the new eu ivdr - world cdx...

The New EU IVDROverview of the Main Changes & Clinical Data Requirements

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The New EU IVDR:Timeline:

EntryintoforceQ2(Apr)2017

Adoption:+6mNB’sapplyfordesignation

5yr.transition:ChoiceofIVDD

orIVDRDoA:Apr2022

IVDsclassifiedasClassAcanbeplacedonmarketunder

IVDR

CECertificatescanberenewedduringthe

transitionperiod:Max- DoA+2years(TBC)

• 5 year transition• Manufacturer can apply either the IVDD or IVDR, however NB

designation will be gating factor • All products must be in compliance at the end of the transition

period otherwise they must be taken off the market• There is no expectation that there will be an extension

The New EU IVDR:Significant Changes:

§ Regulation, not a Directive – will apply uniformly in all member states although some areas are left to member states to legislate e.g. information and counselling in relation to genetic testing

§ IVD Classification Rules based on GHTF/IMDRF Rules (JP, Aus, Can); IVD’s will fall in to 1 of four classes; A to D with A being the lowest risk

§ Requirements included for in-house tests/LDTs – Article 5(5) & Annex I

§ Companion diagnostics specifically defined and have specific

requirements

§ New labelling requirements including UDI

§ Increased Post-Market requirements

§ Creation of Reference Labs for class D IVDs conformity

§ Increased focus on and level of Clinical Evidence

§ Requirement for a QP

§ Specific requirements for Economic Operators and Distributors

The New EU IVDR:Annex VIII - Classification Rules:

The New EU IVDRClass C Assays

In addition to meeting the general safety & performance requirements in Annex I of the regulation, Companion Dx must follow the procedures set out in Annex IX or X combined with XI:

The New EU IVDRAnnex IX (Conformity Assessment) for CDx devices:

In addition to the general requirements of Annex IX, Full Quality Assurance, §5.2 details requirements for Companion Diagnostic Devices:

§ Member State CA for Medicines or the EMA shall be consulted by the

Notified Body as part of the conformity assessment

§ 60 days to provide opinion – may be extended for a further 60 days on

‘justified’ grounds

§ ‘EU technical documentation assessment certificate’ issued by Notified

Body

§ 30-day period for assessment of changes (New submission or

Supplement) to the CDx is provided for along with a requirement for a

supplement to the EU technical documentation assessment certificate

to be issued by the NB

The New EU IVDRDefinitions relevant to IVD performance evaluation:

‘Clinical Evidence’ means the clinical data and performance evaluation results pertaining to a device, of sufficient amount and quality to allow a qualified assessment of whether the device achieves the intended clinical benefit(s) and safety, when used as intended by the manufacturer;

‘clinical benefit of an in-vitro diagnostic device’ means the positive impact of a device related to its function (e.g. screening, monitoring, diagnosis or aid to diagnosis of patients) or a positive impact on patient management or public health;

'scientific validity of an analyte' means the association of an analyte to a clinical condition or a physiological state;

'analytical performance' means the ability of a device to correctly detect or measure a particular analyte;

The New EU IVDRDefinitions relevant to IVD performance evaluation:

‘Performance of a device’means the the ability of a device to achieve its intended purpose as claimed by the manufacturer. It consists of the analytical and, where applicable, the clinical performance supporting the intended purpose of the device;

‘clinical performance' means the ability of a device to yield results that are correlated with a particular clinical condition or a physiological or pathological process or state in accordance with the target population and intended user;

'interventional clinical performance study' means a clinical performance study where the test results may influence patient management decisions and/or may be used to guide treatment;

The New EU IVDRPerformance Evaluation and PMPF:

§ Performance Evaluation is a continuous process of data assessment and

analysis

§ PE covers:

§ Scientific Validity

§ Analytical Performance &

§ Clinical Performance

§ Requires manufacturer to generate a PE Plan and Report (incorporating all 3

‘pillars’ above ) and to continuously conduct and document the performance

evaluation

§ Must be objective considering favourable and unfavourable data

§ As a general rule, clinical evidence should be sourced from performance

studies to be carried out under the responsibility of a study sponsor

(manufacturer or other legal or natural person taking responsibility for the

PE study):

The New EU IVDREstablishing Scientific Validity per Annex XIII (PE §1.2.1):

The manufacturer shall demonstrate the scientific validity based on one or

a combination of the following sources:

§ relevant information on the scientific validity of devices measuring the

same analyte or marker;

§ scientific (peer-reviewed) literature;

§ consensus expert opinions/positions from relevant professional

associations;

§ results from proof of concept studies;

§ results from clinical performance studies.

Much easier for an established biomarker!!

The New EU IVDREstablishing Analytical Performance per Annex XIII (PE §1.2.2):

The manufacturer shall demonstrate the analytical performance of the

device according to all the parameters described in point (a) of Section

6(1) of Annex 1 (General Principles of safety and performance);

Analytical sensitivity; Analytical Specificity; Trueness (bias); Precision

(repeatability and reproducibility); Accuracy (resulting from trueness and

precision); Limits of Detection and Quantitation; Measuring Range;

Linearity; Cut-off;

As well as determination of appropriate criteria for specimen collection

and handling and control of known relevant Endogenous and

Exogenous interference and Cross-reactions;

Unless any omission can be justified as not applicable.

As a general rule, the analytical performance shall always be

demonstrated on the basis of analytical performance studies.

The New EU IVDREstablishing Analytical Performance per Annex XIII (PE §1.2.2):

For Novel Markers:

§ May not be possible to demonstrate trueness as certified reference

materials or reference measurement procedures may not be available.

§ Different approaches may be used e.g. comparison to composite

reference methods or some other well documented methods.

§ If not possible; A Clinical Performance Study comparing

performance of the novel device with current clinical practice is

required.

The New EU IVDREstablishing Clinical Performance per Annex XIII (PE §1.2.3):

The manufacturer shall demonstrate the clinical performance of the device

according to all the parameters described in point (b) of Section 6.1. of

Annex I:

diagnostic sensitivity, diagnostic specificity, positive predictive value,

negative predictive value, likelihood ratio, expected values in normal and

affected populations.

Unless any omission be justified as not applicable.

Clinical Performance shall be based on one or a combination of the

following:

§ clinical performance studies;

§ scientific peer-reviewed literature;

§ published experience gained by routine diagnostic testing.


“Clinical performance studies shall be performed unless it is duly justified to rely on other sources of clinical performance data.”


Clinical Performance Studies §2 Annex XIII:

§ Purpose: To establish or confirm aspects of device

performance which can’t be determined by analytical

performance studies

§ Used to demonstrate compliance with the relevant general

safety and performance requirements wrt clinical performance

§ Every step: from first consideration of the need to publication

of the results shall be carried out in accordance with

recognised ethical principles.


Clinical Performance Studies Contd:

Studies shall be:

§ designed in such a way as to maximize the relevance of the

data while minimising potential bias

§ Performed on the basis of a Clinical Performance Study Plan

which defines:§ the rationale, § objectives, § design methodology, § monitoring, § statistical considerations, § organisation and conduct of the study

and shall contain…


Clinical Performance Study Plan:

a). Identification of the CP study and the CPSP

b). Identification of the Sponsor

c). Identification of the investigator(s), site(s), location and number

of lay persons (self-test devices),

d). starting date and duration

e). Identification and description of device, intended use,

analytes/markers, metrological traceability

f). Specimen type(s)

g). Synopsis: design type (longitudinal/cross

sectional/interventional etc.), objectives, hypotheses, reference to

SoA/clinical practice


Clinical Performance Study Plan Contd:

h). Risks and benefits

i). IFU including training requirements, other devices or medicinal

products to be used in the study

j). Description of the justification for the design, scientific

robustness and validity, statistical design etc. (SAP)

k). Analytical performance

l). Parameters of clinical performance

m). Performance study population

n). Information on the use of data from left-over samples

o). Monitoring Plan

The New EU IVDREstablishing Clinical Performance per Annex XIII (PE §1.2.3)

Clinical Performance Study Plan Contd:

p). Data Management

q). Decision Algorithms

r). Policy regarding amendments or deviations with a clear

prohibition of the use of waivers

s). Device Accountability

t). Ethical & regulatory compliance statement

u). IC Process including Patient Info sheet and ICF

v). Safety recording and reporting

w). Procedures for suspension or early termination of the CPS

x). Follow up procedures


Clinical Performance Study Plan Contd:y). Policy regarding reporting and publication in accordance with legal and ethical requirementsz). List of technical and functional features of the device indicating those that are covered by the performance study. (aa) Bibliography.

Whereanyoftheabove-mentionedelementsarenotdeemedappropriateforinclusionintheCPSPduetothespecificstudydesignchosen(e.g.useofleft-oversamplesversusinterventionalclinicalperformancestudies),ajustificationshallbeprovided.

The New EU IVDREstablishing Clinical Performance per Annex XII (PE §1.2.3):

Clinical Performance Study Report:

• signed by a medical practitioner or any other authorised

person responsible,

• shall contain documented information on the clinical

performance study protocol plan, results and conclusions of

the clinical performance study, including negative findings.

• The results and conclusions shall be transparent, free of bias

and clinically relevant.

• The report shall contain sufficient information to enable it to

be understood by an independent party without reference to

other documents.

The New EU IVDREstablishing Clinical Performance per Annex XII (PE §1.2.3):

Clinical Performance Study Report:

• The report shall also include, as appropriate, any protocol

amendments or deviations, and data exclusions with the

appropriate rationale.

The New EU IVDRPost-Market Performance Follow-up (PMPF) per Annex XIII:

• Manufacturer shall proactively collect and evaluate

performance and relevant scientific data from the use of a

device which bears the CE-mark, placed on the market or put

in to service…

• To confirm safety, performance and scientific validity

throughout the lifetime of the device

• Performed in accordance with a documented PMPF plan

• Amongst other things, confirm safety and performance and:

• Assuring continued acceptability of the clinical evidence and

of the benefit/risk ratio

The New EU IVDRInterventional and high-risk Clinical Performance Studies per Annex XIV:

Sponsor shall draw up and submit application in accordance with

Article 48a including:

• Application form

• Investigator’s Brochure

• Clinical Performance Study Plan

• Other information including;• Declaration of device conformity and ethical compliance

(similar to Annex VIII in directive) • REC opinion• Insurance and indemnification• ICF and patient information• Data protection etc.

The New EU IVDR:CDx – Rx Development Timelines:

Rx-CDx Development&ApprovalTimeline(Standard)

IVDRPublished•Q22017

NBDesignationComplete•12-18mc.Q42018

DoA - AllIVD'smustcomply

•Q22022

2019

2021

2020

IVDRPublished•Q22017

2018

DoA 2022

2019

2020

2021

PhaseII/IIITrial DataAnalysis,Rx- CDx Submission&Review

Launch

We need to be implementing the new clinical requirements NOW!!

The New EU IVDRSignificant Changes:

QUESTIONS?

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