment factor
in the DEEM file.  Results indicate exposure to cyhalofop-butyl residues
is very low and represents less than 0.1 % of the cRfD for all
subpopulations.  Without the use of the PCT as the second adjustment
factor, all exposures are below 0.2% of the cPAD.>

<	ii. Drinking water. A 2001 surface water monitoring study in
California provided initial support for low levels of cyhalofop in
water.  The 2001 monitoring study was commenced just after initial
Section 18 Specific Exemption applications began in the area.  Although
fortified storage stability associated with the study indicated the
ester form was not stable under sampling and storage conditions of this
study (i. e. cyhalofop-butyl converted to cyhalofop (acid form)),
results indicated that no sample had a concentration of either
cyhalofop-butyl or cyhalofop above the limit of detection (LOD) of 0.5
ppb.

Prior to registration, preliminary estimates of drinking water
concentrations were made by the EPA using a modified GENEEC approach for
rice paddies and SCI-GROW.  Based on these results coupled with the 2002
surrogate Q* assessment, the label was modified to include a 7-day
holding pattern to allow time for concentrations of cyhalofop-butyl to
fall below 0.15 ppb.

Since that time, a second larger monitoring study of drinking water in
California has been concluded at a lower LOD.  Clincher* CA herbicide
was applied in California in 2002 under a Section 18 Specific Exemption.
 The 2002 monitoring study was conducted during the time of maximum use
of Clincher* herbicide in the Sacramento River Valley.  The study
monitored drinking water for cyhalofop-buyl and the 3 principal
metabolites (cyhalofop, cyhalofop-diacid and cyhalofop-amide).  Water
was sampled semiweekly from April 30 to July 18.  A total of 48 samples
were collected and analyzed.

Method GRM 99.07 (  NOTEREF _Ref184542359 \h  \* MERGEFORMAT  Error!
Bookmark not defined. ) was modified to achieve a limit of
quantitification of (LOQ) of 0.1 ug/L (ppb).  Neither cyhalofop-butyl
nor its metabolites were present in any of the drinking water samples
above the LOQ.  The limits of detections (LOD) were 0.04 ppb for
cyhalofop-butyl, 0.01 ppb for cyhalofop (acid), 0.01 ppb for
cyhalofop-amide and 0.04 ppb for cyhalofop-diacid.  Only one sample in
48 had a detection above the LOD and only cyhalofop-butyl (no
metabolites) was noted in that sample.  The lack of detections is
understood in light of the known rapid degradation of cyhalofop-butyl
and its metabolites in the environment.

Based on the drinking water monitoring information, 0.05 ppb (½ the
LOQ) has been incorporated as a single point estimate for both direct
and indirect water sources within DEEM.  This study is germane, because
the extension for wild rice was requested for use in California.
Dietary and water exposure were chronically assessed against the cRfD of
0.01 mg/kg/day.

All subpopulations have exposure estimates of < 0.1% cPAD.  Comparison
of DEEM output with and without the water component demonstrates the
additional water exposure has minimal impact on the overall exposure
assessment for all sub populations.>

<	2. Non-dietary exposure. There are no residential uses for this
compound.>

<D. Cumulative Effects>

<	For purposes of this tolerance petition, no assumption of a common
mechanism of toxicity for cyhalofop-butyl with other substances has been
made.>

<E. Safety Determination. >

<	1. U.S. population. Based on the dietary and water exposure
assessments, chronic dietary exposure to cyhalofop-butyl from registered
uses in rice and proposed uses in wild rice plus drinking water will
utilize <0.1% of the cRfD for the U. S. population.  Exposures below
100% of the cRfD are typically below the EPA’s level of concern
because the chronic RfD represents the level at or below which daily
dietary exposures over a lifetime will not pose appreciable risks to
human health.>

<	2. Infants and children. Per Federal Register of June 4, 2002 (67
FRL-7178-5), EPA has previously determined that an FQPA safety factor of
1X is applicable to all population subgroups for cyhalofop-butyl.  The
major identifiable subgroup with the highest chronic dietary exposure is
“non-nursing infants” and “all infants (<1 year)”, but each are
exposed to estimated residues of <0.1 % of the cPAD.  Dow AgroSciences
concludes with reasonable certainty that no harm will result to infants
and children from the aggregate exposure to cyhalofop-butyl residues
from registered and proposed uses.>

<F. International Tolerances>

<	A review of national websites and the Homologa MRL database indicates
several values have been set for cyhalofop in rice globally.  The US
value of 0.03 ppm in rice is higher than values in Europe and Latin
America, but lower than values established in most of the Pacific.  No
MRLs were noted by Codex.

Argentina, Brazil, Australia, Turkey	Rice	0.01	PPM

EU and various individual member states	Rice	0.02	PPM

Japan, South Korea and Taiwan	Rice	0.1	PPM

>

 PAGE

 PAGE   2