Susan Best, NRL, Australia

WHO post-market surveillance for In Vitro Diagnostic Devices (IVD)

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

• 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?

• 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?

PMS for pre-qualified IVDs: why is it needed?

• 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)

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

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

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.

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

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

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

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

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

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

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

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

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)

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

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

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