In order to demonstrate conformity with medical device and in-vitro diagnostic regulations (MDR and IVDR) and to be eligible for CE marking and placing on the market of their products, manufacturers need to comply with a number of requirements outlined in this component:

• general safety and performance requirements;
• clinical investigations and performance evaluations;
• technical documentation;
• quality management system and standards.

Each aspect will be covered in detail in the following sections.

The EU regulations for medical devices and in-vitro diagnostics (MDR and IVDR) outline the “General Safety and Performance Requirements (GSPR)” that need to be complied with in order to gain marketing authorisation.

23 and 20 GSPRs are detailed in Annex I of the MDR and IVDR, respectively, and are structured in three chapters ⁰, ⁰:

• Chapter I: General requirements;
• Chapter II: Requirements regarding design and manufacture (medical devices)/ Requirements regarding performance, design and manufacture (in-vitro diagnostics);
• Chapter III: Requirements regarding the information supplied with the device.

Depending on the class and nature of the medical device or in-vitro diagnostic, some GSPRs will not need to be satisfied in order to demonstrate conformity. However, each GSPR (including subparts) should be assessed in its own right and properly documented in the technical documentation. In practice, this is often achieved through the use of a checklist or table, with a column for applicability and a Yes/No answer against each requirement. When a requirement is not applicable, a statement must be made to that effect and it must be properly justified (e.g. “The device is not powered and is therefore not an active device. This requirement does not apply”) ⁰.

Chapter 1 – General Requirements

Both the EU regulations for medical devices and in-vitro diagnostics (MDR and IVDR) outline GSPRs in great detail and some of the general requirements overlap with each other ^{0, 0, 0}:

• products must perform in a way that aligns with the intended design;
• products must not compromise the health or safety of a patient, user, or any other person associated with the device;
• risks must be reduced as much as possible, but not so much that they negatively affect the ratio of benefit to risk;
• manufacturers must implement and maintain a thorough, well-documented, and evaluative risk management system that continues to be updated throughout the life cycle of a device;
• manufacturers and designers must include any necessary measures for protecting users in cases where risks cannot be completely eliminated;
• manufacturers must provide users with information about any potential risks that remain – this information must be clear, easy to understand, and considerate of the users’ technical knowledge level, use environment, and any applicable medical conditions;
• products must withstand the stresses of normal use for the duration of their lifecycle;
• products must be designed, manufactured, and packaged in a way that protects them from damage during transport and storage;

when it comes to risks and negative side effects that are known and foreseeable, designers and manufacturers must make every effort to minimize negative outcomes – they must also ensure that potential risks are acceptable when compared to the potential benefits of a product to its users.

Chapter 2 – Requirements Regarding Design and Manufacture (medical devices)/ Requirements Regarding Performance, Design and Manufacture (in-vitro diagnostics)

The GSPRs also provide key details regarding specific information about the performance, design and manufacture of medical devices and in-vitro diagnostics. As it relates to design inputs, the GSPRs provide highly-detailed requirements relating to a product’s ^{0, 0, 0}:

• performance characteristics (in-vitro diagnostics only);
• chemical, physical and biological properties;
• potential for infection or microbial contamination;
• use of substances that are considered to be a medicine or that the human body otherwise absorbs or disperses (medical devices only);
• incorporation of biological materials;
• interaction with its environment;
• ability to diagnose or provide measurements;
• radioactive properties;
• systems that are electronically programmable;
• capability for being active and connected to other products;
• capability for being active and implantable (medical devices only);
• ability to withstand mechanical and thermal risks;
• ability to safely supply energy or substances to the user or patient (medical devices only);
• ability to be used by laypersons.

For each of these GSPRs, key details are outlined to which manufacturers must adhere in case the requirements are applicable ⁰.

Chapter 3 – Requirements Regarding the Information Supplied with the Device
Chapter 3 of the GSPRs relates to specific information a manufacturer must supply with a product. The general requirements for this information state that “Each device shall be accompanied by the information needed to identify the device and its manufacturer, and by any safety and performance information relevant to the user, or any other person, as appropriate.” The requirements provide further detail such as the information that must be provided on ⁰, ⁰, ⁰:

• the product label;
• the user instructions;
• the packaging of a product that is intended to maintain its sterile condition.

Clinical evidence and clinical investigations for medical devices
Under the new medical devices regulation (MDR), manufacturers of medical devices are required to conduct clinical evaluations for all their products, regardless of the risk class, including post-market clinical follow-up (PMCF). A clinical evaluation plan is required that details the clinical planning foreseen by the manufacturer to demonstrate clinical safety and the effective benefit of the medical device. Clinical planning can range from exploratory and pivotal studies to post-market clinical follow-up, including a description of milestones and possible acceptance criteria 16.

Clinical evaluation is seen as an essential part of product development and of a manufacturer’s quality management system and is defined as a systematic and planned process for the continuous generation, collection, analysis and evaluation of clinical data on a product. As such, clinical evaluation is intended to verify the product’s safety and performance, including clinical benefit, and is usually based on clinical data from the following sources ⁰:

• clinical investigation(s) from the manufacturer;
• clinically relevant information that the manufacturer obtains from post-market surveillance (PMS), in particular from the post-market clinical follow-up (PMCF);
• technical literature about:
  • clinical investigation or other studies in the literature on a proven similar product,
  • other clinical experience with your own product or a proven similar product.

Waiver of clinical data
A waiver of clinical data according to the MDR specification is only possible for absolutely non-critical products (e.g. screws, wedges, plates and instruments) and must be justified by the manufacturer. This justification is based on risk management, taking into account the specific interactions between the product and the human body, as well as the intended clinical performance ⁰.

Clinical evaluation according to equivalence with similar products
Clinical data from similar products can be used in theory for clinical evaluation, however, the high degree of equivalence for these comparison products must be demonstrated from a technical as well as a biological and clinical point of view. Rules for equivalence of these features are very stringent and require that ⁰:

• there is no clinically meaningful difference in the safety and clinical performance of the products;
• equivalence is based on adequate scientific justification;
• the manufacturer has sufficient access to the data of products with which he wishes to prove similarity;
• the clinical data to which a manufacturer refers in the equivalence assessment must provide adequate clinical evidence to achieve the objectives of the clinical evaluation.

Class III product and implantable medical devices
In particular, for class III products and implantable products, clinical investigations are a strict requirement under the new regulations. Only in a few exceptional cases can a clinical investigation for these products be avoided, including ⁰:

• modified products of an already marketed product from the same manufacturer;
• equivalent products to an already marketed product from another manufacturer;
• old products;
• product types such as sutures, dental restorations, dental or bone plates, staples, dental crowns, wires, fillings, screws, pins, wedges, clamps or connectors.

The Annexes XIV and XV of the EU regulation of medical devices (MDR) detail the specific requirements for manufacturers in regards to clinical evaluations and investigations, including the required documentation for the application of clinical investigations and obligations of the sponsor. In addition, the EU Guideline on “Clinical evaluation: Guide for manufacturers and Notified Bodies” (MEDDEV 2.7./1 rev.4) provides specific guidance on the evaluation of clinical investigations and can be found on this link.

Clinical evidence and performance evaluation for in-vitro diagnostics
The new EU regulation for in-vitro diagnostics reinforces the need for clinical evidence to demonstrate conformity with the relevant general safety and performance requirements of the regulation. The level of clinical evidence needed to demonstrate conformity of an in-vitro diagnostic becomes progressively more stringent as the risk class increases: clinical evidence is based on clinical data and a continuous performance evaluation process by which data are assessed and analysed to demonstrate the scientific validity, analytical performance and clinical performance of an in-vitro diagnostic for its intended purpose as stated by the manufacturer ^{0, 0}.

The manufacturer has to establish and maintain a performance evaluation plan that specifies the characteristics and the performance of the product, as well as the process and criteria applied to generate the necessary clinical evidence to make a qualified assessment of whether the product provides the intended clinical benefit and safety when used as intended by the manufacturer ⁰.

Clinical evidence must be updated throughout the life cycle of the in-vitro diagnostic, also with data obtained from the post-market performance follow-up plan (PMPF), as part of the post-market surveillance system (refer to section 6 of this component) ⁰.

Demonstration of the scientific validity
The manufacturer has to demonstrate scientific validity based on the following sources ⁰:

• relevant information on the scientific validity of devices measuring the same analyses 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.

Demonstration of the analytical performance
Generally, analytical performance has to be demonstrated based on analytical performance studies. However, if there are no comparative methods (e.g. for novel markers without certified reference materials or reference measurement procedures), 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 the performance of the new in-vitro diagnostic to the current clinical standard practice is required ⁰.

Demonstration of the clinical performance
Demonstration of the clinical performance of an in-vitro diagnostic has to be based on the following sources ⁰:

• clinical performance studies;
• scientific peer-reviewed literature;
• published experience gained by routine diagnostic testing.

A waiver of clinical performance studies might be possible if justified that other sources of clinical performance data could be used instead ⁰.

The Annexes XIII and XIV of the EU regulation of in-vitro diagnostics (IVDR) detail specific requirements for manufacturers in regards to performance evaluation studies and clinical performance studies, including the required documentation for application for clinical performance studies and obligations of the sponsor.

Approval of clinical investigations or performance evaluations
Clinical investigations for medical devices and performance evaluations of in-vitro diagnostics must be approved by the responsible national competent authority before they may commence: in Portugal, INFARMED is the responsible national competent authority for clinical investigations of medical devices and for performance evaluations of in-vitro diagnostics.

Common challenges and pitfalls with clinical studies

Challenges often faced by manufacturers in regards to clinical studies include the one highlighted below ⁰.

• Uncertainty about the extent of clinical studies needed: clinical studies are a high investment and costs must be balanced against the potential benefit of conducting them. Careful evaluation of the data required to demonstrate the product’s safety and performance is required to identify potential gaps in respect to already existing data and inform the need for additional clinical studies.
• Imprecise or incorrect endpoints: study endpoints must be chosen carefully in order to ensure that the evidence collected will be suitable for demonstrating the product’s safety and performance.
• Inadequate study design: getting the study design right is critical. An unsuitable study type, an inadequate population size or an unrealistic project plan can limit the value of a study. An agile, iterative incremental approach is rarely appropriate for a clinical study.
• Insufficient monitoring: errors and data gaps, as well as sampling that is not in line with the study protocol, can invalidate the study’s results.
• Lack of equivalence: manufacturers may use study findings to further improve the product. It is important to keep in mind that equivalence must be demonstrated between products used in clinical studies and products that undergo conformity assessment.
• Insufficient number of patients: low patient numbers limit the relevance and evidence provided by a study. Study enrollment might be particularly difficult for rare diseases, low product differentiation to existing products, high-risk products that are perceived as “dangerous” by patients, products with limited attractiveness for study sites/ physicians.

Manufacturers must establish technical documentation to provide evidence of conformity of a medical device or in-vitro diagnostics with the requirements of the EU regulations. The technical documentation must be established prior to submission of an application to the Notified Body or, at the latest, before writing the declaration of conformity, and must be provided upon request by a competent authority or a Notified Body.

The technical documentation has to be developed during the design and development process of a product and is maintained throughout its entire life cycle. Manufacturers or the authorised representative established in the European Community are requested to keep copies of the technical documentation for a period of at least 10 years, in the case of implantable devices at least 15 years, after the last product has been placed on the market ⁰, ⁰.

The technical documentation represents the entirety of documents describing a medical device or in-vitro diagnostic. It, therefore, includes the product’s design, development, validation and verification (including clinical and performance validation), quality assurance as well as its regulatory status within target markets. Furthermore, post-market data is included to demonstrate that early warnings are captured, that the general safety and performance requirements are continuously fulfilled and that the benefits for patients always outweigh the risks. For new products, this may consist of, amongst other things, vigilance data from competitors and the manufacturer’s plan for activities to be implemented once the device is on the market ⁰.

Keeping traceability of all these elements within the technical documentation is, whilst challenging, essential for demonstrating to competent authorities and Notified Bodies the continuous compliance with regulatory requirements. The technical documentation should be structured and presented in order to facilitate its review by competent authorities or Notified Bodies. Annex II and III of the regulations of medical devices and in-vitro-diagnostics give guidance on the detail and extent of the technical documentation required ⁰.

Required content of technical documentation (according to Annex II and III of the MDR and IVDR) includes the following sections as outlined in the table below ⁰, ⁰.

Quality Management System 

The medical device and in-vitro diagnostic manufacturing sector are one of the most regulated sectors in which significant quality systems and product requirements must be satisfied. The regulatory requirements are intended to ensure that manufacturers consistently design, produce, and market medical devices and in-vitro diagnostics that are safe and fit for their intended purpose ⁰.

Based on the EU regulations for medical devices and in-vitro diagnostics manufacturers must have quality management systems in place that cover at least ^{0, 0, 0, 0}:

• regulatory strategy to ensure compliance (incl. conformity assessment procedures, procedures for the management of product modifications);
• identification of applicable general safety and performance requirements and exploration of options to address those requirements;
• management responsibilities;
• resource management, including management of suppliers and sub-contractors;
• risk management;
• clinical evaluation or performance evaluation;
• product realisation (incl. planning, design, development, production and service provision);
• verification of UDI assignment to all relevant products and ensuring consistency and validity of the information provided;
• post-market surveillance system implementation and maintenance;
• reporting of serious incidents and corrective actions in the context of vigilance;
• management of corrective and preventive actions and verification of their effectiveness;
• output monitoring and measurement, data analysis and product improvement;
• communication with competent authorities, Notified Bodies, customers and other stakeholders.

Certification according to ISO 13485 and other harmonised standards
Although not directly required for CE marking of medical devices and in-vitro diagnostics according to EU regulations, demonstration of conformity with requirements for a quality management system can be achieved by certification of the organisation according to existing harmonised European standards for medical devices and in-vitro diagnostics.

ISO 13485 and ISO 14971 are standards most often used for quality and risk management systems for medical devices and in-vitro diagnostics, but there are other standards for other purposes and product types that manufacturers might want to consider.

A list of harmonised EU standards for medical devices and in-vitro diagnostics covering different aspects (e.g. product sterilisation, clinical investigation, performance evaluation) can be found on this link.

Certification of harmonised standards is expected to bring significant benefits to manufacturers by auditing the effectiveness of the manufacturer’s systems and processes ⁰:

• meaningful feedback on the effectiveness of system and processes (e.g. of the quality management system);
• confidence in compliance with a regulation;
• identification of areas requiring attention;
• confirmation that best practises is achieved;
• detection of areas of non-compliance and possible risk;
• reporting and certification that is valuable and recognised.

ISO 13485 is an effective solution to meet the comprehensive requirements for a quality management system. Adopting ISO 13485 provides a practical foundation for manufacturers to address the regulations and basic quality assurance requirements for CE marking as well as demonstrating a commitment to continuous improvement as well as to the safety and quality of medical devices and in-vitro diagnostics. In addition, the standard can be used by other internal and external parties, such as certification bodies, support them with their certification processes, or by supply chain organizations that are required by contract to conform ⁰, ⁰.

ISO 14971 is a risk management system standard and was designed to be compatible with ISO 13485. It helps manufacturers to identify and control risks associated with their products throughout the entire life cycle and also in interaction with other medical devices or in-vitro diagnostics. Increasingly, ISO 14971, in the footsteps of ISO 13485, is becoming an international requirement for manufacturers to meet regulatory expectations globally ⁰.

Common Specifications
Common Specifications are a new concept in the medical device and in-vitro diagnostic regulations. They allow the European Union to bring in additional requirements that must be met in order to claim compliance. The definition of a Common Specification is: ‘A set of technical and/or clinical requirements, other than a standard, that provides a means of complying with the legal obligations applicable to a device, process or system.’ Common Specifications can be introduced in areas where no harmonised standards exist, where they are insufficient, or where there is a public health threat that needs to be addressed.

Medical devices or in-vitro diagnostics that meet the requirements of a Common Specification are presumed to be in conformity with the General Safety and Performance Requirements outlined in the EU regulations. Manufacturers must comply with the Common Specification unless they can justify that they have adopted solutions that ensure a level of safety and performance that is at least equivalent ⁰.

Surveillance, vigilance and notifications of alterations
One area that has changed substantially in the new medical devices and in-vitro diagnostics regulations (MDR and IVDR) over the old EU directives is the oversight by manufacturers and competent authorities of medical devices and in-vitro diagnostics on the market ⁰. Manufacturers must make sure to fully understand and comply with regulatory requirements for the post-market stage, as failure to do so can result in a suspension or withdrawal of the CE marking certification received and / or in legal and financial consequences.

Post-market surveillance

Manufacturers are required to plan and carry out systematic and proactive post-market surveillance activities in order to collect and review experience gained from medical devices and in-vitro diagnostics on the market, for the purpose to identify any need for corrective or preventive actions (e.g. actions by the manufacturer to prevent or reduce the risk of a serious incident with a product on the market).

Post-market surveillance is an integral part of the manufacturers’ quality management system and is undertaken in cooperation with authorised representatives and importers, if applicable, as well as distributors (requirements are laid down in chapter VII of the MDR and IVDR) ^{0, https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0746&from=EN#d1e996-176-1 , 0}.

Post-market surveillance requirements include ^{0, https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0746&from=EN#d1e996-176-1 , 0}:

• post-market surveillance report or Periodic Safety Update Report (PSUR), continuously summarising the results and conclusions of the analysis of post-market surveillance data gathered, as well as for the PSUR preventive and corrective actions taken, benefit-risk assessments, findings of post-market studies as well as information on sales and estimated user population;
• post-market clinical follow-up (PMCF; Annex XIV of the MDR) for medical devices or Post-market Performance Follow-up (PMPF; Annex XIII of the IVDR) for in-vitro diagnostics are part of continuous clinical or performance evaluation measures and link evidence collected in the pre-market stage with data collected at the post-market stage.

Vigilance

Manufacturers are required to report and analyse serious incidents (e.g. death, temporary or permanent serious health deterioration, serious public health threat) as well as field safety corrective actions (e.g. actions by the manufacturer to prevent or reduce the risk of a serious incident with a product on the market) to the relevant competent authorities. Furthermore, manufacturers have to report trends in expected undesirable side effects and incidents that are not classified as serious (requirements are laid down in chapter VII of the MDR and IVDR). Vigilance is a reactive process: timescales for reporting depend on the severity of the serious incident.

The competent authority is required to coordinate the reported events under the EU vigilance system and to react and respond appropriately in the interests of patient safety. In Portugal, INFARMED is responsible for vigilance and evaluation of incident reports, as well as the initiation of risk assessment procedures. If INFARMED concludes that the product has to be changed for safety reasons, it will issue recommendations for the manufacturer and/or the responsible competent authority of the federal state where the manufacturer is established ^{0, https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0746&from=EN#d1e996-176-1 , 0, 0}.

Market surveillance

Market surveillance activities are carried out by competent authorities to check and ensure that medical devices and in-vitro diagnostics on the market comply with the regulatory requirements and do not endanger health, safety or any other aspect of public interest (requirements are laid down in chapter VII of the MDR and IVDR).

Each competent authority is required to develop and fund an annual national surveillance plan within the framework of a European market surveillance programme prepared and coordinated by the Medical Devices Coordination Group (MDCG) ^{0, https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0746&from=EN#d1e996-176-1 , 0}.

Notification of post-market product or QM system alterations

If the product or the QM system is altered after the certification, it is the responsibility of the manufacturer to inform the Notified Body and demonstrate that the changes do not adversely affect the product’s safety or performance. The Notified Body will review the data to ensure conformity and to confirm that the certification remains valid ⁰.

Regular audits
Notified Bodies conduct annual audits to re-examine compliance required for continued CE marking and ISO 13485 certification of the manufacturer and related suppliers. A recertification audit will also be required to renew the CE certificate of the product within five years. In addition to these announced audits, Notified Bodies are also required to perform at least one unannounced audits of the manufacturer and/or related suppliers every five years (more often in case of a history of poor compliance or suspected non-conformity) ⁰, ⁰.