sop validation kits veterinary diagnosis

8/13/2019 SOP Validation Kits Veterinary Diagnosis

http://slidepdf.com/reader/full/sop-validation-kits-veterinary-diagnosis 1/26

Standard Operating Procedure (SOP) for OIE

Validation and Certification of Diagnostic Assays

Information and Administrative Forms

This document (Information and Administrative Forms) describes the background and procedures for

applications to the OIE for recognition and registration of kits for veterinary diagnosis and studies and gives theforms for confidentiality agreements and declarations of interests.

The 'Application Form for Validation and Certification of Diagnostic Tests by OIE' is available for downloadingon the OIE website.

Registration will allow the use of the OIE logo on associated kit materials, recognising the status of a test asvalid for the defined fitness for purpose, or purposes, according to OIE parameters. Registered tests will be published on the OIE web pages and in hard copy.

Successful OIE recognition and registration will depend on supplying quality controlled validation data todemonstrate the fitness of the test or test system to fulfill a defined task or tasks.

Fitness for purpose criteria are further explained in this document.

The ‘Application Form for Validation and Certification of Diagnostic Tests by OIE’ allows applicants to submitdata in a logical way so that scientific reviewers, appointed by the OIE, can assess tests against criteria ofvalidation and fitness for purpose.

Tests may include immunological or molecular-based systems relevant to the veterinary area including zoonotic

diseases. Where a test system is submitted that involves multiple test procedures, then validation of all tests inthat system is required (for example ‘Test A’ as a screening test, with positive samples submitted to ‘Test B’ as aconfirmatory procedure).

Anyone can apply for OIE recognition if they supply the necessary proof of fitness for purpose and can justify toend users, with validation data, the potential applications of the kits .

The OIE aims to produce a register of recognised assays fit for one or more purpose(s).

OIE Members wish to move towards improvement in quality and enhanced confidence in assays and greaterassurance that they correctly classify animal disease status. Therefore they need assays that are validatedaccording to OIE criteria.

OIE 2009



SOP, I NFORMATION AND ADMINISTRATIVE FORMS

SOP for OIE Validation and Certification of Diagnostic Assays

Version 2.1 (06/2009) 3

2.4.5. International recognition .................................................................... ............................................................15

SECTION 3. GUIDANCE ON CONFIDENTIALITY AND DISCRETION ............................................................16

3.1. DUTY OF CONFIDENTIALITY ....................................................................................................................................16 3.2. CONTINUING DUTY OF CONFIDENTIALITY ...............................................................................................................16

SECTION 4. GUIDANCE ON CONFLICTS OF INTERESTS..................................................................... ............17

4.1. I NTRODUCTION .......................................................................................................................................................17 4.2. WHO SHOULD DECLARE? ........................................................... ................................................................ .............17 4.3. WHAT TO DECLARE? ........................................................ ............................................................... ........................17

4.3.1. What is an interest?.........................................................................................................................................17 4.3.2. What are direct and indirect interests?...........................................................................................................18

4.4. WHEN TO DECLARE? ........................................................ ............................................................... ........................18 4.4.1. Initial declaration............................................................................................................................................18 4.4.2. Appointment as CPR or reviewer....................................................................................................................18 4.4.3. Spontaneous declarations ...............................................................................................................................18 4.4.4. Updates ...................................................... ................................................................... ..................................19

4.5. OPERATIONAL ASPECTS ..........................................................................................................................................19 4.5.1. Tasks of OIESVCRDA ....................................................... ................................................................. .............19

4.5.2. Obligations of individuals concerned..............................................................................................................19 4.5.3. Meeting proceedings ............................................................... ...................................................................... ..19

SECTION 5. FEES FOR APPLICATIONS FOR THE OIE VALIDATION AND CERTIFICATION OF

DIAGNOSTIC ASSAYS.................................................................................................................................................20

5.1. BASIC FEES..............................................................................................................................................................20 5.2. R ENEWAL FEE .........................................................................................................................................................20 5.3. METHOD OF PAYMENT ............................................................................................................................................20

SECTION 6. OIE REGISTRATION OF A DIAGNOSTIC TEST AS VALIDATED AND CERTIFIED - RULES

OF RECOGNITION.......................................................................................................................................................21

APPENDIX: DECLARATION FORMS ........................................................... ..........................................................22

FORM A1. CONFIDENTIALITY U NDERTAKING FOR THE EXPERT ADVISERS ..................................................................23 FORM A2. CONFIDENTIALITY U NDERTAKING FOR THE STAFF OF THE OIE AND THE OIE COLLABORATING CENTRE

AND BIOLOGICAL STANDARDS COMMISSION MEMBERS.................................................................................................24 FORM A3. PUBLIC DECLARATION OF I NTERESTS OF R ELEVANT STAFF MEMBERS OF THE OIE ...................................25 FORM A4. PUBLIC DECLARATION OF I NTERESTS OF THE R ELEVANT MEMBERS OF COMMITTEES AND R EVIEWERS.....26





Version 2.1 (06/2009) 4

Section 1. Background information and procedural process

1.1. Legal basis

During the 71st General Session of the OIE in May 2003, the International Committee adopted Resolution No. XXIX.This Resolution endorses the principle of validation and certification of diagnostic assays (test methods) for infectiousanimal diseases by the OIE and gives a mandate to the Director General of the OIE to set up the specific standard procedures to be used before the final decision on the validation and certification of the diagnostic assay is taken by theOIE International Committee.

The Resolution establishes that ‘fitness for purpose’ should be used as a criterion for validation.

The concept of ‘fitness for purpose’ indicates the purpose of the test, e.g.:

• Demonstrate freedom from infection in a defined population (country/zone/compartment/herd)

o “Free” with vaccination.o Historical freedom.o Re-establishment of freedom after outbreaks.

• Certify freedom from infection or agent in individual animals or products for trade/movement

purposes.

• Eradication of infection from defined population.

• Confirmatory diagnosis of suspect or clinical cases (includes confirmation of positive screening test).

• Estimate prevalence of infection to facilitate risk analysis (surveys/herd health schemes/diseasecontrol).

• Determine immune status in individual animals or populations (post-vaccination).

The Resolution states that the Director General of the OIE should make provisions to establish a registry of assays with

levels of validation specified. He is given the mandate to review the procedures involved in the timely approval ofassays and is authorised to recover, if necessary, any costs incurred in the process of validation, certification and

registry of such assays. Resolution No. XXIX establishes that OIE Reference Laboratories should be intimatelyinvolved with the validation procedures and that they should establish serum/sample reference collections to be used forvalidation in line with their mandates.

1.2. Purposes

The aim of the procedure for diagnostic kits is to produce a register of recognised assays for OIE Members and for test

manufacturers. OIE Member need assays that are known to be validated according to OIE criteria in order to improvethe quality of assays, to ensure that the test can be used to correctly establish animal disease status and to enhanceconfidence in assays. This process of producing a register of recognised assays will provide greater transparency and

clarity of the validation process and also a means for recognising manufacturers that produce validated and certifiedtests in a kit format. In order to render the process transparent, all results of the test validation procedure by the OIE will be included in detailed form on the OIE web site.

The submission form, the “Application Form for Validation and Certification of Diagnostic Tests by OIE”, is used to

apply for certification by the OIE of a diagnostic test as 'fit for purpose'. The form guides an applicant through theapplication process by indicating important features of test validation to enable the reviewers to come to a rapid

conclusion about any test's validation status (the extent to which data supports the claims for a particular purpose).

'Fit for purpose' means that the test has to be validated to such a level to show that the test’s results can be interpreted tohave a defined meaning in terms of diagnosis or another biological property being examined. It is no use reporting that atest will detect antibodies to foot and mouth disease (FMD) or any other disease agent or that a polymerase chainreaction (PCR) can detect a genome to a particular analytical level. There must be proof for the purpose of the test in a

diagnostic / detection setting. Enough information has to be given to show that this is a valid statement. There is a needto define the purpose of the test and demonstrate that sufficient data have been obtained to ascribe some confidence toits use, in statistical terms, to answer a defined question.





Version 2.1 (06/2009) 5

Examples:

1. Fitness for purpose to detect antibodies against non-structural proteins for FMD is no useful.

2. Fitness for purpose to detect antibodies against non - structural proteins for FMD in pigs, cattle, sheep and goats to

allow differentiation of infected and vaccinated animals on a herd basis following an outbreak to declare a country freefrom disease, is better.

1.3. Procedure for the submission of a dossier

1.3.1. General outline of the procedure

In order to start the procedure, the completed 'Application Form for Validation and Certification of Diagnostic Tests byOIE' and the applicable fee should be sent by the applicant to the OIE Director General (one complete copy of theapplication in a suitable PC-compatible medium, e.g. CD-ROM (preferred electronic format: Word), and one copy in

paper format).

Director GeneralOIE Procedure for validation and recognition of the diagnostic test

OIE12, rue de Prony75017 ParisFrance

The OIE Central Bureau, through the OIE Secretariat for Validation, Certification and Registry of Diagnostic Assays(OIESVCRDA), will be able to provide more procedural guidance during the pre-submission phase and to prepare the

assessment process.

OIESVCRDA

Dr François DiazSecretariat for Validation, Certification and Registry of Diagnostic Assays, Scientific and Technical Department.

OIE12, rue de Prony75017 Paris, France

Tel: 33 (0)1 44 15 19 69, fax: 33 (0)1 42 67 09 87

Email: [email protected]

The conditions, including the date of submission, should be defined in accordance with the OIESVCRDA to optimisethe timing of the procedure. After receipt of the above-mentioned elements, the OIESVCRDA will check the form and process the application within 30 days. During this phase, the OIESVCRDA is allowed to ask the applicant for furtherinformation to obtain a valid application (should this be the case the clock is stopped while awaiting its arrival).

Most communications between OIESVCRDA and other persons involved in the procedure will be by email

except for informing whether the application is valid before the start of the procedure and whether the

diagnostic test is validated and certified at the end of the procedure. In these cases, the communication will be by

letter. Receipt of e-mail will be acknowledged electronically.

When the application is considered valid, the applicant will be informed by the OIESVCRDA by means of a lettergiving the names of the chairperson and reviewer(s) for the diagnostic test assessment, a procedure number and atimetable for assessment.

The OIESVCRDA, in consultation with the President of the OIE Biological Standards Commission (BSC), should

propose to the OIE Director General an appropriate panel of reviewers included in the OIE list of approved reviewers.The review panel should be composed of a chairperson and at least one reviewer. The number of reviewers will be

proposed by the OIESVCRDA in accordance with the kind of application under review. When selecting the review panel, the OIESVCRDA, with the support of the President of the BSC, will ensure that there is no conflict of interest.





Version 2.1 (06/2009) 6

An undertaking of confidentiality will be signed by all the persons involved in the assessment. Throughout the procedure, the OIESVCRDA is the contact point for the applicant. Exchanges between the chairperson of the review panel (CRP) and the applicant are possible during the assessment of the dossier provided that the OIEVCRDA is dulyinformed.

The total duration of the procedure will be 135 days. Once the clock starts, the reviewers should provide an initial report

within 30 days to the CRP. The CRP should prepare a consolidated report and liaise with the other reviewers. Ifquestions are to be sent to the applicant, the clock is stopped until answers are received.

An assessment report should be sent by the CRP to the OIESVCRDA before day 60. If any questions arise, theOIESVCRDA will send them to the applicant. After receipt of the answer to the questions and acceptable clarification,the CRP, in consultation with the reviewer(s), should provide a final assessment report with a clear proposition within

15 days.

At the next meeting of the BSC, the CRP, if necessary, will present the assessment report and conclusions. If successful,the BSC will then propose to the OIE Director General to place the diagnostic test on the register. The OIE DirectorGeneral will take the final decision. The OIESVCRDA will notify the applicant within 15 days of a successfulapplication and the information will be published on the OIE web site stating that the test has been approved by the OIEDirector General and is proposed for inclusion in the register.

The final inclusion in the OIE register will be discussed and voted on by the OIE International Committee (comprising

the Delegates of the OIE Members) during the General Session through the presentation of a Resolution drafted by theBSC containing a list of recommended validated and certified assays to be registered by the OIE. The final inclusion iseffective within 7 days of the vote of the OIE International Committee.

In cases where the BSC recommends that the test not be included in the register, the applicant may appeal the decisionin writing; at his request, the applicant could appear before the BSC to give an oral appeal. If the appeal is rejected by

the BSC, the final decision of the Director General will be notified to the applicant by the OIESVCRDA.

Once a diagnostic test is placed on the register, any changes to the test must be declared and justified in advance beforeapproval for implementation.

The OIE Central Bureau, through the OIESVCRDA, will require an annual declaration from the applicant stating thatthe test remains valid and should be retained on the registry. Every 5 years, the OIE will insure that the diagnostic testremains within the current state of the art.

1.3.2. Role of the OIESVCRDA

The OIESVCRDA will operate under the Scientific and Technical Department.

The OIESVCRDA will be responsible for:

• Providing procedural guidance during the pre-submission phase;

• Monitoring regularly declarations and preliminary appraisals of compatibility of the interests declared by the

individuals concerned;• Co-ordinating the acceptability of the application submitted and monitoring compliance with the timeframe

provided for processing the application;

• Providing assistance to the Central Bureau, the Applicant, the BSC, the CRP and reviewer(s);

• Verifying that documents are circulated in a timely manner;

• Organising any meeting, as requested by the Central Bureau, the BSC and the CRP;

• Preparing the scientific dossier (in English) for the BSC;

• Co-ordinating, with the President of the BSC, the CRP and the reviewer(s), the preparation of the BSC’sassessment report;

• Providing the necessary follow-up to the BSC opinion (e.g. variations, post-marketing renewals, etc.), inconsultation with the President of the BSC and, where appropriate, the CRP and the reviewer(s);

• Preparing the Resolution containing the list of recommended validated and certified assays to be voted on by the

OIE International Committee;

• Updating the OIE register of validated and certified diagnostic assays.





Version 2.1 (06/2009) 7

1.3.3. Before submission

Before submission, the applicant should fill in the ‘Application Form for Validation and Certification of DiagnosticTests by OIE' (which can be downloaded from the OIE web site). The OIE Central Bureau, through the OIE Secretariat

for Validation, Certification and Registry of Diagnostic Assays (OIESVCRDA), will be able to provide more procedural guidance during this pre-submission phase and to prepare the assessment process.

The conditions, including the date of submission, should be defined in accordance with the OIESVCRDA in order tooptimise the timing of the procedure.

1.3.4. Submission of the dossier and payment of fees

The applicant should submit the completed application form and the relevant fee at the same time.

If it is immediately clear to the OIESVCRDA that the test for which an intention to submit an application has beenreceived does not fall within the OIE priorities and scope, the OIESVCRDA shall notify the company that theapplication is not admissible, stating the reasons. The fee paid by the applicant will be sent back to the applicant.

The OIE should receive the full application fee in Euros, net of all bank charges. Applications will not be processeduntil the full fee has been received.

Fees are composed of two parts. The first is paid for the assessment of the diagnostic test. The second is paid to retainthe OIE validated and certified diagnostic test status (see section 5).

1.3.5. Dossier to be submitted

The OIE requires from the applicant one complete copy of the application in a suitable PC-compatible medium, e.g.

CD-ROM (preferred electronic format: Word), and one copy in paper format. The application should be completed inEnglish.

Applicants should provide with their application a ‘mock-up’ or specimen of the presentation of the diagnostic test‘ready-to-use’: a mock-up is a copy of the flat artwork design (computer generated) in full colour, providing a two -dimensional replica of both the outer packaging and immediate labelling/packaging. At this stage, the mock-up may bein black and white and in English. It is advised that a mock-up of a multilingual pack also be provided in the smallestfont size legible so that the feasibility of multiple languages on the smallest labelling can be tested. The dossier willhave to be completed later, after the OIE Director General’s decision but before the vote of the International Committee

(see timetable), with mock-ups in English, French and Spanish and in colour.

In addition, applicants must provide evidence that they are duly established and provide documents showing theircapacity to perform all the responsibilities required for the manufacturing and the marketing of the diagnostic test. Acontact person responsible for the diagnostic kit should be nominated, and a curriculum vitae, postal address, e-mailaddress, telephone and fax numbers should also be provided (this is incorporated in the ‘Application Form for

Validation and Certification of Diagnostic Tests by OIE').

The OIESVCRDA may require additional electronic and paper copies for reviewers and members of the BSC.

1.3.6. Validation of the dossier by the OIESVCRDA

The OIESVCRDA will send the applicant an acknowledgement of receipt of the dossier and will ensure, within 30 daysfollowing receipt of the dossier, that the application is valid.

In the event that the OIE requires additional data, information or clarification in order to accept the dossier, theOIESVCRDA will contact the applicant requesting these data, information or clarification within a specific time limit.In this case, the dossier can only be accepted after receipt and verification of the information submitted.





Version 2.1 (06/2009) 8

1.3.7. Positive outcome of the validation of the dossier

In case of a positive outcome, the OIESVCRDA shall notify the applicant in writing that the dossier is acceptable. Thenames of the chairperson and the reviewers, the index number for the identification of the application and the timetablefor evaluation will be attached to the letter confirming the acceptance of the dossier.

1.3.8. Selection of the CRP/Reviewer(s)

The appointment of the CRP and the reviewer(s) will be made by the OIE Central Bureau and the President of the BSCfollowing receipt of the completed dossier, if the latter is accepted.

According to the type of application, additional reviewers may be appointed.

The CRP and reviewer(s) will be from OIE Reference Laboratories or may be other internationally renowned experts.

The names of such reviewer(s) will be communicated by letter to the applicant before the start of the evaluation procedure. The applicant may refuse a reviewer, giving arguments for his objection, within 10 days of receiving thisletter.

To avoid conflict of interest, the reviewer(s) will be required to list possible conflicts of interest and to sign adeclaration of interest and a confidentiality undertaking (see section 3 and 4)

The OIESVCRDA, in close co-operation with the President of the BSC, the CRP and the reviewer(s), will ensure thatthe applicant is kept informed of all issues relating to the application. The OIESVCRDA will serve as the liaison person between the OIE, the President of the BSC, the CRP, the reviewer(s) and the applicant.

The OIESVCRDA, Members of the BSC and the appointed reviewers who have received dossiers, are required to fully

protect the confidentiality of the data submitted to them (see section 3).

1.3.9. Negative outcome of the validation of the dossier

Failure to provide sufficient data, information or clarification requested, or failure to pay the fee will result in refusal toaccept the dossier, and the applicant shall be informed in writing.

If the application cannot be assessed, the fee paid will be reimbursed to the applicant with a reduction to coveradministrative costs (15%). The electronic version of the dossier will be destroyed by the OIE.

The applicant will be required to initiate a new procedure should a new complete dossier be submitted in the future tothe OIE.

1.3.10. Management of applications

Once validated, details of the product will be entered into the OIE database. The numbering system allows for clear

identification of any new application, variation, transfer, annual review, and renewal of the status of the test throughoutits life cycle.

Within the OIE, applications for validation of a diagnostic test are primarily identified by the name of the test, thedisease name, and the nature of the test. However, for administrative purposes, each application will also be given acore-number by the OIE Central Bureau and a sequential number for the product identification. The applicant will beinformed of the procedure number in the initial response letter sent by the OIE. In addition, the numbering system willinclude identification of the kind of application.

1.3.11. Need for samples and sample analysis

Samples for testing the proposed diagnostic test are not required at the time of submission of the application. TheOIESVCRDA may, however, recommend and request the testing of samples of the diagnostic test during theassessment of the application. In this case, the CRP and/or reviewer(s) will specify a test protocol in order to completethe relevant information not provided by the applicant. This protocol would include the type of samples, number of





Version 2.1 (06/2009) 9

samples, number of batches, testing to be performed, and specify, in consultation with the OIE Central Bureau, whichlaboratory will carry out the required testing. The cost of this testing will be charged to the applicant. Such informationmay be useful where a submission is regarded as bordering between the outlined validation stages or where there isdisagreement about the fitness for purpose of a test.

The results of the tests will be reported to the Scientific and Technical Department, the CRP, reviewer(s) and the BSC

for consideration in finalising the BSC Assessment Report.

1.4. Scientific evaluation

If the applicant, for any reason, wishes to stop the procedure during this scientific evaluation (from day 1 to day 60), hewill be reimbursed by 10 to 20% of the fee according to how advanced the assessment is.

The panel of experts during the scientific evaluation will consider any evaluations and decisions from the National

Authority on the Diagnostic kits if there are any.

1.4.1. Timetable for the evaluation

Once the application is accepted and provided to the CRP, and the reviewer(s) have confirmed, preferably by electronicmail or by fax, that they have received the application documents, the OIE begins the evaluation process. If the CRP

and the reviewer(s) have not received their copies of the application on the day when the scientific assessment should begin as decided by the OIESVCRDA, the start of the procedure will be delayed until the OIESVCRDA has receivedconfirmation from the CRP and the reviewer(s) that they have received the application.

A timetable will be prepared by the OIESVCRDA, in consultation with the President of the BSC, the CRP and thereviewer(s). This will be notified by the OIE Central Bureau to the Members of the BSC, the reviewer(s), and theapplicant. The timetable will be prepared, wherever possible, such that the next meeting of the BSC corresponds to day120 of the procedure.

An appeal procedure is possible. In this case, the clock is stopped and restarted after oral or written comments have

been provided. The duration of the appeal procedure is 30 days.

The OIE will ensure that the opinion of the BSC is given within 120 days.

Days Timetable for the evaluation

1 Start the procedure

30 Reviewer to provide a first report to the CRP

45 CRP to draft assessment report and potential questions sent to applicant and OIESVCRDA.If question: stop clock

46 Restart clock

60 Final assessment report sent to the OIESVCRDA and Members of the BSC

80 Comments from the BSC120 BSC discussion, adoption of BSC’s opinion, BSC’s assessment report

130 Transmission to the OIE General Director

135 Decision of the Central Bureau that the diagnostic kit is proposed for inclusion in theregister. Notification to the applicant/OIE approved number

Next International Committee meeting of OIE: confirmation of inclusion in the register andupdate of the register within 7 days of the vote of the International Committee.

Once the diagnostic test is registered by the OIE Central Bureau and in all cases before thetest is placed on the market, mock-ups or specimens of the final outer and immediate packaging and the package insert must be submitted to the OIE.

(BSC will be expected to meet every 3 months, if required.)





Version 2.1 (06/2009) 10

1.4.2. Liaison between the applicant and the OIE

For general information regarding the procedure, the applicant is advised to liaise with the OIESVCRDA. If during thecourse of the scientific assessment, clarification is needed regarding specific issues relating to the data submitted, theapplicant and the CRP may liaise directly and then inform the OIESVCRDA of the outcome of their discussions.

1.4.3. Request for additional information

The CRP will, if necessary, send a list of questions to the OIESVCRDA that will be transmitted it to the applicant. Theclock will be stopped at this point.

The applicant would normally be expected to respond within 2 months from the date of receiving the questions. This is

considered enough time to prepare answers for additional information. If the applicant is unable to respond within2 months, then careful consideration should be given to withdrawing the application and resubmitting when the full

information is available. The applicant is advised to consult the CRP and the reviewer(s) if clarification is required onany of the questions. The OIESVCRDA should always be duly informed of those consultations.

1.4.4. Opinion of the BSC

The OIESVCRDA in co-ordination with the CRP and reviewer(s), and taking account of the full scientific deliberation

in the BSC and the conclusions reached, will prepare the final assessment report which, once adopted by the BSC, becomes the BSC assessment report.

The BSC will finalise its opinion in the light of the final recommendation of the CRP and reviewer(s) on or before day120. The BSC’s opinion, which may be favourable or unfavourable, will be the result of scientific consensus.

If consensus cannot be reached, a majority decision of the members will be taken. Any divergent positions expressed, be referenced in the BSC’s opinion. Members expressing divergent positions shall state clearly the grounds on which

they are based. The divergent positions will be appended to the decision. Where the decision is by a majority vote, thenumber of votes shall be clearly mentioned. In the absence of a majority position, the BSC’s opinion is deemed to be

negative. If necessary, the OIESVCRDA, in consultation with the President of the BSC, can organise a written

procedure.

1.4.5. Favorable opinion

In the event of a favourable decision from the BSC, the following documents shall be appended to the opiniontransmitted to the OIE Central Bureau:

• The proposal for inclusion in the register

• Manufacturing conditions of the test

• Category of the test

• Fitness for purpose

• Conditions or restrictions regarding supply and use

• Draft labelling and package insert• The BSC assessment report

• Where relevant, divergent positions of BSC Members with signatures and their grounds for notsupporting the opinion.

Should the BSC want to record any follow-up measures, these will be included in the assessment report and referencedin a letter of undertaking signed by the applicant that will be appended to the assessment report.

The diagnostic kit is validated and certified for only the “fitness for purpose” mentioned in the opinion of theBSC. In order to prevent any off-label use of the kit, the OIE will remove any diagnostic test from the OIE register thatmention other “fitness for purpose” than those validated and certified by the OIE. In this case, the applicant or hisauthorised representative shall no longer state that his diagnostic test is validated and certified by the OIE. Any

violation of this rule is liable to legal action by the OIE against the applicant.





Version 2.1 (06/2009) 11

1.4.6. Specific obligations

When an opinion is granted with specific obligations, the applicant is obliged to submit additional data to theOIESVCRDA, within an agreed timeframe. These additional data, known as specific obligations, are appended to theOIE General Director’s decision and are detailed in the letter of undertaking of the applicant as adopted at the time of

the opinion of the BSC. The specific obligations are to be reviewed at the intervals indicated but no longer than a year.

1.4.7. Non-fulfillment of specific obligations

The applicant must indicate realistic target dates for the submission of the data in his/her letter of undertaking. If nodocumentation is received to fulfil the specific obligations before the previously agreed deadline by the BSC and afterhaving received reminder emails from the OIE, the test can be withdrawn on the decision of the OIE Director General.

1.4.8. Unfavorable opinions

The OIE shall immediately inform the applicant when the opinion of the BSC is that the application does not satisfy thecriteria for inclusion of the test in the OIE register. A document stating the reasons for the unfavourable opinion will betransmitted to the applicant.

1.5. Follow-up to the BSC’s opinion

1.5.1. Transmission of the BSC’s opinion

If, within 10 days of receipt of the opinion, the applicant does not inform the OIE of any intention to appeal, the

OIESVCRDA will forward the decision (and the required appendices) to OIE Central Bureau for action. The decision isthen sent to the applicant by, at most, day 130.

1.5.2. Appeal

The applicant may notify the OIE Central Bureau of his/her intention to appeal within 10 days of receipt of the decision.If the applicant does not appeal in this time, he/she shall be deemed to have agreed with the decision and it becomes

final.

The grounds for appeal must be forwarded to the OIESVCRDA within 30 days of receipt of the decision. If theapplicant wishes to meet the BSC for an oral appeal, the request should also be sent at this stage.

The OIE Central Bureau, through the OIESVCRDA, may decide to appoint a new CRP and/or reviewer(s), to assess theappeal procedure. The BSC will consider whether its opinion is to be revised at its next meeting.

Once the BSC issues a final decision, it is forwarded (with the required appendices) to the OIE Director General foraction.

1.5.3. Negative decision

In the case of a negative decision, a letter will be sent to the applicant stating the reasons for which the negativedecision was reached.

1.6. Changes to a diagnostic test previously included in the register

Any change to the test should be declared to OIE before implementation of the change. For any changes that mightaffect assay performance, supplementary data should be provided well in advance in order to enable the OIE to performan assessment of changes on fitness for purpose and validation criteria.

The assessment of changes will be done according to the previous timetable for evaluation. The OIESVCRDA can setup a shorter timetable taking into account the exact scope of the changes. If substantial changes are proposed (e.g.

another purpose), additional fees will be required.





Version 2.1 (06/2009) 12

This Validation and Certification procedure for Diagnostic Assays establishes the “fitness for purpose” of a diagnostictest. This procedure does not establish the manufacturing quality of the test.

The OIE reserves the right to remove from its validated and certified diagnostic test register, any test that does not perform according to the previously validated fitness for purpose.

1.7. Annual review and Annual fee

The applicant is requested to send annually a letter of undertaking stating that the test is still viable and that no changes

have been performed.

Every year between 1 and 15 January, the manufacturer or his authorised representative shall pay a fee proportional tothe pre-tax annual cumulated turnover of the previous year gained from sales of the diagnostic test validated and

certified by OIE (see section 5).

1.8. Renewal of a registration

The application for renewal of the registration should be submitted to the OIE 5 months before expiry of the 5-year period. The application should be accompanied by the fee to be paid.

The assessment of the renewal will be done according to the timetable for evaluation seen previously. TheOIESVCRDA can set up a shorter timetable taking into account the nature of the changes.





Version 2.1 (06/2009) 13

Section 2. Validation studies overview

Validation is a continuous process. At various stages of development, a test will be used and data obtained. It is thesedata that support test claims and determine the validation status of the test. Four stages of validation are proposed and

OIE acceptance of an application will be linked to a determination of the validation status based on the four stages. Thestages rely on the quantity of work done; the number of people and laboratories where the test is used; the quality ofdata; and measures taken to routinely examine the test in use, both directly by users and indirectly through exercisesdesigned to measure repeatability and reproducibility over time. The data presented in the application will determine thevalidation status. The headings and explanations below are reflected in the ‘Application Form for Validation andCertification of Diagnostic Tests by OIE'.

2.1. Stage 1 validation

Stage 1 validation requires:

2.1.1. Calibration

• Some calibration of a test against standards (in-house at least).• Inclusion of some reference standards (in-house at least).

2.1.2. Repeatability data

• A minimum of three in-house samples representing activity within linear range of assay.

• Within run tests (quadruplicates preferred).

• Between run tests (a minimum of 20 runs total, two or more operators preferably on separate days,where runs are independent).

• Between serial repeatability, ideally three production batches.

• Data should include mean, SD, upper and lower control (UCL and LCL) on unprocessed and processed data.

2.1.3. Analytical specificity data

• Cross-reactivity, near-neighbour data.

• Document cross-reactivity by comparing samples from animals infected with organisms with similarclinical presentations and organisms that are genetically closely related.

• Type/group specificity data.

• Documentation affirming serotype or group specificity.

2.1.4. Analytical sensitivity data

• Specify standard of comparison (i.e. currently accepted test method).

• Comparison may include: end-point titrations; earliest time of detection post-exposure.

• Duration of detection post-exposure (if applicable).



2.2.1. Negative reference animals/samples (Complete description)(Note: negative refers to lack of exposure to or infection with the agent in question)

• Age, sex, breed, etc.

• Immunological status.

• Relatedness to intended target population.

• Selection criteria including historical, epidemiological and/or clinical data.

• Pathognomonic and/or surrogate tests used to define status of animals or prevalence within population.

• Sampling plan and procedures.

2.2.2. Positive reference animals (Complete description)(Note: positive refers to known exposure to or infection with the agent in question).

• Age, sex, breed, etc.

• Immunological status.

• Relatedness to intended target population.





Version 2.1 (06/2009) 14

• Selection criteria including historical, epidemiological and/or clinical data.

• Pathognomonic and/or surrogate tests used to define status of animals or prevalence within population.

• Sampling plan and procedures.2.2.3. Experimental animals

• Complete description

Age, sex, breed, etc. Immunological status. Relatedness to intended target population.

• Exposure. Inoculum, source, dose, etc. Type of exposure – inoculation, aerosol, contact, etc. Sampling plan and procedures.

2.2.4. Threshold determination

• Complete description of method used: empirical, ROC, mean ± SD, etc.

• Descriptive statistics, frequency distribution diagrams, etc.

2.2.5. Performance estimates

• Irrespective of the method chosen, the standard method(s) of comparison should be run in parallel onall samples, i.e. the test methods in current use.

2.2.6. Diagnostic sensitivity and specificity estimates – with defined reference animals

• Conventional method using reference animals.

• Assuming a minimum sensitivity and specificity of 75% with an allowable error of ± 5% in theestimate at a level of confidence of 95%, number of reference animals required is 300 for each population.

• Individual animals must be selected from negative and positive reference populations.

• Include 2x2 table, calculations for diagnostic sensitivity and specificity including error andconfidence.

• Include same calculations for other tests if being compared to the test in question.

2.2.7. Diagnostic sensitivity and specificity estimates – without defined reference animals

• Complete description of model used.

• Bayesian inference, latent class analysis, etc.

• Describe rationale, priors, supporting data.• Population selection criteria, including prevalence estimates.

• Other test methods in evaluated should also include the standard method of comparison.

• Using best available priors, choose test populations with appropriate prevalence and select animals in

sufficient numbers to generate estimates of sensitivity and specificity with an allowable error of ± 5%at a level of confidence of 95%.

2.2.8. Agreement between tests

• Complete description of test methods in comparison.

• Presumptive vs confirmatory tests.

• Relatedness of analytes.

• Potential biases.

• Complete description of samples tested.

• Source of samples may include experimental animals sequentially sampled over time.

• May also include animals or herds defined by reactivity in confirmatory tests or multiple presumptivetests and sampled over a period of time.

• Describe measures of agreement and explanations for results not in agreement.



2.3.1. Laboratory identification

• Selection criteria for candidate laboratories. Location, i.e. country. Status, i.e. regional, national, provincial/ state. Level of expertise, familiarity with technology.





Version 2.1 (06/2009) 15

Accreditation status.

• Number of laboratories included. Minimum of three laboratories should also include OIE Reference Laboratory, if possible.

2.3.2. Evaluation panel

• Description of test panel. Selection criteria, number of samples (minimum of 20).

Sample volume, allowable number of repeats. Panel composition, i.e. number of replicates, range of analyte concentrations/ reactivities. Sample processing requirements, i.e. extractions, spiking, serial dilutions, preservatives,

sterilisation. Coding of unknown (blind) samples. Frequency of testing.

2.3.3. Reproducibility

• Description of type of data/interpretation. Qualitative (categorical). Quantitative or semi-quantitative data. Single dilution vs titration.

• Description of type of analysis. Pre-determined limits, consensus, Youden plots.

• Descriptive statistics. Include mean, SD, range of results. Should include controls, as well as, blind samples. Number and proportion of accepted/rejected runs should be included.



2.4.1. Laboratories

• List laboratories where this test method is in current use. Location, i.e., country. Status, i.e. regional, national, provincial/state. Accreditation status.

2.4.2. Test Applications

• For each laboratory. Indicate purpose of test. Integration with other tests Status test, i.e. official test, supplementary, etc. Throughput, i.e.,daily, monthly, annual. Turn-around-times.

2.4.3. International reference standards

• List type and availability of international reference reagents.

• Source.

• Negative, weak/ strong positive reference reagents.

• Other key biologicals, e.g. antigens, antibodies, etc.

2.4.4. Inter-laboratory testing programmes

• Describe programmes involving inter-laboratory comparisons using this test method.

• National, international.

• Describe eligibility and number of laboratories participating.

2.4.5. International recognition

• List internationally recognised reference laboratory responsible for this test method and/or biologicals.

• Listed international standards containing this test method.

• Listed international programmes employing this test method.





Version 2.1 (06/2009) 17

Section 4. Guidance on conf licts of interests

4.1. Introduction

In order to respect the confidentiality between the OIE and diagnostic test productor (DTP), the Members of the BSC,CRP and reviewer(s) shall not have financial or other interests with the DTP that could affect their impartiality. Allindirect interests that could relate to this process shall be entered into a register held by the OIE. This requirement isextended to all OIE staff and persons involved in the process of OIE Validation, Certification and Registration.

4.2. Who should declare?

• BSC and working party members;

• All reviewers;

• All OIE staff involved in the process.

• OIE collaborating centre staff involved in the process

4.3. What to declare?

Each individual is responsible for the declaration of his/her interests and those held by members of his/her household 1.

Interests may include those held by members of his/her household, membership of an interest group etc. In order tomaintain privacy, the names of household members do not need to be declared.

4.3.1. What is an interest?

There are essentially three categories of interests:

a) Financial interests

Any financial interests with the DTP, including holding of stocks and shares, equity, bonds, partnership interests2 in thecapital of the DTP, one of its subsidiaries or a company in which it has a holding in the capital.

The holding of financial interests connected with a pension scheme previously contracted prior to the nomination as aMember of the Commission or as a reviewer or appointment as a member of the OIE staff, and/or interests in non-nominal unit trusts or similar arrangements would not, in principle, have particular consequences providing theindividual has no influence on financial management.

b) Work carried out for the DTP

During the preceding 5 years, all activities performed for or on behalf of the DTP 3, whether or not these activities have been subject to regular or occasional remuneration in cash or kind, including:

• Participation in the internal decision-making of a DTP (e.g. Board membership, executive or non-executive directorship);

• Permanent or temporary member of the personnel of a DTP. Other activities performed within a DTP(e.g. traineeship) are also subject to declaration;

• Work contracted out by DTPs, through consultancy or otherwise.

1. Spouse or partner and dependent children living in the same household.

2. When declaring financial interests, e.g. stocks and shares, only the kind, number and company name need be stated.3. Company or public laboratory name, position held and activities performed should be set out clearly and precisely.

Where activities relate to specific product(s), declarations must indicate product name and nature of the work.





Version 2.1 (06/2009) 18

c) Other links with industry

During the preceding 5 years, all assistance and support received from industry, whether associated with direct orindirect pecuniary or material benefits, including:

• Grants for study or research allocated by the industry;

• Fellowships or sponsorships endowed by DTPs.

4.3.2. What are direct and indirect interests?

Interests can be direct or indirect depending on their likely or potential impact on the individual’s behaviour at a given point in time.

a) Direct interests

Interests of personal benefit to the individual at the time of declaration, likely to influence or give the appearance ofinfluencing his/her behaviour (e.g. employment with a DTP, financial interests of a certain magnitude). In order toremain in office, the individual concerned would have to take appropriate action to suppress the conflict.

b) Indirect interests

Other interests that may have some influence over the individual’s behaviour and therefore have to be neutralised.Indirect interests should be scrutinised so that precautions can be taken in order to ensure impartiality of decisiontaking. Appropriate actions could include precluding the individual from certain functions or tasks (e.g. CRP, reviewer,

OIESVCRDA) or requiring abstention from part of the relevant proceedings or voting in the meetings of the scientificcommittees and/or working parties.

4.4. When to declare?

Improvements to the declaration of interests’ forms have been introduced with a view to providing more guidance to all

parties concerned on how to fill out and update them.

4.4.1. Initial declaration

Upon nomination as a Member of the BSC involved in the assessment or reviewer or appointment as a member of theOIE staff or OIE collaborating centre staff involved in the process, each individual is required to fill out a declaration ofinterests’ form.

4.4.2. Appointment as CPR or reviewer

Members of the BSC and reviewers should not accept appointment as the CRP or reviewer for an application or referral

if it is apparent that there could be a conflict of interest because he/she has been in any way associated with the studiescontained in the dossier.

4.4.3. Spontaneous declarations

If during assessment or advisory work, a potential conflict becomes apparent to a member or reviewer, then it must bedeclared to the OIE Central Bureau and appropriate action agreed upon. This would include, in particular, the situationwhere a reviewer is asked to assess data from his/her own research or his/her own reviewer report in a dossier. If at anytime during the course of their duties, OIE staff members become aware of any potential conflict, they mustimmediately inform the OIE Central Bureau, which will determine any appropriate action.





Version 2.1 (06/2009) 19

4.4.4. Updates

Declarations of interests must be updated at least annually or as soon as an update is required for any new situationarising. As part of the new reviewers’ database, electronic updates are available to facilitate exchange of information.

4.5. Operational aspects

4.5.1. Tasks of OIESVCRDA

The OIESVCRDA is under the direct responsibility of the OIE Central Bureau and undertakes the following:

• Remind all parties concerned of their obligation to declare their interests;

• Monitor regularly declarations and preliminary appraisal of compatibility of interests declared withgeneral or specific office or duties of the individuals concerned;

• Initiate and facilitate dialogue within the appropriate forum (e.g. committee or working party).

The OIESVCRDA ensures, under the responsibility of the OIE Central Bureau, the availability of all declarations andupdates for public consultation in the OIE headquarters.

4.5.2. Obligations of individuals concerned

The BSC and review panel members and members of the OIE staff have a primary obligation to disclose at any time theexistence of possible conflict of interests that may place the impartiality of the OIE at risk. The individual should statein particular the type and nature of interests, specifying whether they are general or relate to a specific product. If theconflict is product-related, prior involvement of the CRP and reviewer(s) in relation to competing products and past andcurrent links with companies should be disclosed.

In the case of Members of the BSC and reviewers, the primary contact persons should be the CRP and the OIE CentralBureau.

4.5.3. Meeting proceedings

Individuals have the primary responsibility for spontaneously declaring any conflict of interest at all times. Howeverchairpersons of all meetings should periodically – at least every 6 months – remind members and reviewers of theirobligation to update their declarations.

Particular precautions should be taken in the case of ad hoc reviewer groups or other situations where conflicts of

interests are likely, in which case a systematic reminder should be made at the beginning of every such meeting.

Reminders and discussions should be recorded in minutes of meetings together with detailed statements on conflicts.

On the basis of the type and nature of interests noted, meetings could consider various options, including:

• Fundamental incompatibility with membership of the group;

• Incompatibility with the performance of certain functions or tasks (e.g. coordination, reviewer);

• Temporary exclusion from the meeting;

• Abstention from the debate and/or the vote.





Version 2.1 (06/2009) 21

Section 6. OIE regist ration of a diagnost ic test as validated and certif ied- rules of recognition

The OIE logo is a part of the Organisation’s intellectual property and may not be used without the express permission of

the Director General of the OIE.

The OIE logo, name and abbreviation are also protected from being registered as a trade mark under article 6 of theParis Convention for the Protection of Industrial Property.

The use of the OIE logo (marking) signifies the recognition and registration of a test by the OIE through the validationapplication process. The logo can only be used when the test has been reviewed and accepted through the registration process. It could appear on any device associated with the test, on the instructions for use and on the sales packaging.

For the device and sales packaging, it shall be stated under the logo: "Validated and certified by the OIE as fit for the purposes defined in the <leaflet/kit insert/document> provided with this kit" [use appropriate term] and accompanied by

the Registration number. For the instructions for use, it shall be stated under the logo: "Validated and certified by the

OIE as fit for the purposes defined in this <leaflet/kit insert/document>" [use appropriate term] and accompanied by theRegistration number.

Within the main text (introduction) of the leaflet/kit insert/document, a more detailed paragraph should be provided,saying:"The validation data for this kit have been certified by the OIE, based on expert review, as fit for the following

purposes:<give details of the certified purposes> (As stated in the resolution adopted by the OIE International Committee)."The summary of the validation data (Section 4 of the application form), that will be on the OIE Register website, shall be included in this leaflet/kit insert/document.

The OIE agreement will be withdrawn if it appears that the aims and objectives of the certification no longer justify

maintaining such an agreement.

The OIE validated and certified logo shall consist of the initials OIE taking the following form (the OIESVCRDA will provide a jpg or ai file of the OIE logo on request):

Validated and certified by the OIE as fit for the purposes

defined in [this <leaflet/kit insert/document>] or [the <leaflet/kit insert/document> provided with this kit ]*Register number: - - - - - - -

If the logo is reduced or enlarged, the proportions must be respected.

* As relevant





Version 2.1 (06/2009) 22

Appendix: Declaration forms

• FORM A1. Confidentiality Undertaking for the Expert Advisers (see Section 3)• FORM A2. Confidentiality Undertaking for the staff of the OIE and the OIE Collaborating Centre and

Biological Standards Commission members (see Section 3)

• FORM A3. Public Declaration of Interests of Relevant Staff Members of the OIE (see Section 4)

• FORM A4. Public Declaration of Interests of the Relevant Members of Committees and Reviewers (seeSection 3)





Version 2.1 (06/2009) 23

FORM A1. Confidentiality Undertaking for the Expert Advisers

Confidentiality Undertaking for the Expert Advisers, i.e. Chairpersons and Reviewers

In the course of discharging your functions as an expert adviser to OIE under the attached dossier (OIE StandardOperating Procedure for Diagnostic Assays), you will gain access to certain information that is proprietary to OIE orentities collaborating with OIE, including the manufacturers of the product(s) that need to be assessed as part of the procedure. You undertake to treat such information (hereinafter referred to as “the Information”) as confidential and proprietary to OIE or the aforesaid parties collaborating with OIE. In this connection, you agree:

(a) not to use the Information for any other purpose than discharging your obligations under the above-mentioned

procedure; and

(b) not to disclose or provide the Information to any person who is not bound by similar obligations of confidentialityand non-use as contained herein.

However, you will not be bound by any obligations of confidentiality and non-use if you are clearly able to demonstrate

that any part of the Information:• was known to you prior to any disclosure by or on behalf of OIE (including by the manufacturer[s]);

or

• was in the public domain at the time of disclosure by or on behalf of OIE (including themanufacturer[s]); or

• becomes part of the public domain through no fault of your own; or

• becomes available to you from a third party not in breach of any legal obligations of confidentiality.

You also undertake not to communicate your deliberations and findings and/or those of the panel(s) of experts in whichyou will participate, as well as any resulting recommendations to, and/or decisions of, OIE to any third party, except asexplicitly agreed by OIE.

I hereby accept and agree to the conditions and provisions contained in this document.

Signature

Name_________________________________________________________ Date____________________





Version 2.1 (06/2009) 25

FORM A3. Public Declaration of Interests of Relevant Staff Members of the

OIE

Surname: (family name) Fore names

Position Grade:

Please list below all interests in the DTP1

if any:

Employment in the DTP during the previous 5 years:

Financial interests in the capital of a DTP:

Name of company Share type Number of shares:

List the work that you have previously carried out including paid/unpaid traineeships on behalf of the DTP in the 5 preceding years:

Other interests or facts that you consider should be made known to the Agency and the Public including matters

relating to members of your household 2

Declaration

I, __________________________________________________________________________________Do hereby declare on my honour that, to the best of my knowledge, the only direct or indirect interests I and my

household members have in the DTP are those listed above.

I further declare that should any changes occur and should it appear that I have or acquire additional interests thatshould be made known to the OIE, I shall forthwith declare them and complete a new public declaration of interests.

(Signature) _________________________________________________ Date__________________

1 If you have no interests, please indicate “none” in the relevant section.2 Household members means spouse, partner and dependent children living at the same address as the staff member. The names of these persons

need not be declared.

sop validation kits veterinary diagnosis

Documents