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Volume III - 6.5 ORA Method Development and Validation Process

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Other Laboratory Operations

Food and Drug Administration

DOCUMENT NO.:

III-06

VERSION NO.:2.7

Section 6 ORA Method Development and Validation Program

EFFECTIVE DATE:
04-02-04
REVISED: 01-09-14

 6.5.1 Laboratory Method Development and Validation Program (MDVP) Overview

The MDVP program supports five project categories:

Method Development

  • Projects are designed to develop and implement new methods.
  • Expected Outcome: A new method is implemented within the laboratory or method validation proposal for field wide implementation.

Method Validation

  • Projects are designed to evaluate innovator validated methods via peer reviewed assessment and inter-laboratory collaborations.
  • Expected Outcome: Validated regulatory method for field wide implementation.

Method Modification, Enhancement, and Extension

  • Projects are designed to extend an existing method to one or more additional matrices or analytes; projects designed to improve an existing method.
  • Expected Outcome: Modified method implemented within the laboratory or method validation proposal for field wide implementation.

Technology Exploration

  • Projects are designed to investigate and evaluate the usefulness and applicability of new technologies and increase our base expertise in these new technologies.
  • Expected Outcome: New technology accepted by one or more publications summarizing experiments performed, data collected, and recommendations.

Applied Studies

  • Projects are designed to test hypotheses related to FDA mission such as food safety, quality mechanisms, contaminants, analyte/matrix interactions, metabolism studies, degradation/depletion studies, process effects, stability studies. Although method development may be a component of these projects, it is not the primary focus.
  • Expected Outcome: Study, results, and impact for FDA described in one or more publications.

The MDVP process is designed to increase flexibility and timely planning of quality projects that benefit the agency. Each ORA laboratory is required to have an ongoing MVDP plan commensurate with their method development and validation time allotment. A good program is mission related and does not duplicate research work being done elsewhere.

Laboratory management, analysts, and Science Advisors have an important role in managing the program. Throughout the year, method development and validation progress and accomplishments are monitored and adjustments made to react to emerging analytical needs as they arise. Laboratories are expected to fully plan and accomplish their assigned method development and validation time.

 6.5.2 Method Development and Validation Program Procedures

6.5.2.1 Call for Proposals

ORS issues a request for proposals to ORA Laboratories and Centers that address critical Expected Research Outcomes (ERO’s) for the highest priority method development and validation projects that target validation, development, and enhancement of regulatory methods. Additionally, at this same time, laboratories may submit proposals for projects not listed in the call for proposals to be considered for future program needs.

The call for proposals issues at least annually with approximately a thirty (30) day deadline for proposal submission.

6.5.2.2 Proposal Preparation and Submission

NOTE: See ORA-LAB.012 for more detailed instructions.

The Office of Regulatory Science MDVP Call for Proposals issues annually and includes the following information:

  • a list of method development and validation projects requested for study that target critical Expected Research Outcomes (ERO’s);
  • information regarding the procedures required for the electronic submission of an FDA Component Automated Research Tracking System (CARTS) project proposal;
  • information concerning procedure for attachment of associated funding and experimental protocol information that should be submitted with the project proposal

A Method Development and Validation Project Proposal is completed electronically in CARTS by the project lead. Detailed instructions explaining how to complete a CARTS project application can be found on the ‘CARTS Guides and Templates’ webpage: http://inside.fda.gov:9003/it/Applications/ORAApplications/ucm289485.htm

  1. An MDVP proposal shall capture all information required by the electronic application form in CARTS, which includes the following information:
    • project title;
    • anticipated project start and completion dates and associated research projects;
    • research personnel;
    • relevant strategic and expected research outcomes;
    • estimate of FTE’s and timeline;
    • description of the problem the project intends to solve;
    • regulatory significance and relevance to the FDA mission;
    • public disclosure abstract;
    • protocol milestones/ experimental steps and anticipated completion dates;
    • selected project and progress report monitors/approvers
    • supporting documents which may include;
      • current issues and recent accomplishments in the field;
      • experimental plan/methods and materials
        • QC/QA controls, validation/extension protocol requirements from the appropriate source (e.g. Laboratory Manual, Volume II, ORA-LAB5.4.5, AOAC, BAM, CVM protocol, CFSAN/ORS microbiology protocol);
      • budget
        • funding requirements and declaration of funding support; and
  2. Additional information applicable to the following studies shall be included in the MDVP project proposal form and attached to the CARTS proposal using the ‘Add Citations and Documents’ capability of the application:

    Method validation studies
    • method validation protocol (e.g. single lab validation, collaborative study)
       
    Method Modification, Enhancement, or Extension
    • method description;
    • technical details of the modification; and
    • benefits of the modification.
       
    Continuing Projects
    • identify the accomplishments from the previous project;
    • propose a new plan of work or update Experimental Plan/Methods and Materials; and
    • update literature review.

See Appendix I for ‘Additional Project Proposal Information’ Template

All MDVP proposals are received by Office of Regulatory Science.

6.5.2.3 Proposal Review and Project Assignment

Proposals are electronically submitted to ORS through CARTS. Additional documentation/information not captured by CARTS forms are to be electronically attached to the project proposal using CARTS ‘Supporting Documents’ link. For field laboratory submissions, three lab management personnel are selected to electronically complete the initial evaluation of the project after which the proposal is forwarded to the ORS MDVP/CARTS Coordinator. ORS personnel are then assigned to finalize the review which may involve a review conducted internally and/or the assignment of the review to a scientist/science advisor in an FDA Center with expertise in the technology area. Within 30 days of submission a meeting will be held with ORS and science reviewers to determine the proper method pathway to follow. The project will either be recommended for the “Regulatory Pathway Approval” or the “Non-Regulatory Pathway Approval” (Appendix III).

Detailed instructions explaining how to review and approve project proposals can be found on the ‘CARTS Guides and Templates’ webpage: http://inside.fda.gov:9003/it/Applications/ORAApplications/ucm289485.htm

Laboratory and Center management acting as project approvers are responsible for ensuring that all research undertaken in their field labs or centers addresses the needs of the FDA as defined by the Expected Research Outcomes (ERO) requirements for the year. To ensure that supported research focuses on critical capacity building, as defined by the ERO’s, all research projects should be submitted and approved through CARTS before initiation of the actual research protocol.

Proposal review considers, but is not limited to, scientific merit (e.g. objectives are realistic and scientifically sound), mission importance, FDA impact, literature background, budget, timeframe, accuracy completeness of the submission, and likelihood of success.

Assignments will be based on review, FTE distribution, and availability of hours.

Because laboratories have specific capabilities and programs, resources will not be limited to only the high priority projects. Low priority projects will be considered if high and medium priority projects are addressed and resources are still available.

See Appendix III for ‘MDVP Approval Process Flowchart’

6.5.2.4 Regulatory Pathway Approval

After proposals are received, ORS will organize a meeting with the appropriate Center review scientists to discuss each project. This Review Committee will review each proposal and will either recommend the proposal for one of two pre-defined pathways (the Regulatory Pathway or Non-Regulatory Pathway), or the proposal will be rejected with comments to the investigators. Additionally, The Office of Foods through the Science and Research Steering Committee (SRSC) has developed validation guidelines of analytical food methods for Agency-wide implementation in a regulatory capacity. A Method Validation Subcommittee will have the responsibility to provide guidance and oversight to all Foods Program laboratories during the method development and validation process and will be the responsible authority for recommendations, evaluations and final approval of all validation studies.

If the MDVP Review Committee concludes that the project is appropriate for the Regulatory Pathway, the committee will notify the laboratory of its decision. The proposal will either be approved as written or approved with minor revisions. Final approval of the project proposal will result in its appearance on the CARTS Intramural Projects list and will represent the start date of the research.

Once the project is completed, all required progress reports and quarterly assessments must be completed and approved before the project will be listed as completed on the CARTS project list.

If the method studied merits consideration for validation, ORS will coordinate with the Centers to validate the method according to a recommended validation level, if applicable. After the method is validated at the appropriate recommended level, the method should be submitted for inclusion into a regulatory compendium (i.e AOAC), an approved FDA compliance program, or peer reviewed journal. If a method fails validation, it may be determined not fit for use and terminated or re-proposed for validation by the principle investigators.

6.5.2.5 Non-Regulatory Pathway Approval

If the MDVP Review Committee concludes that the proposal is not appropriate for the Regulatory Pathway, ORS will decide whether the proposal is appropriate for the Non-Regulatory Pathway. ORS will review the proposal to determine its value as a non-regulatory method such as for use as a laboratory screening tool. If ORS determines there is no value in this proposal as a non-regulatory method, the proposal will not be approved and the laboratory will be notified why.

If ORS does determine there is value in the project as a non-regulatory method, the MDVP Coordinator will send the laboratory a review decision as approved or approved with minor revisions. The MDVP Coordinator will grant the proposal research hours and the laboratory will move forward with the accepted project. Once the laboratory completes the research, they will present their data and conclusions to ORS for final evaluation.

ORS will then review the data and conclusions and decide if the project is fit for non-regulatory use. If ORS concludes that the project is not fit for non-regulatory use, the laboratory will be notified that further research is necessary. If ORS does conclude that the project is appropriate for non-regulatory use, ORS and the laboratory will again present the project, along with the new data and conclusions, to the MDVP Review Committee for inclusion into the Regulatory Pathway.

If the MDVP Review Committee concludes that the project is now appropriate for the Regulatory Pathway, the project will proceed down this pathway (see Section 6.5.2.4) at the point of method validation. If the MDVP Review Committee concludes that the project is still not appropriate for the Regulatory Pathway, the laboratory should proceed with publication of the project in a peer-reviewed journal or as a Laboratory Information Bulletin (LIB).

6.5.2.6 Project Execution and Reporting

Projects are managed and executed at the laboratory.

Accurate and timely reporting of research hours are provided through FACTS. Researchers should enter the CARTS Project number to which the hours apply in the FACTS report ‘Description’ textbox. The number of FACTS miscellaneous hours reported are expected to correspond to the FTE’s recorded in the CARTS project record:

  • report hours under the Miscellaneous Operation Screen.
  • FACTS instructions
    1. select Navigate
    2. select Miscellaneous Accomplishment Hours
    3. select Create
    4. enter Research Operation Code: 01 or 02
    5. enter accomplishment dates, district
    6. enter Reference Number: Research Project Number (if applicable)
    7. enter Description: “CARTS project number
    8. enter name, hours, applicable PAC code

The recommended timeline and schedule for project completion is:

≤ 500 hours = 6 months
> 500 hours = 12 months

The project status is monitored by progress reports, quarterly assessments and a final report/LIB that are electronically submitted and approved within the CARTS application. Progress report updates are completed on a semi-annual basis and approved by two laboratory management personnel. Quarterly assessments of progress are completed four times a year by the project lead’s first level approver. The progress report should include information related to the successful completion of technical milestones that have been designated in the project record. Additional information regarding the regulatory impact, publications, presentations, collaborative studies, adoption as official methods (adoption by other field and headquarters laboratories), and inclusion in compliance programs can be electronically attached to the project record as an addendum. The report and assessment are designed to assist the laboratory managers and ORS coordinators in ensuring satisfactory progress toward stated research goals and with planning for future research support.

Detailed instructions explaining how to review and approve progress reports and assessments can be found on the CARTS Guides and Templates webpage: http://inside.fda.gov:9003/it/Applications/ORAApplications/ucm289485.htm

Upon project completion, a final project report, a Laboratory Information Bulletin or article for a peer- reviewed journal is submitted to ORS summarizing results and conclusions. The wording of the LIB title should correspond to the CARTS project title and the CARTS project number must be indicated directly below the title.

See Appendix II, ‘Laboratory Information Bulletin Format’ for guidelines.

6.5.2.7 Presentation, Assessment, and Implementation

The basic product of scientific research is information. Dissemination of information ensures others interested in the problem can use the data. To accomplish this, ORA encourages and supports several types of research products.

Scientific Articles

All MDVP outcomes, at a minimum, should be published as a Laboratory Information Bulletin (LIB), or preferably published in a peer-reviewed journal. Manuscripts for outside publications must be reviewed and approved for technical correctness and adhere to Agency and ORA policy and guidance on review and clearance. See Section 6.6. LIB or outside publications require confirmation of a corresponding CARTS project title and project number in order to be considered or approved for publication.

Authors are expected to produce manuscripts that are coherent, scientifically sound, and likely to be accepted for publication.

Local management is responsible for funding and ordering reprints. Manuscripts intended for publication as an LIB must be reviewed and approved by the Science Advisor, Laboratory Director, and District Director before submission to ORS.

Results may be presented at scientific meetings as lectures or audio-visual sessions. Review and clearance of the presentations is in accordance with Agency and ORA policy. See section 6.6.

If the intellectual property produced by authors has potential for patent application or licensing, the Laboratory Director should submit PHS Employee Invention Form (PHS-6364) with other supporting materials to CRADA for further evaluation. Any publication submission including LIB will be withheld pending the CRADA decision.

Studies

Some studies will become basis for new projects (e.g. new methods go on to validation studies) and be listed in the next call for proposals

After the study initiator has performed ruggedness testing or intra-laboratory collaboration to ensure that a method is likely to succeed in a full-scale study, a request, accompanied by the method and collaborative study protocol, is sent to ORS to select collaborators for the study. ORS will review the proposed study for suitability of the method and clarity of the directions as stated in the protocol. ORS issues the call for collaborators and informs the initiator of those who agree to participate. In an AOAC collaborative procedure, the initiator must obtain approval from local management before requesting Associate Referee status from the appropriate AOAC General Referee.

Assessment and Implementation

ORS, in conjunction the appropriate Center or headquarter offices, and with ORA laboratory management input, can determine how methods are to be implemented. Methods can be implemented through compliance programs, FERN tests, and assignments. New or improved methods, validated methods, adoption of new technology or rapid methods can be implemented field wide.