Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU (Text with EEA relevance. )

For novel markers or other markers without available certified reference materials or reference measurement procedures, it may not be possible to demonstrate trueness. If there are no comparative methods, different approaches may be used if demonstrated to be appropriate, such as comparison to some other well-documented methods or the composite reference standard. In the absence of such approaches, a clinical performance study comparing performance of the novel device to the current clinical standard practice is required.

Analytical performance shall be demonstrated and documented in the analytical performance report.

1.2.3.   Demonstration of the clinical performance

The manufacturer shall demonstrate the clinical performance of the device in relation to all the parameters described in point (b) of Section 9.1. of Annex I, unless any omission can be justified as not applicable.

Demonstration of the clinical performance of a device shall be based on one or a combination of the following sources:

• — clinical performance studies;

• — scientific peer-reviewed literature;

• — published experience gained by routine diagnostic testing.

Clinical performance studies shall be performed unless due justification is provided for relying on other sources of clinical performance data.

Clinical performance shall be demonstrated and documented in the clinical performance report.

1.3.   Clinical evidence and performance evaluation report

• 1.3.1. The manufacturer shall assess all relevant scientific validity, analytical and clinical performance data to verify the conformity of its device with the general safety and performance requirements as referred to in Annex I. The amount and quality of that data shall allow the manufacturer to make a qualified assessment whether the device will achieve the intended clinical benefit or benefits and safety, when used as intended by the manufacturer. The data and conclusions drawn from this assessment shall constitute the clinical evidence for the device. The clinical evidence shall scientifically demonstrate that the intended clinical benefit or benefits and safety will be achieved according to the state of the art in medicine.

• 1.3.2. Performance evaluation report

The clinical evidence shall be documented in a performance evaluation report. This report shall include the scientific validity report, the analytical performance report, the clinical performance report and an assessment of those reports allowing demonstration of the clinical evidence.

The performance evaluation report shall in particular include:

• — the justification for the approach taken to gather the clinical evidence;

• — the literature search methodology and the literature search protocol and literature search report of a literature review;

• — the technology on which the device is based, the intended purpose of the device and any claims made about the device's performance or safety;

• — the nature and extent of the scientific validity and the analytical and clinical performance data that has been evaluated;

• — the clinical evidence as the acceptable performances against the state of the art in medicine;

• — any new conclusions derived from PMPF reports in accordance with Part B of this Annex.

• 1.3.3. The clinical evidence and its assessment in the performance evaluation report shall be updated throughout the life cycle of the device concerned with data obtained from the implementation of the manufacturer's PMPF plan in accordance with Part B of this Annex, as part of the performance evaluation and the post-market surveillance system referred to in Article 10(9). The performance evaluation report shall be part of the technical documentation. Both favourable and unfavourable data considered in the performance evaluation shall be included in the technical documentation.

2. CLINICAL PERFORMANCE STUDIES

2.1.   Purpose of clinical performance studies

The purpose of clinical performance studies is to establish or confirm aspects of device performance which cannot be determined by analytical performance studies, literature and/or previous experience gained by routine diagnostic testing. This information is used to demonstrate compliance with the relevant general safety and performance requirements with respect to clinical performance. When clinical performance studies are conducted, the data obtained shall be used in the performance evaluation process and be part of the clinical evidence for the device.

2.2.   Ethical considerations for clinical performance studies

Each step in the clinical performance study, from the initial consideration of the need for and justification of the study to the publication of the results, shall be carried out in accordance with recognised ethical principles.

2.3.   Methods for clinical performance studies

2.3.1.   Clinical performance study design type

Clinical performance studies shall be designed in such a way as to maximize the relevance of the data while minimising potential bias.

2.3.2.   Clinical performance study plan

Clinical performance studies shall be performed on the basis of a clinical performance study plan (CPSP).

The CPSP shall define the rationale, objectives, design and proposed analysis, methodology, monitoring, conduct and record-keeping of the clinical performance study. It shall contain in particular the following information:

• (a) the single identification number of the clinical performance study, as referred to in Article 66(1);

• (b) identification of the sponsor, including the name, address of the registered place of business and contact details of the sponsor and, if applicable, the name, address of the registered place of business and contact details of its contact person or legal representative pursuant to Article 58(4) established in the Union;

• (c) information on the investigator or investigators, namely principal, coordinating or other investigator; qualifications; contact details, and investigation site or sites, such as number, qualification, contact details and, in the case of devices for self-testing, the location and number of lay persons involved;

• (d) the starting date and scheduled duration for the clinical performance study;

• (e) identification and description of the device, its intended purpose, the analyte or analytes or marker or markers, the metrological traceability, and the manufacturer;

• (f) information about the type of specimens under investigation;

• (g) overall synopsis of the clinical performance study, its design type, such as observational, interventional, together with the objectives and hypotheses of the study, reference to the current state of the art in diagnosis and/or medicine;

• (h) a description of the expected risks and benefits of the device and of the clinical performance study in the context of the state of the art in clinical practice, and with the exception of studies using left-over samples, the medical procedures involved and patient management;

• (i) the instructions for use of the device or test protocol, the necessary training and experience of the user, the appropriate calibration procedures and means of control, the indication of any other devices, medical devices, medicinal product or other articles to be included or excluded and the specifications on any comparator or comparative method used as reference;

• (j) description of and justification for the design of the clinical performance study, its scientific robustness and validity, including the statistical design, and details of measures to be taken to minimise bias, such as randomisation, and management of potential confounding factors;

• (k) the analytical performance in accordance with point (a) of Section 9.1 of Chapter I of Annex I with justification for any omission;

• (l) parameters of clinical performance in accordance with point (b) of Section 9.1 of Annex I to be determined, with justification for any omission; and with the exception of studies using left-over samples the specified clinical outcomes/endpoints (primary/secondary) used with a justification and the potential implications for individual health and/or public health management decisions;

• (m) information on the performance study population: specifications of the subjects, selection criteria, size of performance study population, representativity of target population and, if applicable, information on vulnerable subjects involved, such as children, pregnant women, immuno-compromised or elderly subjects;

• (n) information on use of data out of left over specimens banks, genetic or tissue banks, patient or disease registries etc. with description of reliability and representativity and statistical analysis approach; assurance of relevant method for determining the true clinical status of patient specimens;

• (o) monitoring plan;

• (p) data management;

• (q) decision algorithms;

• (r) policy regarding any amendments, including those in accordance with Article 71, to or deviations from the CPSP, with a clear prohibition of use of waivers from the CPSP;

• (s) accountability regarding the device, in particular control of access to the device, follow-up in relation to the device used in the clinical performance study and the return of unused, expired or malfunctioning devices;

• (t) statement of compliance with the recognised ethical principles for medical research involving humans and the principles of good clinical practice in the field of clinical performance studies as well as with the applicable regulatory requirements;

• (u) description of the informed consent process, including a copy of the patient information sheet and consent forms;

• (v) procedures for safety recording and reporting, including definitions of recordable and reportable events, and procedures and timelines for reporting;

• (w) criteria and procedures for suspension or early termination of the clinical performance study;

• (x) criteria and procedures for follow up of subjects following completion of a performance study, procedures for follow up of subjects in the case of suspension or early termination, procedures for follow up of subjects who have withdrawn their consent and procedures for subjects lost to follow up;

• (y) procedures for communication of test results outside the study, including communication of test results to the performance study subjects;

• (z) policy as regards the establishment of the clinical performance study report and publication of results in accordance with the legal requirements and the ethical principles referred to in Section 2.2;

• (aa) list of the technical and functional features of the device indicating those that are covered by the performance study;

• (ab) bibliography.

If part of the information referred to in the second paragraph is submitted in a separate document, it shall be referenced in the CPSP. For studies using left-over samples, points (u), (x), (y) and (z) shall not apply.

Where any of the elements referred to in the second paragraph are not deemed appropriate for inclusion in the CPSP due to the specific study design chosen, such as use of left-over samples versus interventional clinical performance studies, a justification shall be provided.

2.3.3.   Clinical performance study report

A 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 report shall also include as appropriate any protocol amendments or deviations, and data exclusions with the appropriate rationale.

3. OTHER PERFORMANCE STUDIES

By analogy, the performance study plan referred to in Section 2.3.2, and the performance study report, referred to in Section 2.3.3, shall be documented for other performance studies than clinical performance studies.

PART B

POST-MARKET PERFORMANCE FOLLOW-UP

• 1. PMPF shall be understood to be a continuous process that updates the performance evaluation referred to in Article 56 and Part A of this Annex and shall be specifically addressed in the manufacturer's post-market surveillance plan. When conducting PMPF, the manufacturer shall proactively collect and evaluate performance and relevant scientific data from the use of a device which bears the CE marking and is placed on the market or put into service within its intended purpose as referred to in the relevant conformity assessment procedure, with the aim of confirming the safety, performance and scientific validity throughout the expected lifetime of the device, of ensuring the continued acceptability of the benefit-risk ratio and of detecting emerging risks on the basis of factual evidence.

• 1. PMPF shall be performed pursuant to a documented method laid down in a PMPF plan.

• 5.1. The PMPF plan shall specify the methods and procedures for proactively collecting and evaluating safety, performance and scientific data with the aim of:

• (a) confirming the safety and performance of the device throughout its expected lifetime,

• (b) identifying previously unknown risks or limits to performance and contra-indications,

• (c) identifying and analysing emergent risks on the basis of factual evidence,

• (d) ensuring the continued acceptability of the clinical evidence and of the benefit-risk ratio referred to in Sections 1 and 8 of Chapter I of Annex I, and

• (e) identifying possible systematic misuse.

• 5.2. The PMPF plan shall include at least:

• (a) the general methods and procedures of the PMPF to be applied, such as gathering of clinical experience gained, feedback from users, screening of scientific literature and of other sources of performance or scientific data;

• (b) the specific methods and procedures of PMPF to be applied, such as ring trials and other quality assurance activities, epidemiological studies, evaluation of suitable patient or disease registers, genetic databanks or post-market clinical performance studies;

• (c) a rationale for the appropriateness of the methods and procedures referred to in points (a) and (b);

• (d) a reference to the relevant parts of the performance evaluation report referred to in Section 1.3 of this Annex and to the risk management referred to in Section 3 of Annex I;

• (e) the specific objectives to be addressed by the PMPF;

• (f) an evaluation of the performance data relating to equivalent or similar devices, and the current state of the art;

• (g) reference to any relevant CS, harmonised standards when used by the manufacturer, and relevant guidance on PMPF, and;

• (h) a detailed and adequately justified time schedule for PMPF activities, such as analysis of PMPF data and reporting, to be undertaken by the manufacturer.

• 1. The manufacturer shall analyse the findings of the PMPF and document the results in a PMPF evaluation report that shall update the performance evaluation report and be part of the technical documentation.

• 1. The conclusions of the PMPF evaluation report shall be taken into account for the performance evaluation referred to in Article 56 and Part A of this Annex and in the risk management referred to in Section 3 of Annex I. If, through the PMPF, the need for preventive and/or corrective measures has been identified, the manufacturer shall implement them.

• 1. If PMPF is not deemed appropriate for a specific device then a justification shall be provided and documented within the performance evaluation report.

ANNEX XIV

INTERVENTIONAL CLINICAL PERFORMANCE STUDIES AND CERTAIN OTHER PERFORMANCE STUDIES

CHAPTER I

DOCUMENTATION REGARDING THE APPLICATION FOR INTERVENTIONAL CLINICAL PERFORMANCE STUDIES AND OTHER PERFORMANCE STUDIES INVOLVING RISKS FOR THE SUBJECTS OF THE STUDIES

For devices intended to be used in the context of interventional clinical performance studies or other performance studies involving risks for the subjects of the studies, the sponsor shall draw up and submit the application in accordance with Article 58 accompanied by the following documents:

• 1. Application form The application form shall be duly filled in, containing the following information:
• 1.1. name, address and contact details of the sponsor and, if applicable, name, address and contact details of its contact person or legal representative in accordance with Article 58(4) established in the Union;
• 1.2. if different from those in Section 1.1, name, address and contact details of the manufacturer of the device intended for performance evaluation and, if applicable, of its authorised representative;
• 1.3. title of the performance study;
• 1.4. single identification number in accordance with Article 66(1);
• 1.5. status of the performance study, such as. the first submission, resubmission, significant amendment;
• 1.6. details and/ or reference to the performance study plan, such as including details of the design phase of the performance study;
• 1.7. if the application is a resubmission with regard to a device for which an application has been already submitted, the date or dates and reference number or numbers of the earlier application or in the case of significant amendment, reference to the original application. The sponsor shall identify all of the changes from the previous application together with a rationale for those changes, in particular, whether any changes have been made to address conclusions of previous competent authority or ethics committee reviews;
• 1.8. if the application is submitted in parallel with an application for a clinical trial in accordance with Regulation (EU) No 536/2014, reference to the official registration number of the clinical trial;
• 1.9. identification of the Member States and third countries in which the clinical performance study is to be conducted as part of a multicentre or multinational study at the time of application;
• 1.10. brief description of the device for performance study, its classification and other information necessary for the identification of the device and device type;
• 1.11. summary of the performance study plan;
• 1.12. if applicable, information regarding a comparator device, its classification and other information necessary for the identification of the comparator device;
• 1.13. evidence from the sponsor that the clinical investigator and the investigational site are capable of conducting the clinical performance study in accordance with the performance study plan;
• 1.14. details of the anticipated start date and duration of the performance study;
• 1.15. details to identify the notified body, if already involved at the stage of application for the performance study;
• 1.16. confirmation that the sponsor is aware that the competent authority may contact the ethics committee that is assessing or has assessed the application;
• 1.17. the statement referred to in Section 4.1.

• 1. Investigator's brochure The investigator's brochure (IB) shall contain the information on the device for performance study that is relevant for the study and available at the time of application. Any updates to the IB or other relevant information that is newly available shall be brought to the attention of the investigators in a timely manner. The IB shall be clearly identified and contain in particular the following information:
• 2.1. Identification and description of the device, including information on the intended purpose, the risk classification and applicable classification rule pursuant to Annex VIII, design and manufacturing of the device and reference to previous and similar generations of the device.
• 2.2. Manufacturer's instructions for installation, maintenance, maintaining hygiene standards and for use, including storage and handling requirements, as well as, to the extent that such information is available, information to be placed the label, and instructions for use to be provided with the device when placed on the market. In addition, information relating to any relevant training required.
• 2.3. Analytical performance.
• 2.4. Existing clinical data, in particular:
• — from relevant peer-reviewed scientific literature and available consensus expert opinions or positions from relevant professional associations relating to the safety, performance, clinical benefits to patients, design characteristics, scientific validity, clinical performance and intended purpose of the device and/or of equivalent or similar devices;
• — other relevant clinical data available relating to the safety, scientific validity, clinical performance, clinical benefits to patients, design characteristics and intended purpose of similar devices, including details of their similarities and differences with the device in question.
• 2.5. Summary of the benefit-risk analysis and the risk management, including information regarding known or foreseeable risks and warnings.
• 2.6. In the case of devices that include tissues, cells and substances of human, animal or microbial origins detailed information on the tissues, cells and substances, and on the compliance with the relevant general safety and performance requirements and the specific risk management in relation to those tissues, cells and substances.
• 2.7. A list detailing the fulfilment of the relevant general safety and performance requirements set out in Annex I, including the standards and CS applied, in full or in part, as well as a description of the solutions for fulfilling the relevant general safety and performance requirements, in so far as those standards and CS have not or have only been partly fulfilled or are lacking.
• 2.8. A detailed description of the clinical procedures and diagnostic tests used in the course of the performance study and in particular information on any deviation from normal clinical practice.

• 1. Performance study plan as referred to in Sections 2 and 3 of Annex XIII.

• 1. Other information
• 4.1. A signed statement by the natural or legal person responsible for the manufacture of the device for performance study that the device in question conforms to the general safety and performance requirements laid down in Annex I apart from the aspects covered by the clinical performance study and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject.
• 4.2. Where applicable according to national law, a copy of the opinion or opinions of the ethics committee or committees concerned. Where under national law the opinion or opinions of the ethics committee or committees is not required at the time of the submission of the application, a copy of the opinion or opinions shall be submitted as soon as available.
• 4.3. Proof of insurance cover or indemnification of subjects in case of injury, pursuant to Article 65 and the corresponding national law.
• 4.4. Documents to be used to obtain informed consent, including the patient information sheet and the informed consent document.
• 4.5 Description of the arrangements to comply with the applicable rules on the protection and confidentiality of personal data, in particular:
• — organisational and technical arrangements that will be implemented to avoid unauthorised access, disclosure, dissemination, alteration or loss of information and personal data processed;
• — a description of measures that will be implemented to ensure confidentiality of records and personal data of subjects;
• — a description of measures that will be implemented in case of a data security breach in order to mitigate the possible adverse effects.
• 4.6. Full details of the available technical documentation, for example detailed risk analysis/management documentation or specific test reports shall be submitted to the competent authority reviewing an application upon request.

CHAPTER II

OTHER OBLIGATIONS OF THE SPONSOR

• 1. The sponsor shall undertake to keep available for the competent national authorities any documentation necessary to provide evidence for the documentation referred to in Chapter I of this Annex. If the sponsor is not the natural or legal person responsible for the manufacture of the device intended for performance study, that obligation may be fulfilled by that person on behalf of the sponsor.

• 1. The sponsor shall have an agreement in place to ensure that any serious adverse events or any other event as referred to in Article 76(2) are reported by the investigator or investigators to the sponsor in a timely manner.

• 1. The documentation mentioned in this Annex shall be kept for a period of time of at least 10 years after the clinical performance study with the device in question has ended, or, in the event that the device is subsequently placed on the market, for at least 10 years after the last device has been placed on the market. Each Member State shall require that the documentation referred to in this Annex is kept at the disposal of the competent authorities for the period indicated in the first subparagraph in case the sponsor, or his contact person, established within its territory, goes bankrupt or ceases its activity prior to the end of this period.

• 1. The sponsor shall appoint a monitor that is independent of the investigation site to ensure that the clinical performance study is conducted in accordance with the Clinical Performance Study Plan, the principles of good clinical practice and this Regulation.

• 1. The sponsor shall complete the follow-up of investigation subjects.

ANNEX XV

CORRELATION TABLE

[^E0001]: Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery (OJ L 157, 9.6.2006, p. 24).

[^E0002]: Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the application of patients' rights in cross-border healthcare (OJ L 88, 4.4.2011, p. 45).

[^E0003]: Commission Recommendation of 6 May 2003 concerning the definition of micro, small and medium-sized enterprises (OJ L 124, 20.5.2003, p. 36).

[^E0004]: Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67).

[^E0005]: Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (OJ L 158, 27.5.2014, p. 1).

[^E0006]: Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006 (OJ L 353, 31.12.2008, p. 1).

[^E0007]: Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) (OJ L 136, 29.5.2007, p. 3).

[^E0008]: Council Directive 80/181/EEC of 20 December 1979 on the approximation of the laws of the Member States relating to units of measurement and on the repeal of Directive 71/354/EEC (OJ L 39, 15.2.1980, p. 40).

[^E0009]: Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ L 136, 30.4.2004, p. 1).