In Vitro Diagnostic Devices Require Extensive Analytical and Clinical Technical Documentation for IVDR 2017/746 Compliance

Author: Dr. Suzanne Broussard

The In Vitro Diagnostic Device Regulation (IVDR) 2017/746 is making sweeping changes to the European Union regulatory requirements for in vitro diagnostic (IVD) devices. The expanded Technical Documents requirements and the need for a life cycle approach in the Quality Management System are some of the biggest changes.    

Change in direction

A Technical Document is required for all classes of IVDs and mandates a Performance Evaluation Plan (PEP) and Performance Evaluation Report (PER), as well as Post-Market Surveillance Plan (PMSP) and Post-Market surveillance report.  

It will be challenging to get your organization’s IVDs compliant by the May 26, 2020 deadline. The increased number of IVDs that will be up-classified and require Notified Body (NB) review will only make the transition much more difficult. Here we will introduce some of the major requirements and list some of the important considerations for IVDR 2017/746 compliance. As always, check with your regulatory and legal team to ensure you are in compliance with all country’s jurisdictions.   

Technical Documentation 

All four classes (A-D) require technical documentation for compliance. The scope of the technical documentation is extensive, and every IVD device will need to write or remediate its technical documents. 

Annex II addresses required technical documentation, and Annex III focuses on post-marketing technical documentation. IVDR is clear that “The technical documentation and, if applicable, the summary thereof to be drawn up by the manufacturer shall be presented in a clear, organized, readily searchable and unambiguous manner and shall include in particular the elements listed in this Annex.”  

The six sections of Annex II are: 

  1. DEVICE DESCRIPTION AND SPECIFICATION, INCLUDING VARIANTS AND ACCESSORIES 
  1. INFORMATION TO BE SUPPLIED BY THE MANUFACTURER 
  1. DESIGN AND MANUFACTURING INFORMATION 
  1. GENERAL SAFETY AND PERFORMANCE REQUIREMENTS 
  1. BENFIT-RISK ANALYSIS AND RISK MANAGEMENT 
  1. PRODUCT VERIFICATION AND VALIDATION 

To comply with the General Safety and Performance Requirements (GSPR), manufactures will need to perform a detailed gap analysis. Conformity with GSPR requires clinical evidence, and this is a significant change for many manufacturers. Furthermore, Performance Evaluation needs to be performed, and if studies are needed manufacturers will need to get up to speed quickly.  

Legacy products still need to meet all the IVDR requirements; they will be re-classified, have increased clinical evidence needs, and will likely need NB review.

Class B, C, and D devices are subject to pre-market approval by NBs. These regulations include the safety and performance of medical devices, as well as the manufacturing process, to ensure that the product meets safety at all stages of production. All of these new requirements will increase regulatory and clinical costs.  

The performance studies and evaluation requirements for IVDs outlined in Annex XIII of the IVDR in 2 parts: Part A and Part B.  

Part A focuses on the pre-market phase, and Part B focuses on Post-Market performance. The IVDR views the performance and evaluation of an IVD as a cyclic event that occurs during the entire life-cycle of the device. The 3 parts of the performance evaluation in Part A are compiled into a Performance Evaluation Report in which the manufacturer must demonstrate there is sufficient clinical evidence to support the device’s intended use. In Part B, the manufacturer continuously reviews the Performance Evaluation Report to ensure the device is meeting conformity. This includes a periodic “state of the art” review. Here is an outline of these requirements. 

Part A: Performance Evaluation & Performance Studies 

Performance Evaluation 

  • Performance Evaluation Plan 
  • Scientific Validity, analytical performance, and clinical performance 

– Key evidence for the Performance Evaluation Report (PER) 

  • Clinical Evidence and PER 

Clinical Performance Studies: 

  • Purpose of clinical performance studies 
  • Ethical considerations for clinical performance studies 
  • Methods for clinical performance studies (design, plan, report)

Performance Evaluation Report documenting scientific validity data, analytical performance data, and clinical performance data, as well as their assessment and the clinical evidence derived from them, is required.  

Further instructions for performance evaluation in Chapter VI Article 56 (3) states that manufacturers must follow a defined and methodologically sound procedure for the demonstrations of the following in accordance with Article 56 and Part A of Annex XIII: 

(a) Scientific validity 

(b) Analytical performance

(c) Clinical performance 

Annex XIII Part A 1.2 provides the general principles by which manufacturers must demonstrate scientific validity and analytical and clinical performance. 

  • Identify through a systematic scientific literature review the available data relevant to the device and its intended purpose and identify any remaining unaddressed issues or gaps in the data;  
  • Appraise all relevant data by evaluating their suitability for establishing the safety and performance of the device; 
  • Generate any new or additional data necessary to address outstanding issues.

Scientific Validity 

In order to demonstrate scientific validity, the manufacturer must use one or a combination of the following criteria, and this must be demonstrated and documented in the scientific validity report. Annex XIII Part A, 1.2.1  

  • 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.

See our white paper on how to perform a ‘state of the art’ literature review or contact us directly to see how we can help demonstrate scientific validity.

Analytical Performance 

Analytical performance, as defined in Annex XIII Part A, 1.2.2, must be demonstrated on the basis of analytical performance studies and must be demonstrated and documented in the analytical performance report.  

Clinical Performance 

The clinical performance study plan (CPSP) provides the basis for clinical performance studies. Annex XIII Part A, 2.3.3 outlines the particular information that needs to be addressed in the CPSP, which is outlined in the clinical performance study: 

  • rational
  • objectives
  • design and proposed analysis
  • methodology
  • monitoring
  • conduct
  • record keeping

Clinical performance studies are required to obtain data and the subsequent assessments and conclusions that provide clinical evidence. The performance evaluation reports for class C and D devices must be updated annually, or earlier as necessary. There is a dramatic increase in clinical performance studies requirements for IVDs, and meeting these criteria will take time.  

Furthermore, the quality of the clinical evidence will be more heavily scrutinized by NBs. The IVDR clearly states that the clinical evidence must support the intended purpose of the device as stated by the manufacturer. Note, this is based on a continuous process of performance evaluation.  

The IVDR 2017/746 Corrigendum published in May 2019 amends IVDR 2017/746 replacing the international standard ISO 14155:2011 with ISO 20916:2019 In vitro diagnostic medical devices – Clinical performance studies using specimens from human subjects – Good study practice.  

  1. (66) The rules on performance studies should be in line with well-established international guidance in this field, such as the international standard ISO 2019 on clinical performance studies using specimens from human subjects, currently under development, so as to make it easier for the results of performance studies…’. 

Part B: Post-Market Performance Follow-up (PMPF) 

PMPF is a continuous process to update the performance evaluation and addresses the post-market surveillance plan.  

Post-market Surveillance 

Post-market Surveillance requirements are detailed in Annex XIII and Article 78. The Post-Market Performance Follow-Up (PMPF) needs to be designed as a continuous process that updates the performance evaluation and specifically address the manufacturer’s post-market surveillance plan. This plan needs to proactively collect and evaluate data on device performance, as well as other relevant scientific data.  

Labeling 

The IVDR requires that every device have a Unique Device Identifier (UDI) on the label. 

This is Big – Every Label Will Change! 

Major changes to labels will be needed to accommodate UDI. The UDI system applies to all devices placed on the market, with devices used for performance studies being the exception.  

The use of the UDI is intended by the EU to provide traceability of IVDs, and thus “significantly enhance the effectiveness of the post-market safety-related activities of the devices, which is owing to improved incident reporting, targeted field safety corrective actions and better monitoring by competent authorities. It should also help to reduce medical errors and to fight against falsified devices.”  

The European database on medical devices (EUDAMED) will use the UDI to track devices. The EUDAMED provides a secure, web-based portal that EU competent authorities use to enter information from NBs and manufacturers to exchange information with the European Commission.  

As with many aspects of the new regulations on medical devices, information continues to evolve. The Medical Device Coordination Group (MDCG) released 2 new documents in April of 2019 to clarify the inconsistencies in the timelines. These considerations apply mutatis mutandis to the IVDR”. 

MDCG 2019-4 Timelines for registration of device data elements in EUDAMED      

MDCG 2019-5 Registration of legacy devices in EUDAMED    

Keep these documents in mind when considering your transition game plan. 

Quality Management System (QMS) 

The biggest change to the QMS it the need for a life cycle approach. Article 9 (4) states that “Manufacturers shall draw up and keep up to date the technical documentation for those devices. The technical documentation shall be such as to allow the conformity of the device with the requirements of this Regulation to be assessed. The technical documentation shall include the elements set out in Annexes II and III.” 

For example: 

The PMPF is an integral part of the manufacturer’s quality management system and is active for the life of the IVD. Technical documents need to update accordingly.  

The GSPR is integrated into the QMS. The GSPR must be taken into account in the QMS such that the GSPR must be identified and guide the process. 

The QMS must demonstrate that it is responsible for the Vigilance process, with the manufacturer doing its due diligence in reporting serious incidents and field safety corrective actions “with deadlines, responsibilities and reconciliation management.” This may be challenging in supply lines that use importers and distributors.  

CONCLUSION:  

The implementation of IVDR 2017/746 regulation is in full swing and it will significantly affect the manufacturers of IVDS by forcing them to focus on clinical proof and the maintenance of a robust QMS.  


Criterion Edge is ready to help your organization meet these challenges. Contact us to find out how we can help.  

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