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REAL WORLD EVIDENCE (RWE)

REAL WORLD DATA AND PMCF ACTIVITIES

RWE has become increasingly important following the implementation of the Medical Device Regulation MDR 2017/745, fully implemented from May 2021.

Medical device manufacturers are required to develop and implement a Clinical Evidence Generation system that generates real-world data on device safety and performance while remaining in compliance with all relevant legislation.

Real World Evidence (RWE) is the clinical evidence regarding the usage, and potential benefits or risks, of a medical product derived from analysis of RWD. 

Examples of RWD: 

data derived from electronic health records (EHRs)

insurance claims and billing data,

data from product and disease registries,

patient-generated data including in home- use settings

data gathered from other sources that can inform on health status, such as mobile devices.

WHAT ARE THE DIFFERENCES BETWEEN REAL WORLD EVIDENCE (RWE) AND TRADITIONAL CLINICAL TRIAL?

“Traditional clinical data” is generated through traditional clinical trial (clinical investigation) that are defined as a research study in which one or more human subjects are prospectively assigned. 

At the end of a clinical trial, there is usually limited knowledge of the medium and long-term safety and performance of the device. Estimates on longer-term data can be made on the basis of premarket trial durations, still these are generally inadequate to validate extrapolation hypothesis in real life, particularly implant longevity hypotheses (Hannan EL 2008).

In contrast to RWE data collection activity, a traditional clinical trial is more likely to have restrictive eligibility criteria designed to ensure that the participants have the disease of interest or have specific patient characteristics.  

The aims of collecting RWE data as part of PMCF activities are: 

  • Study population that represents the entire population indicated in the IFU.  
  • Does not involve experimental exposure.  
  • Aiming to cover the “entire lifetime of the device 
  • Is conducted at all types of clinical sites, not just specialist units  

A MEDICAL DEVICE CRO WITH RWE SOLUTIONS MATCHING NOTIFIED BODIES EXPECTATIONS

Our approach allowed our clients to obtain the CE certificate under MDR.

REAL WORLD EVIDENCE (RWE)
Each step is handled by our team of experts (Biostatisticians, Data Analysts, Clinical Research Assistants, Clinical Project Managers) who rely on best clinical practices such as ISO14155:2020, advanced analysis techniques and a strong Quality Management System.

A MEDICAL DEVICE CRO WITH RWE SOLUTIONS MATCHING NOTIFIED BODIES EXPECTATIONS

REAL WORLD EVIDENCE (RWE)

With ECLEVAR MEDTECH, before engaging in RWE clinical study, a feasibility study is conducted to ensure the quality and the quantity of data. it is important to demonstrate that the data source is of sufficient quality and quantity for the intended use. The advantages of using RWD as a valid PMCF activity are of no relevance if the data source is of poor quality, as reliable decisions cannot be made based upon an unreliable data source. 

Data quality is the completeness, consistency and accuracy of the data across the investigational centre involved in the study.

WHAT DOCUMENTATION IS REQUIRED FOR REAL WORLD EVIDENCE STUDY UNDER THE EU MDR?

Real World Evidence generation systems, as a component of PMCF, will need to be documented in accordance with requirements for technical documentation as specified in the MDR. Annex II and III specify a range of documents that must be produced in support of every medical device, including a PMCF Plan, PMCF Report and a Clinical Evaluation Report (CER).  

Additionally, MDR Annex XV lists a range of requirements that must be adhered to for every form of clinical study, including those intended to generate RWE. These requirements include the need to produce a clinical investigation plan and information letter to patients, case report form as well as a statistical plan. Transparency and validity of studies may increase with the publication of statistical analysis plans (SAPs) before data have been accessed to discern data-driven analyses from pre-planned analyses.

In accordance with MDR requirements (as documented in Annex XV of the MDR), we are committed to providing you with high quality the following deliverables:

Project phase Deliverables
1 - STUDY DESIGN• Study synopsis • Clinical Study Plan (CSP)
2 - HOSPITAL MANAGEMENT • Data check • Hospital Agreement • Regulatory requirements and documents
3 - DATA COLLECTION• Data collection files • Data audit reports • Final database
4 - ANALYSES• Statistical Analysis Plan (SAP) • Statistical report
5 - RESULTS RESTITUTIONS• Clinical Study Report (CSR)
6 - PROJECT MANAGEMENT • Project management

PMCF STUDY APPROACH ADHERING TO INTERNATIONA STANDARD AND REGULATIONS

Our methodology adheres to the standards of good clinical practice outlined inISO 14155:2020 and GCP and ISO 9001.  

For more information read our whitepaper with the BSI

Case Studies:

The medical device:

vascular prostheses made of knitted polyester fabrics, in straight tubular shapes, impregnated with ultra-purified collagen of bovine origin, and are indicated for replacement or bypass of arteries damaged by an aneurysm or arterial occlusive disease.
 

Problem:

As shown by the Clinical Evaluation Report, intended claims on clinical safety and performance are not sufficiently supported by existing clinical evidence. To maintain a “
Vascular patch “in the European market, the sponsor has to conduct a PMCF study to generate sufficient clinical data in accordance with “Chapter VI – Clinical Evaluation and Clinical Investigations, specifically sections 62 – 82”. As well as ISO 14155:2020.  

Objectives 

  • Confirming safety and performance of the Vascular device throughout its expected lifetime and both anatomic locations: Carotid and femoral. 
  • Identifying and analysing emergent risks based on factual evidence. 
  • Ensuring the continued acceptability of the benefit-risk ratio referred to in EU MDR. 
  • Identifying possible systematic misuse or off-label use of device X to verify that the intended purpose is correct. 
Vascular medical device can be defined as a device that is used during open surgery techniques. It encompasses the cardiovascular, neurovascular.

Methodology  

A Sponsor conducted RWE multicentre study to collect clinical data for Vascular patch. The objective was to examine short and long-term outcomes of using the device when exposed to a larger and more varied population. 

All data were retrieved from medical charts for each patient from the time of surgery (considered as the baseline of study) until a maximum of 3 years after surgery. 

A minimum of 250 up to a maximum of 300 subjects were evaluated from 3 to 8 different sites. At least 100 subjects were evaluated in carotid location and at least 100 in femoral location. 

Hospital network involved: 

 

Our KOLs Involved in the study: 

  • Prof.Yann Goueffic  
  • Prof. Blandine Maurel-Desanlis 
  • Dr. Bahaa NASR 
 

Benefits 

  • Contribute to a larger body of evidence being developed: 
  • Representative population 
  • Accepted by the notified body. 

Applicable regulation and guideline: 

  • Article 61, Annex I and Annex XIV of the Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices (MDR), 
  • ISO 14155:2020-07 (section 6.3, Justification for the design of the clinical investigation) Clinical investigation of medical devices for human subjects — Good clinical practice. 
  • Regulation EU 722/2012: Regulation (EU) concerning particular requirements regarding the requirements laid down in Council Directives 90/385/EEC and 93/42/EEC concerning active implantable medical devices and medical devices manufactured utilizing tissues of animal origin. 
  • NF EN ISO 7198: 2017- Cardiovascular implants and extracorporeal systems. Vascular prostheses. Tubular vascular grafts and vascular patches. 

Global regulatory considerations when generating RWE part of PMCF activity

REAL WORLD EVIDENCE (RWE)

IN EUROPE

Depending on the country you conduct your PMCF activity, whether you are putting in place a registry or conducting an observational study or simply a survey, the activity must comply with ISO 14155 and GDPR. 

The PMCF study will be conducted in compliance with GDPR, and depending on the country, it follows a specific methodology (examples in France and Germany are provided below).

The advantage of using RWE as a valid PMCF activity, it requires light regulatory burden as the competent authority and the ethical committee approval are not required as long as the methodology of the PMCF activity will not deviate from the routine clinical practice.

REAL WORLD EVIDENCE (RWE)

How to collect RWE clinical data in France?

REAL WORLD EVIDENCE (RWE)

By using a reference methodology called « MR004 » to conduct studies, research and evaluations on retrospective and prospective health data that do not include the human person 

Each hospital would be following the MR004 as data controller, this includes:

  • Conduct an impact assessment on the data processed in advance
  • Send pseudonymised data (within the meaning of section 4 of the GRPD)
  • Issue a Patient information: generally, and individually (thanks to a web page)
  • Guarantee a right of access, rectification and opposition to the processing of data by each data protection officer’s hospital
  • Establish a contract with the hospital governing the obligations regarding the processing of personal data
  • Do not collect data relating to religious opinions, to offences or the NIR.
  • Other security actions undertaken by sub-contractor:
  • Collect data in accordance with the principle of privacy by design and privacy by default established by the GDPR
  • Store the collected data on a certified health data hosting (in accordance with art. R1111-9 of the French Public Health Code.
REAL WORLD EVIDENCE (RWE)

How to collect health data in Germany? 

REAL WORLD EVIDENCE (RWE)

By way of derogation from Article 9 of the GDPR, health data treatment shall be allowed if necessary for reasons of public interest in the field of public health, to ensure high standards of quality in medical devices (Art. 22 German Data Protection Code)

Processing: appropriate and specific measures shall be taken to safeguard the interests of the data subject and considering the state of art, scale, nature, and severity of the risks to the rights and freedom of natural persons.

Measures to ensure data protection: 

  • Appointment of a data protection officer (DPO) 
  • Conduct an impact assessment   
  • Issue a Patient information (art. 13 and 14 GDPR) 
  • Guarantee a right of access, rectification and opposition to the processing of data by each data protection officer’s hospital  
  • Pseudonymisation of personal data 
  • Restriction of access to personal data within the Controller  
REAL WORLD EVIDENCE (RWE)

How to collect RWE clinical data in the UK?

In the UK, the Information Commissioner’s Office (ICO) is the independent authority set up to uphold information rights in the public interest, promoting openness by public bodies and data privacy for individualsi. 

Processing: Research organisations must meet all legal requirements relevant and a legal basis under the UK GDPR must be identified. An Article 9 derogation will likely be required as sensitive personal data is being processed.

Relevant legal frameworks such as the common law duty of confidentialityii through consent must also be met. Though, the interpretation of consent as a legal basis is considered impractical for processing data for health and social care research.

The sponsor, who determines the data to be collected through the protocol, acts as the controller in relation to the research data. If the data is routine data, also collected for other means, such as primary care records then there will be joint controllers of that data. Joint controllers add complexity to the collection and processing of data and must be taken into consideration.

Exemptions for research 

  • Articles 14(5)(b) UK GDPR: right to be informed when data collected from sources other than the individual.
  • Schedule 2 Paragraphs 27 and 28 of DPA 2018: right of access
  • Schedule 2 Paragraphs 27 and 28 of DPA 2018: right of rectification
  • Article 17(3)(d) of UK GDPR: Right to erasure
  • Schedule 2 Paragraphs 27 and 28 of DPA 2018: Right to restrict processing
  • Schedule 2 Paragraph 28 of DPA 2018: Right to data portability – for archiving purposes in the public interest only. There is no exemption from the right to data portability for scientific or historical research, or statistics.
  • Article 21(6) of UK GDPR & Schedule 2 Paragraphs 27 and 28 of DPA 2018: Right to object – Art. 21 is for scientific or historical research and statistical purposes only. Schedule 2 paragraph 28 is for the purposes of archiving in the public interest

A researcher can restrict these rights as set out within the exceptions on the basis that fulfilling these obligations would prevent or significantly hinder the research protocol and planned aims. There must be clear safeguards in place to minimise the risk of removing these rights. The decision to remove these rights should be evidence-based, and the context of that right within the research at that time. For example, removing one participant at the earliest stages of a project would likely have no impact, and therefore the right to erasure may be granted, yet removing 30% of participants at a more developed stage could significantly impact the research and its findings, therefore there would be more justification to utilise this exemption. 

Due to the impact of leaving the EU, the UK regulatory framework requires a little more consideration. 

For Northern Ireland, the EU MDR applies, and therefore the new requirement around PMCF should be followed.

For Great Britain – England, Scotland and Wales, the requirements of PMCF/PMS remain in line with the directives and relevant MEDDEVs mentioned earlier.

As for all countries, data protection is key when using RWD. In May 2018, the UK government put in place the Data Protection Act 2018 (DPA 2018); this Act applied all the clauses from the GDPR. Following the UK’s exit from the EU, the EU-GDPR no longer protected UK citizens. To prevent the loss of data protection, the UK government published an update to the DPA 2018 called the ‘Data Protection, Privacy and Electronic Communication (amendments etc) (EU exit) regulations 2019’. The GDPR is retained in domestic law as UK GDPR and sits alongside the amended DPA 2018.

The key principles, rights and obligations remain the same. The introduction of the GDPR has the aim of harmonising the differing national implementations of data protection, although the risk of diverging interpretations in case law now exists.

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