current regulatory lansdscape in europe ... - medidee services

03/06/2020

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ISO 9001 & ISO 13485 Certified company

COVID-19 tests

Current Requirements of Registra8on in Europe03.06.2020 Silvia Anghel, PhD

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ISO 9001 & ISO 13485 Certified companyMedidee Services © 2020

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Current Regulatory Lansdscape in Europe

• Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices (IVDD)

• A "directive" is a legislative act that sets out a goal that all EU countries must achieve. However, it is up to the individual member state to decide how by transposition in national law.

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Register an IVD on the EU maket

• Any manufacturer who places devices on the market under his ownname shall notify the competent authorities of the Member State inwhich he has his registered place of business

• When a manufacturer who places devices on the market under his ownname does not have a registered place of business in a Member State,he shall designate an authorised representative (EC Rep). Theauthorised representative shall notify the competent authorities of theMember State in which he has his registered place of business

• Once the device is registered in a Member State, the manufacturer canmake devices available on the territory of the Community

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Register an IVD on the EU maket_country specific limitations

• General limitaVon and COVID-19 specific limitaVon

• AddiVonal country-specific requirements may exist, parVcularly relatedto the labelling (labels and InstrucVon For Use of the device) andregistraVon of economical operators

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ISO 9001 & ISO 13485 Cer@fied companyMedidee Services © 2020

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Register an IVD on the EU maket_country specific limita?ons

• On 17 March 2020, Belgium has also adopted the Royal Decree concerning the prohibition of supply, putting into service and use of rapid self-tests for the measurement or detection of antibodies of SARS-COV-2 VIRUS. The purpose of this prohibition, which applies until 17 September 2020, ….

• “ …..currently illegal to supply tests for use by members of the public (self-tests) in the UK,” MHRA website 28.05.2020

• “Stakeholders (manufacturers, distributors) should contact the HPRA prior to supplying IVD test kits for COVID-19 to the Irish market. As this is a rapidly evolving situation, the HPRA can advise if a particular test is in line with the national strategy for COVID-19 testing in Ireland at a point in time.” HPRA; Ireland

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Register an IVD on the EU maket_Humanitarian use of non-CE-marked devices

• Country specific application, devices is not available on the wholeterritory of the Community

• Limited authorization (time, conditions of use)

• Does not waive the assessment of the Technical Documentation andcompliance to Essential Requirements by the Competent Authorities

“You are expected to have evidence that the device performs as intended.For example, you should include performance data such as bench testing(including any that comply with a relevant standard – harmonised orother) and any study data you have.” MHRA_UK

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Procedure for the Registration of IVD medical devices in EU: Conformity Assessment

• Prior to placing an IVD on the market, the device undergo a conformity assessment procedure

• Conformity assessment:o is the name given to the process that is used to demonstrate that a device

meets EssenVal Requirements as stated in the Annex I of IVDD.

• When the conformity assessment procedure is successful, a DeclaraVon of Conformity may be issued, and the device can registered on the EU market.

• The conformity assessment process depends on the classificaVon of the device

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Classification of the IVD medical device under IVDD

General

low risk

List A

high risk

List B

moderate risk

Self test

low to moderate risk

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Classifica?on of the IVD medical device under IVDD

General

low risk

List A

high risk

List B

moderate risk

Self test


List A

high risk

reagent products for determining blood group

per ABO systemreagent products for

detec9on of HIV, Hepa99s B, C and D

List B

moderate risk

reagent products for determining blood group

per anti-Duffyreagent products for

detection of toxoplasmosisreagent products for

determining PSA tumoralmarker

blood glucose self-test

Self test


Pregnancy self-testCholesterol self-test

General

low risk

InstrumentsSpecimen receptaclesAll the other tests not covered by List A or B

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Classification of COVID-19 tests under IVDD

Self test


Self- test for COVID-19

General

low risk

COVID-19 test for health professional use

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Conformity Assessment of COVID-19 tests

Self testHealth Professionals

• Under the sole responsibility of the manufacturer

• The manufacturer must prepare the technical documenta6on

• The manufacturer must show evidence that the manufacturing process follows the principles of quality assurance

• The manufacturer must keep up to date a procedure for post market surveillance

• Intervention of a notified body is required for the design-related requirements of the IVDD

• The assessment will include additionally, test reports of studies carried out with lay person, suitability of the device for self-testing in view of its intended purpose, labels and IFU

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Quality Management System (QMS)

Evidence of QMS

Process for Control of design and development changes

Quality control (QC) and batch release procedures (final QC)Proof of

control of critical suppliers

List of critical suppliers

Manufacturing workflow with QC points and manufacturing sites

Process for PMS

• The quality management standard EN ISO 13485:2016 Medical devices —Quality management systems — Requirements for regulatory purposes is considered a benchmark in quality management for manufacturers of IVDs

Manufacturing Process valida6on

Identification of the legalmanufacturer

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Technical Documenta?on_Descrip?on of the device

Iden6fica6on of the device

What is detected?

What is the Intended use?

Qualitative/Quantitative?

Specimen Type?

Testing population?

Intended user? Principle of ac6on?

Variants? Information on the origin of tissue/susbtances human origin

• Product descrip[on including variants (configura[ons) and accessories

Automated assay?

Software?

Control material?

List of accessories/products not provided but requierd

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Technical Documenta?on_Regulatory Informa?on

Classification List of countries in which the device is intended

• Clarification which variant/version is intended for the EU market

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Technical Documentation_Essential Requirements (ER checklist)

Applicability with jus6fica6on in case of N/A

Applied Standard Solution to meet ER

Method(s) used to demonstrate conformity

Complying Document(s)

• The legal manufacturer shall show evidence of conformity to applicable Essen[al Requirements, Annex I IVDD

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Technical Documenta?on_Risk Management

Risk Analysis

Risk of false negative/positive results to patient and community

Product associatedhazards(instability)

User-relatedhazards

• Iden[fica[on and quan[fica[on of all known or foreseeable hazards –EN ISO14971:2012- Medical devices - Applica[on of risk management to medical devices

Risk Management Report: risk:benefit ra6o

RiskAssessment

Risk Mi6ga6onProof of mitigation

Risk Management Plan

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Technical Documenta?on_Device Design

Specimen type,collection,processing

List of ingredients

Sequence for primers and probes (epitopes)

Safe disposal

Descrip6on of controls (internalcontrols )

Device Specifica6ons

• Control of Device Design

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Technical Documentation_ Performance

• The manufacturer shall submit evidence of relevant inves[ga[ons to support the intended use.

• AnalyVcal AND Clinical Performance

• List of harmonized standards

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Technical Documentation_ Performance_ Standards

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Technical Documentation_ Performance_IVD guidelines

• IMDRF MDCE WG/N57FINAL:2019 - Clinical InvesVgaVon• IMDRF MDCE WG/N56FINAL:2019 - Clinical EvaluaVon• IMDRF MDCE WG/N55 FINAL:2019 – Key DefiniVon and Concepts• GHTF/SG5/N8:2012 - Clinical Evidence for IVD Medical Devices - Clinical

Performance Studies for In Vitro DiagnosVc Medical Devices• GHTF/SG5/N7:2012 - Clinical Evidence for IVD medical devices – ScienVfic

Validity DeterminaVon and Performance EvaluaVon

• MEDDEV guidelines (IFU, IVD registraVon)

• TGS-4 Technical Guidance Series (TGS): for WHO PrequalificaVon – DiagnosVc Assessment ; Guidance on test method validaVon for in vitro diagnosVc medical devices

• Clinical & Laboratory Standards InsVtute (CLSI) : EP series

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Technical Documentation_ Performance_COVID-19 specific guidelines

• International level and EU level• WHO_PQDx_ 347 version 3 28 April 2020 _In vitro diagnostics (IVDs) Detecting

SARS-CoV-2 Nucleic Acid _Emergency Use Listing of IVDs• WHO_PQDx_352 version 1. 17 April 2020_Instructions for Submission

Requirements: In vitro diagnostics (IVDs) Detecting Antibodies to SARS-CoV-2 virus • FIND_Comparative evaluation of molecular tests that directly detect the nucleic

acid of the virus that causes COVID-19/SARS-CoV-2• FIND_Comparative evaluation of lateral flow assay tests that directly detect

antigens of SARS-CoV-2 • FIND_Comparative evaluation of lateral flow assay (LFA) and ELISA tests that

detect human antibodies specific to SARS-CoV-2 to support COVID-19 case management

• EU 2020/C1221/01 - Guidelines on COVID-19 in vitro diagnostic tests and their performance

• Working document of Commission services -Current performance of COVID-19 test methods and devices and proposed performance criteria (16 April 2020)

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• Country level

• UK_MHRA_ TARGET PRODUCT PROFILE An[body tests to help determine if people have immunity to SARS-CoV-2

• FR_ Haute Autorite de Sante - Cahier des charges définissant les modalitésd’évalua[on des performances des tests sérologiques détectant les an[corps dirigés contre le SARS-CoV-2, 16 Avril 2020

Technical Documentation_ Performance_COVID-19 specific guidelines

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Technical Documentation_ Analytical Performance

• AnalyVcal performance studies shall be designed to address:• Accuracy (repeatability, reproducibility, recovery)• Analy>cal sensi>vity (working range, linear range, limits of blank,

detecVon and quanVtaVon)• Analy>cal specificity (cross-reacVvity, interferences, in-silico study)• Appropriate criteria for specimen type, collecVon and handling• Stability

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• Meaningful conclusions about the IVD performance can only be derived fromperformance studies that make use of specimens in which the true analyte orclinical status has been determined to a high level of confidence.• The true status of a specimen or subject should be determined using an

appropriate reference method (the best available method for establishing thepresence or absence of the target condition). In some cases, the referencestandard may be a single state-of-the-art test; in others, a validated testingalgorithm may be required.

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Technical Documenta?on_ Analy?cal Performance

Specimen type

• Identification of the different specimen types that can be used with the product • When the assay can be used with multiple specimen types, a matrix equivalency

study should be used to support certain specimen type claims that were not evaluated during the clinical study (with samples in all range of analyte positive to negative, around LOD)• A specimen stability study is required to support the specimen stability for each

specimen type. • Storage conditions (e.g., temperature limits, freeze/thaw cycles), transport

conditions.

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Repeatability & Reproducibility

• Repeatability : within-run precision• Reproducibility: between-days, runs, sites, lots, operators and instruments

precision• Both repeatability and reproducibility studies should include specimens in the

whole range from negaVve to posiVve (LOD, moderately posiVve, posiVve)

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Technical Documenta?on_ Analy-cal PerformanceAnalytical Sensitivity (LOD/cut-off)

• The LoD of the IVD shall be determined uVlizing the enVre test system from specimen preparaVon, nucleic acid extracVon, to detecVon for each clinical specimen type/matrix claimed. • It is possible to use spiked samples• LOD is established using diluVons spanning the tentaVve LoD to obtain a more

accurate esVmate of the LoD (to demonstrate that the organism was detected with a minimum 95% posiVvity). • If this confirmatory study achieves a posiVvity of 100%, then a lower concentraVon

needs to be tested unVl <100% posiVvity is obtained. • The LoD shall be determined for each claimed specimen type.

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Analytical Specificty (interference)

• Endogenous and exogenous substances shall be spiked into the appropriate negaVve matrix at the highest levels found in individuals

• Each endogenous and exogenous specimen shall be tested unspiked and spiked with the analyte at an appropriate low concentraVon (e.g. approx. 2 – 3 x LoD)

• Samples should be tested with only one claimed specimen type/matrix unless significant differences in LoD are observed between specimen matrices

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Analytical Specificty (cross reactivity)• RT-PCR: • Organisms/strains which are likely to be observed in the currently affected

areas should be tested since these organisms/strains will be an important part of the differenVal diagnosis of SARS-CoV-2 infecVon (MERS; Influenza; coronaviruses..)• Wet-lab tes>ng: One claimed specimen type/matrix is required in this study.• In-silico tes>ng: include mulVple representaVve strains from GenBank

sequence database for each organism. • Serology:• TesVng specimens containing anVbodies to other microorganisms that could

potenVally cause false posiVve results –use of near-neighbour species/strains and of organisms whose infecVon produces symptoms similar to those observed for COVID-19• If tests detect IgG and IgM the cross-reacVon between IgG and IgM should also

be assessed

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Valida@on of the Primer choice (RT-PCR)

• Evidence supporting the choice of primers and probes sequences shall be provided and shall include: oThe target gene(s) and sequence for primers and probes

oThe rationale for selection of primers and probes and specific sequences used

oJustification for alignments made to generate consensus sequences or best-fit modifications made to existent sequences e.g. to permit maximum homology to several strains.

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Hook Effect (Serology)

• Provide diluVon experiments of relevant paVent specimens or spiking negaVve paVent specimen with high concentraVon analytes to assess the concentraVon of analyte at which the hook effect is observed

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Stability

• Shelf-life: Accelerated studies or extrapolated data from real time data are acceptable for initial shelf life claim, • Transport: Conditions to mimic extremes of conditions (temperature, humidity,

pressure) exposed to during transport/shipping. • In –use: open pack or open vial stability; all labile components (e.g. buffers vials,

sealed cartridges, etc.) shall be evaluated.

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Technical Documentation_ Clinical Performance

• Specimens from all secVons of the populaVon for which claims are made in the IFU and from the regions where the test will be used, shall be tested.

• The results should be compared to a predicate (an approved/reference method)_PCR method (not serology)

• Clinical performance should be ideally evaluated for each claimed clinical specimen type

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Technical Documentation_ Clinical Performance

• RT-PCR:• Clinical sensiVvity: ideally 50 prospecVve posiVve samples or at least 25

retrospecVve/prospecVve and the remaining contrived samples with samples to LOD and up to 5xLOD• Clinical specificity: A minimum of 100 negaVve specimens, collected from

symptomaVc individuals in the region where the assay will be used, shall be tested.

• Serology:• Clinical sensiVvity: ideally 200 specimens (100 known posiVve specimens and

100 signs and symptoms suggesVve of COVID-19)• Clinical specificity: ideally 200 individual tested negaVve and 1000 general

populaVon with respiratory symptoms

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Conclusion• Registration of COVID-19 tests:

o intended for self-test, involvement of a notify bodyo intended for health professional use are not on List A or B of Annex II IVDD,

self certification - notification to competent authorities following a conformity assessment procedure conducted by the manufacturer and issue of a Declaration of Conformity to ERs as per Annex I of IVDD

• Country specific limitations/requirements may exist• The Conformity Assessment requires the review of the technical documentation

for compliance to IVDD• Legal manufacturer shall take advantage of the free availability of IVD standards

through the National Standardization Bodies and from the international and national guidelines related to the design of the analytical and clinical performance studies.

• Humanitarian Procedures allow to put on the EU market a non-CE-marked products for a limited time and with restrictions

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ISO 9001 & ISO 13485 Cer@fied company

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Silvia [email protected]

Medidee Services © 2020

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