Reviewing incidents 15-18 November, Post-market surveillance and market surveillance for regulators of medical devices

Anita SANDS, Incidents and Substandard/Falsified Medical Products Team, WHO, Geneva

§ An incident is

(any) “malfunction or deterioration in the safety, quality or performance of a device made available on the market, any inadequacy in the information supplied by the manufacturer and undesirable side-effects.”

§ Incidents are reportable by the manufacturer to the NRA when

§ there is a serious public health threat*, or

§ when death or serious deterioration in health of patient/user/other person occurred or might have occurred

What is an incident?

All feedback provided by users to

manufacturer

Incidents reported by manufacturer to NRA

§ Sometimes called an adverse event, AE reporting is often known as vigilance

§ An incident can be related to product quality and/or patient safety

*Any event type or device deficiency which could result in imminent risk of death, serious deterioration in the state of health, serious injury, or serious illness of more than one patient, user or other person that requires prompt remedial action.

Users role: provide feedback to manufacturers

§ Detect issues related to devices

§ Check labelling for manufacturer’s contact details

§ Check for any evidence of tampering of labels and/or packaging

§ Check for problems with labelling (including IFU)

§ Check for manufacturing, packaging or shipping problems

§ Request a certificate of analysis

§ Review clinical records, site logbooks, registries

§ Document feedback

§ Report feedback to manufacturer immediately

§ Users are not expected to conduct investigation

§ Retain samples of device, and software files to support manufacturer’s investigation

Case study: user feedback § A patient with hepatitis B diagnosed elsewhere using

another (competitor) product came to our clinic, the doctor asked for perform testing on a new specimen on your product and it was HBsAg negative.

§ A specimen was sent to a reference laboratory and the HBV viral load was confirmed as high.

§ Male, 49 years old.

§ 2 tests from same product were false negative

§ User was laboratory staff.

§ Patient was being assessed for antiviral treatment

§ NRA can provide a template form for user feedback

§ Reporter details

§ Email address/phone number

§ Product details

§ Lot numbers and expiry date for reagents

§ Serial number for devices/instruments

§ Incident details

§ How many devices and how many patients were involved

§ Description of device problem (what went wrong) and health impact (death, serious deterioration in health, misdiagnosis etc.)

Standardized simple user feedback

Manufacturers role: collect and analyze feedback

§ Collects feedback (positive and negative)

§ Other economic operators (agent, distributor, authorized representative) may collect feedback but should forward to the manufacturer

§ Classifies feedback and determines reportability to NRA

§ Uses IMDRF N43 terminology

§ Undertakes root cause analysis

§ In some jurisdictions

§ Other economic operators may report incidents to NRAs.

§ Other EOs may conduct investigation at the request of and/or in agreement with manufacturer.

§ Use relevant NRA report form, or WHO report form

Manufacturers role:report incidents to relevant NRAs

What to report Time to report to NRA (or national timelines)

Who to report to

Serious public health threat Immediately but no later than 48 hours

§ All relevant NRAs§ WHO (if WHO

recommended product)

Death, serious deterioration in state of health of patient, user or other person occurred

ASAP but no later than 10 calendar days

Death, serious deterioration in state of health of patient, user or other person might have occurred

ASAP but no later than 30 calendar days

Standardized manufacturer investigation report

Regulators role: review incidents

§ Forwards user feedback to manufacturer

§ Reviews manufacturer investigation reports

§ Reviews manufacturer field safety corrective actions

§ Decides if regulatory action is needed

§ Shares information with other NRAs

§ Public repository of field safety notices

Manufacturer investigation reporting form; see annex 2

Regulators role:reviewing incident/investigation reported

Submitted to: Name of NRA and any other NRAs

Reported by: § Manufacturer name§ Manufacturer special point of contact § Manufacturer incident/case identifier

Type of report: § Initial§ Follow-up § Combined initial and final § Final

Product details: § Product name§ Product code/catalogue number § Lot number/serial number§ Expiry date § Associated devices/accessories§ IFU version number§ Software version number § UDI-DI/UDI-PI§ Falsification check

Manufacturer investigation reporting form; see annex 2

Regulators role:reviewing incident/investigation reported

Event details: § Where incident happened§ Date incident happened § Date manufacturer was made aware of incident

§ Incident narrative

§ IMDRF Medical Device Problem Code (Annex A)§ IMDRF Medical Device Problem Component (Annex G)

§ Who was user at time§ Has more than one user experienced the problem § Number of devices§ Number of patients

§ IMDRF Clinical Sign Codes (Annex E)§ IMDRF Health Impact (Annex F)

§ IMDRF N43 terminology

§ Annex A - Medical Device Problem

§ Annex G - Medical Device Component

§ Annex E - Health Effects - Clinical Signs and Symptoms or Conditions

§ Annex F - Health Effects - Health Impact

Regulators role:reviewing coding of incident

Annex Useful terms as examples

Annex A (Medical Device Problem)

A090803 (false negative)A090804 (false positive)A090805 (non reproducible results)

Annex G (Medical Device Component)

G01006 (test strip)G0200803 (user interface)G02011 (device reader)

Annex E (Health Effects -Clinical Signs and Symptoms or Conditions)

E2301 (alteration in body temperature)E0403 (immunodeficiency)E1102 (hepatitis)

Annex F (Health Effects - Health Impact)

F13 (misdiagnosis/misclassification)F04 (delay to diagnosis)F05 (delay to treatment/therapy)

http://www.imdrf.org/workitems/wi-aet.asp

Manufacturer investigation reporting form; see annex 2

Regulators role:reviewing initial manufacturer investigation report

Manufacturer’s preliminary comments

§ Investigation narrative, including § root cause analysis§ analysis of any impacted areas

§ IMDRF Type of Investigation (Annex B)§ IMDRF Investigation Findings (Annex C)§ IMDRF Investigation Conclusion (Annex D)

§ Initial correction (fix now) – may take place before root cause is established

§ Expected date of next report

§ Manufacturer investigation should contain:

§ Root cause cause analysis (how/why did this happen)

§ Analysis regarding related areas (is this same issue impacting/occurring elsewhere)

§ Scale and scope of issue

§ Manufacturer should use documented procedures, and tools

Regulators role:reviewing manufacturer’s root cause analysis

§ IMDRF N43 terminology

§ Annex B - Cause Investigation -Type of Investigation

§ Annex C - Cause Investigation -Investigation Findings

§ Annex D - Cause Investigation –Investigation Conclusion

Regulators role:reviewing coding of investigation

Annex Useful terms as examplesAnnex B (Cause Investigation -Type of Investigation)

B02 (Testing of Device from Same Lot/Batch Retained by Manufacturer)B14 (Analysis of Production Records)

Annex C (Cause Investigation -Investigation Findings)

C1403 (Change in Target Marker/Variant/ Mutant)C1304 (Incorrect Interpretation of Results/Data)C060201 (Improper Composition/ Concentration)C0501 (Inadequate Labelling and/or Instructions for Use)

Annex D (Cause Investigation –Investigation Conclusion)

D13 (Falsified Device)D1101 (Failure To Follow Instructions)D0302 (Quality Control Deficiency)

http://www.imdrf.org/workitems/wi-aet.asp

Manufacturer investigation reporting form; see annex 2

Regulators role:reviewing final manufacturer investigation report

Manufacturer’s final comments

§ Updated investigation narrative

§ IMDRF Type of Investigation (Annex B)§ IMDRF Investigation Findings (Annex C)§ IMDRF Investigation Conclusion (Annex D)§ Any additional corrections

§ Corrective/preventive action to be implemented § FSCA by manufacturer§ Date FSN issued§ FSN identifier § Time schedule for identified actions § Any previous similar events for this device with similar root cause § Signature

Regulators role:falsified medical devices

§ Falsified devices may be detected and/or reported to the NRA by

§ Legal manufacturer

§ Authorized representatives

§ Users

§ Other mitigation

§ Implementing UDI and traceability systems

§ How users can detect falsified devices

§ Check for any evidence of tampering of labels and/or packaging

§ Compare against approved labelling and packaging

§ Request certificate of analysis

§ Higher than expected invalid rates, unreturnable results, error rates, etc.

§ Price overly low or supplier does not seem reputable

Regulators role:tracking incidents

§ Record incident and its investigation

§ Risk-based approach for review

§ High risk incidents review more quickly

§ Low risk

§ Set deadline to review investigation and provide findings

§ Record of FSCA (usually in another jurisdiction)

Regular review of incident trends

• Type of reporter• Type of problem

• Investigation conclusion

Regulatory innovation – enhancing user feedback for post-market surveillance § User accesses application via web

browser using QR code or similar

§ User collects information:

§ Product - using Unique Device Identifier (UDI)

§ Incident – IMDRF classification

§ Reporter - using secure identity management

§ WHO guidance for medical devices including IVDs

§ Guidance on post-market and market surveillance here

§ Global Model Regulatory Framework, under review

§ Global benchmarking tool for regulators of medical devices, under development

§ Other international organizations

§ ISO Medical devices – post-market surveillance for manufacturers, ISO/TR20416:2020

§ IMDRF/GHTF

§ IMDRF terminologies for categorized adverse event reporting (AER);terms, terminology structure and codes, IMDR/AE WG/N43

§ GHTF WG2 on Post-market surveillance/vigilance here

§ GHWP/AHWP

§ AMDF

Normative guidance and expanded bibliography

https://www.who.int/health-topics/substandard-and-falsified-medical-products#tab=tab_1

Regulation and Prequalification Department

Anita SANDS

Incidents and Substandard/Falsified Medical Products Team sandsa@who.int

Any questions?