1. Susan Best, NRL, Australia WHO post-market surveillance for In Vitro Diagnostic Devices (IVD)

2. Background Problems with IVDs may be detected pre- or post-market ISO standards oblige manufacturers to conduct post-market activities –Quality, safety, performance Post-market surveillance (PMS) enables continuous feedback Manufacturer maintains a high standard of product quality and customer satisfaction

3. A manufacturer of a WHO prequalified IVD on the market must ensure that: – It continues to meet all safety and performance requirements applied at PQ – Any problems are corrected and reported through appropriate channels PMS is as important PQ activities PMS for pre-qualified IVDs: why is it needed?

4. Helps the manufacturer with understanding of the safety, quality and in-field performance of the IVD PMS processes and procedures: – Early warning system – Minimise exposure to adverse events – Guide appropriate handling of identified incidents – Field Safety Corrective Action (FSCA) PMS for pre-qualified IVDs: why is it needed?

5. Complaint reporting alone cannot capture all risks related to the use of IVDs Programs for the systematic collection of data on IVD performance post-market exist WHO is developing a PMS system for collecting information on lots delivered to countries (and to end users in the field)

6. WHO post-market surveillance of IVDs WHO PMS system has both reactive and proactive elements Users, manufacturers and National Regulatory Authorities (NRA) all have a role In some settings, WHO acts to fill the gap for NRAs who lack capacity WHO prequalified product Reactive PMS Field Safety Notice Complaints Lot verification testing Proactive PMS Field Safety Corrective Action

7. PMS roles and responsibilities Key stakeholders: manufacturers, NRAs, national reference laboratories (NRL), WHO/ Prequalification Team – Diagnostics, end users Different stakeholders each play important roles in ensuring PMS data are collected, assessed and acted upon – End users are crucial as they usually first report problems – Mx have duty to ensure that users will forward PMS data – NRAs often lack capacity for post-market oversight – WHO assists countries by ensuring investigation of complaints and promoting PMS practice in-country

8. Reactive PMS: definitions A complaint is a statement that a situation is unsatisfactory or unacceptable Vigilance is one component of the post-market activities undertaken by the manufacturer, it is reactive in nature An adverse event (or “incident”) is defined as a product defect (i.e. malfunction or failure, deterioration in characteristics or performance, or inadequacy of labelling or of instructions for use) that, directly or indirectly, has led or might have led to serious medical consequences, namely death or serious deterioration in the state of health of the patient, user or another person.

9. Reactive PMS: complaint reporting / vigilance End user identifies problem – E.g. high background, high rate of invalid rate, false negative, false positive User verifies problem – To ensure that it was not mistake or avoidable error in their testing practices User reports problem to Mx and/or to WHO i.e. makes a complaint Mx investigates problem and takes appropriate action, including informing the NRA and/or WHO

10. Reactive PMS: IVD complaint reporting through WHO In settings where regulation for IVDs is poor or not enforced, WHO: – coordinates complaint reporting from users to manufacturers – ensures Mx undertakes appropriate investigation and FSCA, if required

11. WHO guidance to be developed for vigilance For users – Guidance for user investigation to verify problem – Standardized WHO IVD complaint form (already exists will be updated) For manufacturers – Guidance for investigation undertaken by Mx – Guidance on FSCA reporting – Guidance on Field Safety Notices General – Flow chart for reporting complaints to WHO – Classification Rules for the type of complaint

12. Reactive PMS: Field Safety Corrective Action Field Safety Corrective Action (FSCA) is an action taken by the manufacturer to reduce the risk of a death or serious deterioration in the state of health associated with use of a medical device (including IVD) that has already been placed on the market A FSCA is triggered when there is an unacceptable increase in risk associated with use of the IVD FSCAs may include: – return of IVD to supplier, device modification, device exchange, device destruction, retrofit by purchased of device according to Mx modification\design control

13. Reactive PMS: Field Safety Notice A Field Safety Notice: communication from manufacturer or its representative related to a FSCA It tells their customers about an FSCA they are undertaking – Sent to all end users for their attention and possible action – Sent to all NRAs in the country of supply as a record See GHTF Medical Devices: Post Market Surveillance: Content of Field Safety Notices, SG2(PD)/N57R6

14. Reactive PMS: Advisory notices issued by WHO An additional Information Notice for Users may be issued WHO when: – Mx has not undertaken an appropriate FSCA and/or – Mx has not issued a FSN – MX action not timely While a product already on the market is undergoing WHO prequalification, WHO may: – Issue a WHO Field Safety Notice – in response to findings of the prequalification laboratory evaluation – Issue a WHO Notice of Concern – in response to findings of the prequalification site inspection

15. Adverse event: WHO pre- qualified IVD What will WHO do? WHO will monitor the manufacturer's investigation related to the incident and any required FSCA – Course (the direction the investigation is taking) – Conduct (how the investigation is being carried out) – Progress (how quickly the investigation is being carried out) – Outcome (whether the results of device analysis are satisfactory) – Mx risk assessment of incident is important Receive manufacturers investigation report Decide: – To inform NRAs – If WHO PQ status is affected – Whether further action is needed

16. Proactive post-market surveillance of IVDs Lot verification testing by users A “user” may be NRA, NRL, other designated body – independent of the manufacturer To ensure consistency with established performance and quality criteria (as determined during WHO pre- qualification) WHO prequalified product Reactive PMS Field Safety Notice Complaints Lot verification testing Proactive PMS Field Safety Corrective Action

17. Proactive PMS of IVDs: lot testing Lot verification – Through physical inspection of packaging, labelling and instructions for use; and – Testing of samples from a lot against a characterised panel of specimens Lot testing should be centrally performed by suitable qualified laboratory Lot acceptance criteria must be in place (pass/fail)

18. Proactive PMS of IVDs: panels for lot testing Ideally, same core panel of characterised specimens for each lot of the same IVD; some local samples Suggested minimum requirements: – Verify analytical sensitivity Dilution series optimised to the product (must pass from positive through to negative) – Verify false positive rate – Verify background appearance Defined criteria for expected performance

19. Proactive PMS of IVDs: sampling for lot testing Pre-distribution – Potentially all lots examined or a random sample – Prevents delivery of poorly performing lots – Requires more resources Sampling from the field – Random lots examined – More flexible – Less resource-intensive – More difficult to recall defective lots – Management of individuals already tested using those lots May use a risk-managed approach to decide on sampling interval, depends on size of lot

20. Recent WHO activities; next steps Recent WHO consultation on User PMS for key countries, partners and experts – Discuss mechanisms for PMS – Identify barriers – Facilitate uniform approaches – Help WHO develop guidance Second consultation before end of 2014