MDR Clinical Investigations

Clinical investigations are conducted to verify the intended purpose, clinical benefits, performance and safety of the device.

MDR Definitions:

clinical investigation’ means any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device;

‘sponsor’ means any individual, company, institution or organisation which takes responsibility for the initiation, for the management and setting up of the financing of the clinical investigation;

investigator’ means an individual responsible for the conduct of a clinical investigation at a clinical investigation site;

legal representative: Article 62(2) Where the sponsor of a clinical investigation is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication with that legal representative shall be deemed to be a communication with the sponsor.

Clinical investigations requirements are defined in article 62 to 80 and Annex XV.

Article 72(5): Member States shall inspect investigation site(s) to check that clinical investigations are conducted in accordance with the requirements of the MDR and the clinical investigation plan (CIP).

·       Article 62 General requirements regarding clinical investigations conducted to demonstrate conformity of devices

·       Article 63 Informed consent

·       Article 64 Clinical investigations on incapacitated subjects

·       Article 65 Clinical investigations on minors

·       Article 66 Clinical investigations on pregnant or breastfeeding women

·       Article 67 Additional national measures

·       Article 68 Clinical investigations in emergency situations

·       Article 69 Damage compensation

·       Article 70 Application for clinical investigations

·       Article 71 Assessment by Member States

·       Article 72 Conduct of a clinical investigation

·       Article 73 Electronic system on clinical investigations

·       Article 74 Clinical investigations regarding devices bearing the CE marking

·       Article 75 Substantial modifications to clinical investigations

·       Article 76 Corrective measures to be taken by Member States and information exchange between Member States

·       Article 77 Information from the sponsor at the end of a clinical investigation or in the event of a temporary halt or early termination

·       Article 78 Coordinated assessment procedure for clinical investigations

o   Process for submitting a clinical investigation application where the investigation is planned to be conducted in more than one Member State.

·       Article 79 Review of coordinated assessment procedure

·       Article 80 Recording and reporting of adverse events that occur during clinical investigations

 Application submission process given below,

ANNEX XV Chapter I General requirements of clinical investigations

·       Clinical investigations shall be carried out in accordance with recognised ethical principles.

·       it shall be performed in accordance with the clinical investigation plan.

·       All the technical and functional features of the device including safety and performance, and their expected clinical outcomes shall be appropriately addressed in the investigational design.

·       It shall in line with the clinical evaluation plan as referred to in Part A of Annex XIV

ANNEX XV CHAPTER II Documentation regarding the application for clinical investigation

Sponsor shall submit the following documents to conduct a clinical investigation

Documents required for clinical investigations:

1.       Application form

2.       Investigator's Brochure (IB): Summary of clinical and non-clinical information

3.       Clinical Investigation Plan:

·       Rationale

·       Objectives

·       Design methodology

·       Monitoring, conduct, record-keeping

·       Method of analysis for the clinical investigation

Content of application form is given below:

 

Sponsor obligations

Article 80 Report adverse events and device deficiencies that occur during clinical investigations to the Member States in which those clinical investigations are being conducted.

Article 72(6): Establish a procedure for emergency situations which enables the immediate identification and, where necessary, an immediate recall of the devices used in the clinical investigation

Article 77: Update the end of a clinical investigation or in the event of a temporary halt or early termination through electronic system.

ANNEX XV Chapter I: Arrange and verify the training to the personnel involved in the conduct of an investigation.

ANNEX XV Chapter I: Other sponsor obligations

1.Prepare and keep the documentation per annex XV Chapter II. Keep the documentation for 10 years after the clinical investigation completed or device placed on the market. Time period for implantable devices are at least 15 years.

2.Ensure proper monitoring.

·       appoint a monitor that is independent from the investigational site

3.Shall complete the follow-up of investigation subjects

4.Conduct internal or external inspection to check the investigation is being conducted in line with good clinical practice

5.Prepare a clinical investigation report

Click below link to know more about IVDR Clinical Performance Study :https://meddev-info.blogspot.com/2021/04/ivdr-clinical-performance-study.html

 Source: 

1.REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC

2.BSI whitepaper on Medical device clinical investigations – What’s new under the MDR?

MDR/IVDR UDI (Unique Device Identification)

 UDI is series of numeric or alphanumeric characters which are designed by globally accepted device identification and coding standard

UDI is used for the identification and facilitate the traceability of devices. Only manufacturer shall place the UDI on the label of the device or on its packaging. Higher levels of packaging shall have their own UDI. Shipping container doesn’t require any UDI.

UDI is used for reporting serious incidents and field safety corrective actions in accordance with Article 87.

UDI comprises two parts,

·      UDI-DI (Device Identifier) specific to a manufacturer and a device. Access key to information stored in UDI database

·     UDI-PI (Production identifier) identifies the unit of device production and if applicable the packaged devices, requirements are mentioned in Part C of Annex VI. Different types of UDI-PIs include serial number, lot number, software identification and manufacturing or expiry date or both types of date.

 UDI is conveyed through UDI carrier by using AIDC (Automatic identification and data capture) and / or Human Readable Interpretation (HRI). Examples of UDI carrier is linear bar code, 2D/Matrix bar code, RFID.

Reusable devices shall bear an UDI carrier on the device itself. After reprocessing of reusable devices (cleaning, disinfection, sterilisation or refurbishing between patient uses) UDI carrier shall be permanent and readable.

MDR ONLY:Direct part marking of UDI on Reusable devices are exempted when this marking is affecting the safety or performance of the device; or if this marking is not technologically feasible.

It shall be readable during normal use and throughout the intended lifetime of the device.

Basic UDI:

·       Primary identifier of a device model.

·       DI assigned at the level of the device unit of use.

·       Linked with UDI database and referenced in relevant certificates and EU declarations of conformity.

Unit of Use DI:

This is used to associate the use of a device with a patient in instances in which a UDI is not labelled on the individual device at the level of its unit of use, for example in the event of several units of the same device being packaged together.

When new UDI is required:

The following UDI database data elements change may trigger a new UDI-DI:

·       name or trade name

·       device version or model,

·       labelled as single use,

·       packaged sterile

·       need for sterilization before use

·       quantity of devices provided in a package

·       critical warnings or contra-indications: e.g. containing latex or DEHP.

The following device software change may trigger a new UDI-DI:

·       new or modified algorithms

·       database structures

·       operating platform

·       architecture or new user interfaces or new channels for interoperability

UDI Database:

Manufacturer shall submit all core UDI database data elements referred to in Part B of this Annex (UDI-DI). see below figure.It shall not include any UDI-PIs and no commercially confidential product information.

UDI requirements are covered in MDR ANNEX VI Part B & Part C, Article 27 & 28/ IVDR ANNEX VI Part B & Part C, Article 24 & 25.

Source:

REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC

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

MDR/IVDR Market surveillance

Market surveillance activities are performed by competent authority to ensure that device meets the MDR.

CA shall perform appropriate checks on the conformity characteristics and performance of devices.it will review the documentation and physical or laboratory checks based on adequate samples.

Every CA shall allocate an enough material and competent human resources in order to carry out those activities and prepare annual summary activity plans.

CA shall prepare an annual summary of the results of their surveillance activities and make it accessible to other competent authorities through Electronic system on market surveillance.

Flow :

CA Prepare annual summary activity plans—Medical device inspection to verify MDR compliance –Inform economic operator & get comments from them –CA will upload the report in electronic system.

Member states will check the CA market surveillance activities at least every four years and the results shall be communicated to the other Member States and the Commission.

Article 94 discuss that CA shall evaluate the devices that may present an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health; or otherwise does not comply with MDR.

Economic operators need to take appropriate and duly justified corrective action to bring the device to compliance with MDR.if not, CA will perform below actions (MDR Article 95 & 97/IVDR Article 91 & 92))

·       Restrict the making available of the device on the market

·       Making available of the device to specific requirements

·       Device withdrawal

·       Device recall

References

REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC

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

MDR/IVDR Vigilance

 Vigilance Requirements: MDR Articles 87 - 90 ,IVDR Articles 82-85

Manufacturer will analyse and find out whether the incidents are serious incidents or undesirable side-effects. Serious incidents are needs to be reported to competent authority (CA) per MDR article 87 / IVDR article 82. Non serious incidents or that are expected undesirable side-effects shall be documented in trend reporting (MDR article 87/ IVDR article 83)

Timelines for reporting of serious incidents and field safety corrective actions (MDR Article 87/IVDR Article 82)

Manufacturers needs to report serious incidents to competent authorities once a causal relationship to the device has been established.

·       Serious incidents (SI) -no later than 15 days

·       Serious public health threat -no later than 2 days

·       Death or an unanticipated serious deterioration in a person's state of health the report -no later than 10 days

·       Field safety corrective action (FSCA) -Without undue delay

Manufacturer may submit an initial report that is incomplete followed up by a complete report to CA. Final report is submitted by manufacturer through electronic system. Final report shall have conclusions about the incident investigation and corrective actions.

Periodic summary reports

Manufacturer shall submit this report when below listed conditions are fulfilled

·       Similar serious incidents that occur with the same device or device type and

·       These incident root cause has been identified or a field safety corrective action implemented

·       Incidents are common and well documented

Manufacturer shall coordinate with CA and CA needs to agree the Periodic summary report format, content and frequency .

Healthcare professionals, users and patients also report the report suspected serious incidents to the CA.CA will inform the manufacturer about this incident and manufacturer will analyse and takes appropriate action if required

MDR Article 88/IVDR Article 83 Trend reporting

·       Reported in electronic system

·       Frequency or severity of Not serious incidents or that are expected undesirable side- effects

·       These incidents have significant impact on the benefit-risk analysis

·       PMS plan shall have effective methods and tools to establish any statistically significant increase in the frequency or severity of incidents within time period

MDR Article 89/IVDR Article 84 Analysis of serious incidents and field safety corrective actions

After reporting serious incident, the manufacturer shall conduct risk assessment of the incident and take any required field safety corrective action. This will be evaluated by CA.

The following factor are considered by CA while evaluating the SI & FSCA

·       Causality, detectability and probability of recurrence of the problem

·       Frequency of use of the device

·       Probability of occurrence of direct or indirect harm

·       Severity of that harm

·       Clinical benefit of the device

·       Intended and potential users, and population affected

National competent authority or the EMA scientific opinion is needed for Devices with incorporates, as an integral part, a substance(MDR)/ companion diagnostic(IVDR).

Field safety notice (FSN)

Manufacturer shall inform field safety corrective action to users through FSN. FSN shall be written in official Union language or languages determined by the Member State in which the field safety corrective action is taken.

Before informing user, FSN shall be submitted to CA .CA will provide the comments .

FSN shall be uploaded in  the electronic system and it shall be accessible to the public

FSN shall include the below information

·       Device identification including UDIs, SRN

·       Reason for the field safety corrective action

·       Malfunctioned device reference

·       Associated risks for patients, users or other persons

·       Actions to be taken by users.

MDR Article 90/IVDR Article 85 Analysis of vigilance data

Commission shall, in collaboration with the Member states analyse the vigilance data to  identify trends, patterns or signals in the data that may reveal new risks or safety concern.

if there any new risk arises then it will inform manufacturer.

MDR Article 92/ IVDR Article 87 Electronic system on vigilance and on post-market surveillance

The following reports are submitted electronically,

·       Serious incidents and field safety corrective actions

·       Periodic summary reports

·       PSURs

·       Trend Reports

·       Field safety notices

·       Information to be exchanged between the competent authorities of the Member States and between them and the Commission

References

·       REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC

·       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

 

MDR Post market surveillance (PMS)

 MDR PMS Requirements: Article 10(10),83,84,85,86 and Annex III

In MDR, PMS defined as ‘post-market surveillance’ means all activities carried out by manufacturers in cooperation with other economic operators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediately apply any necessary corrective or preventive actions;

Manufacturer shall set-up, implement and maintain a post-market surveillance system, in accordance with Article 83.

CHAPTER VII POST-MARKET SURVEILLANCE, VIGILANCE AND MARKET SURVEILLANCE SECTION 1 Post-market surveillance Article 83

- Manufacturer shall plan, establish, document, implement, maintain and update a post-market surveillance system

- It is depending on risk class and appropriate for device type.

- This is part of the manufacturer's quality management system (QMS) referred to in Article 10(9).

- This PMS will actively and systematically be gathering, recording and analysing relevant data (quality, performance and safety) throughout its entire lifetime,

- This helps to draw necessary conclusions and to determine, implement and monitor any preventive and corrective actions.

Uses of PMS gathered data

1.To update the benefit-risk determination, design and manufacturing information, instructions for use, clinical evaluation, summary of safety and clinical performance and to improve the risk management 

2. To identify needs for preventive, corrective or field safety corrective action and options to improve the usability, performance and safety of the device

3. To detect and report trends

4. To contribute to the post-market surveillance of other devices

Article 84 Post-market surveillance plan (PMSP)

 PMS system shall be based on a PMS plan. It shall be part of the technical documentation.

PMS Plan requirements based on Section 1.1 of Annex III.

PMS Plan shall address the collection and utilization of available information, in particular:

—Serious incidents and field safety corrective actions

—Information from PSURs

—Non-serious incidents and data on any undesirable side-effects

—Trend reporting

— Relevant specialist or technical literature, databases and/or registers

 —Feedbacks and complaints, provided by users, distributors and importers

— Publicly available information about similar medical devices

Post-market surveillance plan shall cover at least:

This process shall allow a correct characterisation of the performance of the devices and shall also allow a comparison to be made between the device and similar products available on the market

Effective and appropriate methods and processes to assess the collected data. Suitable indicators and threshold values can be used to continuous reassessment of the benefit- risk analysis and of the risk management

Effective and appropriate methods and tools - To investigate complaints and analyse market-related experience collected in the field; -Trend reporting: To establish any statistically significant increase in the frequency or severity of incidents as well as the observation period - To communicate effectively with competent authorities, notified bodies, economic operators and users - To identify and initiate appropriate measures including corrective actions and effective tools to trace and identify devices for which corrective actions might be necessary

Reference to procedures to fulfil the manufacturers obligations laid down in Articles 83, 84 and 86;

PMCF plan or a justification as to why a PMCF is not applicable.

 

Article 85 Post-market surveillance report (PMSR)

Applicable device: Class I devices

Report content:

1. Results and conclusions of the analyses of the post-market surveillance data

 2.A rationale and description of any preventive and corrective actions taken.

Timelines: The report shall be updated when necessary and made available to the competent authority upon request

Article 86 Periodic safety update report (PSUR)

Applicable device: Class IIa, class IIb and class III devices

Report content:

1. Results and conclusions of the analyses of the post-market surveillance data

 2.A rationale and description of any preventive and corrective actions taken.

(a) Benefit-risk determination conclusions

(b) Main findings of the PMCF

(c) Sales volume and usage frequency (estimate evaluation of the size and other characteristics of the population using the device)

Timelines:

Class IIb and class III devices -annually

Class IIa devices -update when necessary and at least every two years

Class III devices or implantable devices-Manufacturer will submit the PSUR in Electronic system on vigilance and on post-market surveillance. The notified body shall evaluate, and these reports can be made available to competent authority through electronic system.

Click below link to know more about IVDR PMS requirements:https://meddev-info.blogspot.com/2021/04/ivdr-post-market-surveillance.html

References

REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC