Internal Guidance for the Efficacy Protocol Review Process
Purpose: To provide Antimicrobials Division (AD) staff with
guidance for efficacy protocol reviews
Introduction:
If an accepted efficacy test protocol does not
exist, then an Agency protocol review is needed. In such cases, the steps
as outlined in this guidance should be followed by AD staff.
There may be situations where guidance is available
for modifying an existing efficacy test method. These instances may involve
a minor modification to an existing efficacy test method. However, the
Agency should be consulted as to whether modification of an existing protocol
will allow adequate assessment of a products performance.
In situations where there is no guidance available
for modifying an existing protocol, a great amount of time and effort
on the part of both the Agency and the applicant, as well as a great amount
of discussion and guidance on protocol design, development and validation
may be required. Depending on the complexity of the proposed protocol
and/or use pattern, AD may consult with scientists outside of the Agency
and/or other OPP scientists.
AD Staff Responsibilities:
1.
AD staff will strongly encourage the applicant to schedule a meeting as
soon as possible to discuss protocol design and development with the appropriate
AD Product Manager (PM), prior to submitting a formal request to review
a protocol. An agenda should be submitted prior to the meeting.
Note: There is no requirement that a meeting
occur prior to Agency review of a protocol. However, a meeting is strongly
advised so that issues can be surfaced and discussed early in the protocol
review process. Ideally, meetings with the applicant should occur
prior to a protocol being formally submitted to the Agency for review.
A "draft" protocol may be submitted for discussion along
with pertinent questions that the applicant wants the Agency to address.
It should be noted that such a meeting will not substitute for a formal
Agency review of a new protocol.
2. To ensure
that meetings are productive, AD staff will communicate to the applicant
that background materials should be provided to AD staff preferably two
weeks or more prior to the meeting. These materials should include a brief
description of the subject product, its intended use pattern, a proposed
label listing the related claims, the draft protocol (if available), and
any supporting data.
3. AD staff
will also communicate to the applicant that the applicant is best served
to have present at the meeting individuals with sufficient technical expertise
to explain the product, the proposed protocol, and any supporting data.
4. AD staff
will inform the applicant that, during the initial meeting, the applicant
should present a detailed description of the product. If available, pictures,
samples, or product demonstrations would be extremely helpful. The presentation
also should include a complete listing of use sites expected to be proposed,
label claims, and details of preliminary efficacy testing and data.
5.
Prior to meeting with the applicant, an internal meeting will be scheduled
between regulatory and science staff and Branch Chiefs. Typically, the
participants at this meeting should include: the Product Manager, PM Team
Reviewer, Efficacy Team Leader, Efficacy Scientist, and Regulatory and
Product Science Branch Chiefs, and the AD Liaison for the efficacy protocol
review process. If the applicant has requested a meeting, the internal
meeting will be scheduled by the appropriate Product Manager.
Note: If the applicant has chosen to submit
a protocol for review but has not requested a meeting with the Agency,
the internal meeting will take place within 10 working days of
receipt of the protocol in AD. If the applicant has not requested a meeting,
the internal meeting will be scheduled by the AD Liaison. In such cases,
it is the responsibility of the PM to provide the liaison with all materials
pertaining to the protocol submission as soon as they are received.
6. To ensure
prior tracking of protocol submissions, the PM must send an electronic
message to the AD Liaison and carbon copy his/her Branch Chief acknowledging
receipt of the protocol in the division and distribution of it to the
appropriate persons/branch (i.e., AD Liaison and the Product Science Branch).
7. Prior
to the internal pre-meeting, the Product Science Branch (PSB) scientists
are to have completed an initial review of the submission and are expected
to be prepared to discuss questions and concerns with the regulatory staff.
PSB scientists are to have reviewed the submitted background materials
prior to the meeting with the applicant.
8. At the
internal pre-meeting, the submitted background materials are to be reviewed
and the following determinations made:
A) the performance standard for the proposed
claims,
B) practicality of the "directions for use,"
C) the appropriate "control" scenario for efficacy testing,
D) the need for additional science policy guidance,
E) whether expert panel review is required and the type of expertise needed,
and
F) whether other Agencies, such as USDA, FDA, or CDC, should be contacted.
Note: If the product under consideration is a new technology or if
there are questions about the performance criteria for proposed claims,
it is possible that new policy may need to be established before proceeding
with protocol review. In such cases, management (Division Director and
Associate Director) needs to be notified as soon as possible. Similarly,
if questions exist regarding the appropriate control scenario for efficacy
testing or if the "directions for use" are deemed to be impractical,
management needs to be notified as soon as possible prior to meeting with
the applicant.
9. AD will
provide the appropriate regulatory and scientific staff at the protocol
design and development meeting with the applicant. The Product Manager
needs to schedule the meeting with the applicant at a date and time when
key staff are able to attend.
10. If deficiencies
have been identified in the protocol submission, then the package is to
be logged out of the tracking system (PRAT) and returned to the applicant,
noting the deficient items and requesting a resubmission.
11. The Product
Manager must provide minutes of the meeting to the applicant within 30
calendar days following the meeting and circulate them to all in attendance.
The Product Manager must circulate the minutes internally for comments/change
prior to sending them to the applicant.
12. If the
protocol is to be reviewed "in-house," AD shall make every effort
to provide written comments on the proposed protocol or modification within
120 calendar days of receipt of the protocol and background materials.
However, if it was determined at the internal meeting (see item 9) that
appropriate expertise is not available to review a protocol, the protocol
will be sent outside of the Agency for expert scientific review. AD shall
endeavor to finalize a decision based on the recommendations of such peer
review panel within 365 calendar days of first submission of the
protocol to the division.
Note: Occasionally, due to resource constraints,
it will be necessary to send a draft protocol out for external review
even though appropriate expertise exists "in-house." In such
cases, AD will make every effort to make a final decision regarding the
protocol acceptability within 120 calendar days of receipt of the
protocol and background materials in AD.
13. If it
is determined that the protocol will be submitted to the expert panel,
the PM needs to take steps to see if the protocol can be submitted without
a confidential claim and with a confidential claim waiver/release to allow
its transmittal to the expert panel for review. To prevent delays in the
review process, the applicant will be encouraged to submit protocols that
are not stamped "confidential,"along with a waiver of any possible
confidential claims and a release to allow its transmittal to the expert
panel for review. In the event a protocol is stamped "confidential,"
the PM will contact the applicant and, consistent with applicable requirements
and procedures, request a protocol which is not designated as "confidential,"
along with a waiver of any possible confidential claims, and a release
to allow its transmittal to the expert panel for review. The Agency will
take necessary precautions to assure that the panel members are aware
that the protocols must not be released to or discussed with the public.
The panel members will be made aware that the action/review may not be
released until it is designated final by the Agency.
14. The following
procedures will be followed if an expert panel review is needed. The list
of current panel members is attached.
A. The AD
Liaison distributes protocol and supporting information (once any actual
or potential claims are waived and released by the applicant) to the selected
panel members and to the Fort Meade laboratory (contact person is the
laboratory team leader). Also, the liaison contacts other agencies as
appropriate. The protocol will be transmitted with a cover letter stating
the request, the due date, and the point of contact at the Agency. There
must be no interaction between the experts and the applicant without an
EPA representative being present. If there is a need for such interaction,
the requestor must contact the AD liaison to discuss the need for such
interaction and to facilitate any necessary discussions.
B. Protocol
reviews from the selected panel members will be received by the AD Liaison
and forwarded to the appropriate Regulatory Branch Product Manager. The
liaison is also responsible for tracking the protocol distributions and
receipt. If the AD Liaison does not receive the protocol by the assigned
due date, the liaison needs to get a projected completion date from the
selected panel member(s) and forward the revised due date to the Product
Manager.
C. Upon receipt
of the selected panel members reviews, if there is no concurrence
among those panel members, the AD Liaison schedules a conference call
with the selected panel members to discuss the issue(s). The Division
Director, Product Science and Regulatory Branch Chiefs, and the appropriate
regulatory and efficacy staff also need to be present for the conference
call. Once agreement is reached, the Efficacy Team scientist prepares
the Agency protocol review for the required signatures. If there is no
agreement among the panel members, the Divisions management will
determine the approach that will be taken.
15. The efficacy
scientist will format the protocol review as follows and submit it to
the Efficacy Team Leader, who will forward the review to the Division
Director (through the Product Science Branch Chief), prior to sign-off.
A. Background
B. Use Directions
C. Agency Standards for Proposed Claims
D. Summary of the Submitted Protocol (This should not be an
assessment or critique.)
E. Comments on the Proposed Protocol (general or, preferably, bulleted
discussion of how the protocol will or will not facilitate assessment
of the products ability to meet claims when used as directed.)
F. Conclusions and Recommendations (These must be numbered
and structured in such a way that the applicant can easily make protocol
revisions and complete an acceptable efficacy study, ideally without the
need for additional Agency review of the protocol.)
16. Upon
receipt of the draft protocol review, the Division Director will forward
the review to the AD liaison for distribution to the management team for
review and comment. After incorporation of comments received, the Efficacy
Team Leader (through the Product Science Branch Chief) will forward the
revised protocol review to the Division Director again (via E-mail) for
concurrence prior to sign-off. The Efficacy Team Leader will forward the
final/signed review to the appropriate PM and to the AD liaison.
17. The AD
liaison will maintain a computer storage of the final protocol reviews,
including expert panel reports. Once registration has been granted and
any confidentiality issues resolved, the PM will submit an electronic
copy of the final review to the Administrative Team Leader for posting
on the AD webpage.
General Protocol Design Criteria for Consideration by the Science
Reviewers:
1. Will the protocol allow assessment of the products
ability to meet the established performance standard for claims made?
- Does the method reflect the proposed use directions?
- Are the test organisms those specified in the established performance
standard?
2. Is the method reliable and does it provide reproducible results?
- Independently validated in three laboratories (one of which is the
primary laboratory developing the protocol)? (Guidance on independent
laboratory validation will be provided in a companion document.)
- Is the method statistically valid? (Guidance on statistical validity
criteria will be provided in a companion document.)
3. Is the method practical (for other antimicrobial products and for
enforcement purposes)?
- Are the costs feasible?
- Can the study results be obtained in a reasonable time period?
- Are equipment and supplies available from reliable sources?
Antimicrobials Division
Efficacy Protocol Review Expert Panel
Larry R. Beuchat, Ph.D.
University of Georgia
Griffin, GA 30223-1797
Robert E. Brackett, Ph.D.
Food and Drug Administration
Washington, DC 20204
Ms. Myra Cheng
California Department of Pesticide Regulation
Sacramento, CA 95812
Mr. John P. Douglas
Franklin Square Hospital Center
Baltimore, MD 21237-3998
P. Doyle, Ph.D.
University of Georgia
Griffin, GA 30223-1797
Tom Lessie, Ph.D.
University of Massachusetts
Amherst, Massachusetts 01003
John LiPuma, Ph.D.
Medical College of Pennsylvania
Philadelphia, Pennsylvania 19118
Syed Sattar, Ph.D.
University of Ottawa
Ottawa, Ontario Canada K1H8M5
Arnold Smith, M.D.
University of Missouri Columbia
Columbia, Missouri 65212
Mark Sobsey, Ph.D.
University of North Carolina
School of Public Health
Chapel Hill, NC 207599
Pam Sokol, Ph.D.
University of Calgary
Calgary, Ab T2N 4N1
Mr. Stephen Tomasino
U.S. EPA Fort Meade Laboratories
Fort Meade, MD 20755
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