WHO guidance on post-market surveillance for manufacturers of in vitro diagnostics (IVDs) and their economic operators: policy brief

Use standardized complaint forms and reports http://www.who.int/diagnostics_laboratory/postmarket/en/ Ensure end-users report complaints A complaint is any communication that alleges a deficiency related to safety, quality or performance of a product after it is released for distribution. In the context of post-market surveillance for in vitro diagnostics (IVDs), a complaint may be an adverse event related to an individual (patient, end-user or any other person) or a product problem. All complaints received should be recorded, verified and classified by the manufacturer according to post- market surveillance plan and risk management outputs for the product. Complaints should be reported by end-users to the manufacturer (or any economic operators) when any of the following occurs or might have occurred: Complaint classification Adverse event that happened to patient, end-user or any other person Death of the patient, end-user or any other person Serious Serious deterioration in health of the patient, end-user or any other person Serious A false negative test result Serious A series of false positive test results (more than 2) Moderate Adverse event caused by patient conditions Mild Adverse event caused by device exceeding its service life or shelf life Mild Expected and foreseeable side effects Mild Problem that happened to the reagents, consumables or instrument Increased rate of invalid or unreturnable test results or other anomalies2 Moderate Deficiency found by the user prior to use such as damaged packaging/labelling Moderate Please note that this is not an exhaustive list, any issue that you suspect might affect the test result should be reported.3 Role of economic operators Any economic operators (e.g. authorised representative, importers, distributors, suppliers) must forward all categories of complaints to the manufacturer, as soon as they become aware. 1 Authorised representatives, importers, distributors, suppliers, etc. 2 Note: Guidance from International Medical Device Regulators Forum (IMDRF) states that when protection against a fault functions correctly, it does not need to be reported but WHO recommends that these events be reported. 3 Refer to International Medical Device Regulators Forum (IMDRF) terminologies for categorized adverse event reporting: terms, terminology structure and codes. IMDRF/AE WG/N43FINAL:2017. WHO guidance on post-market surveillance for manufacturers of in vitro diagnostics (IVDs) and their economic operators1 P O L I C Y B R I E F 2 Use standardized investigation forms such as http://www.who.int/diagnostics_laboratory/postmarket/en/ Inform national authorities and WHO In accordance with the relevant regulations, the manufacturer must submit investigation reports to the regulatory authority in the country where the complaint occurred. If the product is WHO prequalified, investigation reports must be submitted to WHO. The manufacturer’s pathway of investigation, and corrective action if required is reviewed: • Root cause analysis (how/why did this happen); • Analysis regarding related areas (is this same issue impacting/ occurring elsewhere); • Correction (fix now) with completion dates; • Corrective action, if applicable (to prevent recurrence) with planned completion dates. The manufacturer must submit subsequent follow-up investigation reports in a timely manner. Each authority will have its own timelines for reporting which must be observed. For WHO prequalified IVDs, the following timelines for initial reporting to WHO must be followed: • Serious complaint – 10 days after manufacturer became aware • Moderate complaint – 30 days after manufacturer became aware • Mild complaint – 30 days, only if any trend emerges. An annual report for the preceding calendar year for all complaints must be reported to WHO by product on 28 February each year. Conduct investigation All complaints (irrespective of their classification – serious, moderate or mild) must be evaluated by the manufacturer, and when necessary escalated for investigation. An investigation will determine the need for any immediate corrective action and verify that the product still meets safety, quality and performance claims. The root cause should be established using a documented methodology such as a fishbone (Ishikawa) diagram, etc. It is not sufficient to assign a certain root cause simply because all other potential root causes have been ruled out. For example, there must be evidence from additional experimental data that the root cause, such as uncontrolled storage conditions, could contribute to increased rate of invalid results. Certain measures such as review of batch manufacturing records, testing of retained samples of the affected lot(s) and, where possible, testing of returned samples of the affected lot or additional patient specimens are recommended. The risk management file for the product should be reviewed, and possibly updated for each complaint by the manufacturer. This includes risk analysis, risk evaluation, risk control, evaluation of overall residual risk acceptability, risk management reporting, with inclusion of production and post-production information. 3Issue field safety notices Field safety corrective actions are notified to customers by field safety notice. Manufacturers are obliged to ensure that end-users receive any critical safety information. National regulatory authorities should post these field safety notices on their website. Make corrections/implement corrective actions Using the findings of the complaint investigation and risk management review, the manufacturer must consider undertaking actions to mitigate any newly identified or elevated risks. In most circumstances, these actions will be done at the manufacturing site and the end-user (customer) will not need to be informed. However, in some circumstances, for example where any changes could impact other lots of product already placed on the market, these actions need to be communicated to end-users. The so-called field safety corrective actions are usually in the form of a recall or modification to the product which includes labelling and instructions for use. Changes to WHO prequalified IVDs because of corrective actions must be reported to WHO as per procedure “Reportable changes to a WHO prequalified in vitro diagnostic medical device” (WHO/ EMP/RHT/PQT/2016.01). Approved changes will be reflected in the WHO Prequalification Public Report for the product. Periodic review of post market surveillance data The manufacturer should conduct periodic reviews of post market surveillance data, including the outcomes of complaint investigations to allow for the timely identification of trends. The period for review should be commensurate with the risk class of the product and product safety performance. Product failures should be reviewed against rate of occurrence in previous periods and expected rate of occurrence as given by product performance claims. Where adverse trends in performance are identified these should be investigated in the same manner as a customer complaint. Complaint received and classified Investigation (including root cause analysis) Verification of effectiveness of corrective actions Correction and corrective action Where do I find any current product alerts for WHO prequalified RDTs? https://www.who.int/diagnostics_laboratory/procurement/complaints/en/ W HO /M VP /E M P/ SA V/ 20 19 .07 © W or ld He alt h O rg an iza tio n 2 01 9. So m e r igh ts re se rv ed . T his w or k i s a va ila ble un de r t he CC BY -N C- SA 3. 0 I GO lic en ce . Where do I find information on current product issues for IVDs? For Australia, Canada, European Union, Japan, Singapore, USA: http://www.imdrf.org/safety/safety.asp For WHO prequalified IVDs: http://www.who.int/diagnostics_laboratory/procurement/complaints/en/ How to minimize impact of poor supply planning on quality, safety and performance of IVDs Poor supply planning and inefficient procurement processes can put programmes at risk. End-users in low and middle-income settings will typically place large annual orders i.e. one order with one delivery for one year’s supply. This practice offsets long lead times for delivery but may exacerbate quality, safety and performance issues as risks are introduced as products must be stored longer term. Furthermore, adequate physical space must be found for the products to be stored at the recommended storage conditions. WHO recommends national programmes consider staggered deliveries, for example, delivery each quarter instead of larger one-off deliveries to reduce risks related to longer term storage of product. Another critical aspect for supply planning of IVDs is the concept of negotiating an acceptable remaining shelf life upon delivery. This term differs from shelf life upon manufacture which is a claim made for product stability that is independently confirmed as part of the regulatory assessment. However, it is not reasonable to expect that all orders (especially large volumes) would be manufactured freshly for each request. Furthermore, large orders might be shipped by sea which takes weeks/months and customs clearance can take days/weeks. Therefore, the concept of guaranteed shelf life upon delivery takes on critical importance. The supplier (usually the manufacturer) will guarantee a remaining shelf life for the product upon delivery to the named place. This allows for a regular production schedule to be set with a rotating stockpile of product within the warehouse, rather than each consignment being manufactured to order which may lead to longer lead times and increased risks within the quality management system with ad-hoc production. Further reading: World Health Organization. Policy on remaining shelf life of medical products. Geneva. QAS/19.788.