Quality and Regulatory Systems
US vs EU
According to the 21 CFR 820.3(v) a quality system is defined as the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management. In the US, the quality management system is also known as the Current Good Manufacturing Practise or cGMP. In this system, medical device manufacturers have the responsibility to use good judgement when developing their quality system. They must also apply the sections of the 21 CFR 820 that are relevant to their specific products and operations. The FDA quality system regulation identifies essential elements of a quality system, but does not prescribe the way they are to be achieved (Health, n.d.).
Looking at the US system for quality there are seven sub-systems. These are (1) records, documents and change controls, (2) material controls, (3) design controls, (4) corrective and preventative actions, (5) production and process controls, (6) equipment and facility controls and (7) management. Of these seven sub-system’s there are four main sub-systems. One of them is the management sub-system. Its purpose is to establish responsibility and authority, to ensure the establishment and effective functioning of a quality system and to provide acceptable resources for device design, manufacturing, quality assurance, distribution, installation, and servicing. Another main sub-system is design control. Its objective is to control the design process and to assure the device design meets user needs, intended uses, and specified requirements. The third main sub-system is the production and process controls sub-system. This is in place to ensure products are manufactured that meet specifications. This is done by developing processes that are adequate, validating or fully verifying the results those processes and monitoring and controlling the manufacturing processes. The corrective and preventative action sub-system is the fourth main sub-system. Its fundamental purpose is to verify or validate corrective and preventative actions, communicate these actions to the correct personnel, provide information for management to review and to document all these activities (Tartal, n.d.; Wilbon, n.d.).
In the EU, the International Organisation of Standardisation have the ISO 13485. It is based on the ISO 9001 but is specific to medical devices. It is the standard for medical device manufacturers quality management system and related services. The ISO 13485 is harmonised through the European Medical Devices Directive or MDD (Directive 93/42/EEC) together with the In-Vitro Diagnostics Directive or IVDD (Directive 98/79/EC) and the Active Implantable Medical Device Directive or AIMDD (Directive 90/385/EEC). ISO 13485 focuses on meeting customer requirements, including regulatory requirements and maintaining the effectiveness of the quality management system. The ISO 13485 contain eight sections in total. Sections one to three are introductory sections. Sections four to eight contain requirements that must be fulfilled to be compliant with the standard. These sections are (4) quality system model. (5) management responsibility, (6) resource management, (7) measurement analysis and improvement and (8) product realization. The purpose of the section on the quality system model is to give general requirements. These include identification of specific processes and how they interact as well as responsibility for outsourced processes. Section five’s purpose is to ensure the management of a company take an active part in the establishment and maintenance of the ISO 13485. The purpose of section six is to outline the requirements for the provision of resources. The seventh section looks at the feedback and other information required for management to maintain effectiveness of the quality management system. This includes corrective and preventative actions and customer complaints. Section eight looks at everything required to realize a product, from customer requirements, to designing, manufacturing, installing and supporting a medical device (Blunnie, n.d.; Lane, n.d.).
Although the ISO 13485 and the 21 CFR 820 are structured very differently, they do not conflict each other. The FDA participated in the writing of the ISO 13485 to ensure their requirements aligned with the ISO standard. The 21 CFR 820 is however more specific than the ISO 13485. It is more demanding in the areas of labelling and packing controls, complaint controls and reporting and documentation. Personally, I believe the quality system put in place by the US is the better one. This is because there is only one document to refer to, this being the 21 CFR 820 which is very well laid out (“21 CFR 820 and ISO 13485 — Harmonized Quality System Requirements for Medical Devices – E.M.M.A. International Consulting Group – Healthcare & Life Sciences,” n.d., e-CFR, n.d., “FDA QSR 21 CFR 820 vs ISO 13485 Comparison |,” 2016).
The primary document for medical device regulation in the US is Title 21 of the Code of Federal Regulations Parts 800 to 1299 (21 CFR 800 to 1299). The Centre for Devices and Radiological Health (CDRH) is the division responsible for medical device regulation. In the EU, there are three primary documents or directives for medical devices, the medical device directive 93/42/EEC, the IVDD 98/79/EC and the AIMDD 90/385/EEC.
When looking at regulation of medical devices the first main difference between the US and EU can be seen in device classification, pre-marketing controls and registration. The FDA have pre-market controls in place that are device and device classification specific. These controls may include clearance to the market by 510(k) application or approval by Pre-Market Approval (PMA). The FDA has 1700 generic groups of medical devices. These groups are classified within 16 specialties – CFR 862-892. There are three classes for classification of medical devices, Class I, Class II and Class III. Class I medical devices are low risk devices and adhere to general controls as per 21 CFR 860. There are approximately 780 products in this class. These devices are generally simple to design and manufacture and have a history of safe use. Class II devices present a moderate risk. The devices therefore must adhere to general controls and special controls. This is because the general controls are not sufficient to assure safety and effectiveness. There are approximately 800 products in this class. These devices typically require pre-market notification by submission and FDA review of a 510(k) application. Exemptions to pre-market notification do apply to a few class II devices and can be found in the 21 CFR 862-892. Class III medical devices have the most stringent regulatory controls as they are high risk medical devices. The application of both general and special controls does not provide sufficient information to assure safety and effectiveness. They must adhere to general controls and must apply for Premarket Approval (PMA). A few class III medical devices only require a 510(k) clearance to be marketed. The FDA also provide a product classification database online. New devices that have not yet been classified automatically default to high risk therefore requiring PMA. The other option involves submitting a De Novo application to the FDA. This classification process uses a risk based strategy. After De Novo is granted the new device is legally marketed and new classification is established. The US regulatory system also includes Post Marketing Controls. These include device listing, medical device reporting (MDR) and establishment registration and quality system compliance inspection. In order to get a medical device registered once classification has been completed, a quality management system must be implemented that adheres to FDA cGMP. If clinical studies are required an investigational device exemption (IDE) must be applied for. A 510(k) notification is applied for class II products whilst a PMA application is completed for class III devices. The FDA conducts facility inspections of all major suppliers involved in the design and production of all class III medical devices. This is to check all parties are compliant with the 21 CFR 820. Approval letters for 510(k) and PMA applications are posted online. Random inspections can be carried out at any time. The device must be listed on the FDA website and companies must be registered in compliance with the 21 CFR 807. The device is now registered and can be sold in the US as long as certain changes are not made (Blunnie, n.d.; Clerkin, n.d.; “De Novo Classification Process,” n.d., “Drugs, Devices, and the FDA: Part 1: An Overview of Approval Processes for Drugs – 1-s2.0-S2452302X1600036X-main.pdf,” n.d., e-CFR, n.d., “Product Classification,” n.d.; Van Norman, 2016).
In the EU devices must be assessed to conform with the EU directives. Like the US classification the assessment is risk based. However, unlike the US, authorisation of a medical device is granted by a declaration of conformity. The declaration is issued by the manufacturer but is verified by a certificate of conformity. Verification is undertaken by a notified body, who are accredited to validate compliance under MDD 93/42/EEC. There are four classes, Class I low risk, Class IIa medium risk, Class IIb higher risk and Class III highest risk. Medical devices are classed based on classification rules. Rules 1-4 apply to non-invasive devices, 5-8 are for invasive devices, 9-12 apply to active devices and 13-18 are special rules pertaining to devices that contain tissues of the animal origin or drug/device combinations. To determine classification the duration of contact between the medical device and the patient is considered, the degree of invasiveness, whether it’s active and which part of the body is affected are all taken into consideration. These rules are found in Annex IX of the MDD 93/42/ECC. The controls are increased based on the risk of the medical device determined by these rules. To register and commercialize a medical device or in-vitro diagnostic in the EU a CE mark certificate is required. The certification verifies that the device meets all the regulatory requirements of the MDD 93/42/EEC, IVDD 98/79/EC and the AIMDD 90/385/EEC as they apply to the product. Once classification is completed using Annex IX of the MDD 93/42/EEC, like the US a quality management system is put in place but in the EU, it is in accordance with Annex II or V of the MDD 93/42/EEC and in compliance with the ISO 13485. For class III and AIMD devices a technical file must be prepared that details compliance with MDD 93/42/EEC. The technical file and quality management system for all classes expect class I devices are audited by a notified body. Following a successful audit, the company will be issued with a CE mark certification for the medical device and an ISO 13485 certification (Blunnie, n.d.; Clerkin, n.d.; Kramer et al., 2012; “MDD 93/42/EEC,” n.d.; Van Norman, 2016).
After looking at both the US and EU regulations for classification and registration of a medical device, I personally feel the regulations for classification of a medical device in the EU are better than that of the US. This is because I find the rules for classification in Annex IX of the MDD 92/42/EEC easier to follow than that of the 21 CFR 860 in the US. However, in the EU, the process of registration is not handled by just one body so in this case I feel the US have the upper hand as everything is processed through the FDA. There are no private notified bodies and everything is available to the public to view. In the EU, any information on class III medical devices submitted to the notified bodies is considered “commercially confidential” and is not released to the public. I believe the openness of the US system is better for person or company looking for information for research purposes.
The regulations regarding combination devices in US is found in the 21 CFR 3. The 21 CFR 820.3(e) defines a combination product as: 1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; (3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labelling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labelling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or (4) Any investigational drug, device, or biological product packaged separately that according to its proposed labelling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect (Commissioner, n.d.). The designation of the lead FDA review centre for a combination product is based on the Primary Mode of Action or PMOA of the product. This is in adherence with the 21 CFR 3.4. There are three centres in total the Centre for Biologics Evaluation and Research (CBER), the Centre for Drug Evaluation and Research (CDER) and as mention previously the Centre for Devices and Radiological Health (CDRH). This means the combination products must slot into one of these centres.
In the EU, a medical device with a drug/ device combination are regulated as either a medical device or a medicinal product. The MDD 93/42/EEC defines a: medical device means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of: (1) diagnosis, prevention, monitoring, treatment or alleviation of disease, (2) diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap, (3) investigation, replacement or modification of the anatomy or of a physiological process, (4) control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means (“MDD 93/42/EEC,” n.d.). A medicinal product is defined in the Directive 2001/83/EC as am/ended by the Directive 2004/27/EC as: Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis (“2001/83/EC,” n.d., “2004/27/EC,” n.d.). To decide whether a new product falls under the MDD 93/42/EEC or the Directive 2008/83/EC as amended by Directive 2004/27/EC the primary mode of action of the product must be taken into account. So, whilst the definition of a combination is spilt differently in the EU the end of the process is very similar to the system in place in the US (“2001/83/EC,” n.d., “2004/27/EC,” n.d., e-CFR, n.d., “MDD 93/42/EEC,” n.d., “Regulatory Pathways of Drug-Device and Device-Drug Combination Products in the EU – md_regulatory_pathways_j31.pdf,” n.d., “regulatory_rapporteur_june_2015_a_european_perspective.pdf,” n.d.; Commissioner, n.d.).
Looking at both the quality management systems and regulations for medical devices, in-vitro diagnostics and combination products the US, in my opinion have the better system. Whilst there are aspects of the EU system that I prefer, like the rules for classification of a medical device or in-vitro diagnostic, the US system is far more precise and easier to navigate. Safety has always been a high concern for the US and can be seen throughout the FDA’s 21 CFR 800-1299. That said, as of 4th April 2017 the EU has put new regulations in place. The MDD 93/42/EEC and AIMDD 90/385/EEC have been replaced by the Regulation (EU) 2017/745. The IVDD 98/79/EC has been replaced by the Regulation (EU) 2017/746.
The new rules have considered technological advancement. Around the registration of high-risk device’s, the new regulations involved panels of independent experts at EU level, in a hope to combat inconsistencies that arise when using separate notified bodies. Clinical trials taking place in more than one member state will now only be subject to a single coordinated assessment as opposed to being subjected to multiple national assessments. Many of the aesthetic products, like coloured contact lenses, are no longer regulated as general products but are now considered to be medical devices, making the regulations and controls around them much stricter. Stricter regulations are in place for in-vitro diagnostic medical devices aswell with four out of five being checked by notified bodies before being placed on the market, instead of the previous regulation that stipulated only one in five needed to be checked. The European database, which had limited information on medical devices and was not publicly accessible, now has extensive information on medical devices and most of it will be available to the public to access. Simplified registration procedures mean that a medical device only has to be registered once by manufacturers at an EU level. An implant card now must accompany an implanted medical device, giving the patient more detailed information. These are just some of the many needed changes that the EU have implemented.
With these changes from the EU the US will definitely have to look at reviewing their procedures. If and when they will decide to do this is still not known. When both regulations- 2017/745 and 2017/746 are in place I believe the EU system for regulation and quality of medical devices could stand out to be the better one, especially as we move towards newer technologies and innovations.
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