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 product’s 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.

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 Division’s 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 product’s 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 product’s 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?

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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