Overview of the Main Changes & Clinical Data Requirements Advance Regulatory Consulting Ltd.
: Timeline: Entry in to force Q2 (Apr) 2017 Adoption: +6m NB s apply for designation IVDs classified as Class A can be placed on market under IVDR 5 yr. transition: Choice of IVDD or IVDR DoA: Apr 2022 CE Certificates can be renewed during the transition period: Max - DoA + 2 years (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
: 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
: Annex VIII - Classification Rules:
Class 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:
Annex 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
Definitions 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;
Definitions 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;
Performance 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):
Establishing 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!!
Establishing 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.
Establishing 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.
Establishing 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.
Establishing Clinical Performance per Annex XIII (PE 1.2.3): Clinical performance studies shall be performed unless it is duly justified to rely on other sources of clinical performance data.
Establishing Clinical Performance per Annex XIII (PE 1.2.3): 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.
Establishing Clinical Performance per Annex XIII (PE 1.2.3): 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
Establishing Clinical Performance per Annex XIII (PE 1.2.3): 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
Establishing Clinical Performance per Annex XIII (PE 1.2.3): 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
Establishing 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
Establishing Clinical Performance per Annex XIII (PE 1.2.3): Clinical Performance Study Plan Contd: y). Policy regarding reporting and publication in accordance with legal and ethical requirements z). List of technical and functional features of the device indicating those that are covered by the performance study. (aa) Bibliography. Where any of the above-mentioned elements are not deemed appropriate for inclusion in the CPSP due to the specific study design chosen (e.g. use of left-over samples versus interventional clinical performance studies), a justification shall be provided.
Establishing 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.
Establishing 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.
Post-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
Interventional 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.
: CDx Rx Development Timelines: IVDR Published DoA - All IVD's must comply 2021 Q2 2017 NB Designation Complete 2019 Q2 2022 2020 12-18m c. Q4 2018 Rx-CDx Development & Approval Timeline (Standard) IVDR Published Q2 2017 DoA 2022 2020 2018 2019 Phase II/III Trial 2021 Data Analysis, Rx - CDx Submission & Review Launch We need to be implementing the new clinical requirements NOW!!
Significant Changes: QUESTIONS?