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Regulations and laws
Chapter 101
Regulations and laws Zijad Džemića, Haris Memićb, Almir Badnjevićc a
Institute of Metrology of Bosnia and Herzegovina, Sarajevo, Bosnia and Herzegovina, bDepartment for Legal Metrology, Institute of Metrology of Bosnia and Herzegovina, Sarajevo, Bosnia and Herzegovina, c Medical Devices Verification Laboratory Verlab Ltd., Sarajevo, Bosnia and Herzegovina
Introduction People usually do not make any difference between laws and regulations but there is certain difference in hierarchy between laws and regulations. In the United States, e.g., Congress, and only Congress, creates laws. Federal executive departments and administrative agencies write regulations to implement the authority of laws. Regulations (as well as Executive Orders and Proclamations) are ancillary or subordinate to laws but both laws and regulations are enforceable. The US Code is the official compilation of current, codified laws by subject; the US Statutes-at-Large is the official chronological compilation of all laws; and the Code of Federal Regulations is the official compilation of regulations (http://wemakeitsafer.com/blog/2010/06/ laws-regulations-and-standards-whats-the-difference/). Laws are actually rules and guidelines that are set up by the social institutions to govern behavior. In simple terms, laws are basically things that a person can and cannot do. These laws are made by government officials. Laws must be obeyed by all, including private citizens, groups, and companies as well as public figures, organizations, and institutions. Laws set out standards, procedures, and principles that must be followed. Many people have heard laws and regulations being used in the same sentence. It is also assumed that they are related to each other in many ways. However, definitions of both the words often cause confusion between the two words making people believe that they are the same. These words are different from each other in distinct ways. Laws are rules that are enacted by governing body, while regulation is the process of monitoring and enforcing the rules. Regulations can be used to define two things: a process of monitoring and enforcing legislations and a written instrument containing rules that have law on them. It can come in many forms including legal restrictions, c ontractual
722
obligations, self-regulation, co-regulation, third-party regulation, certification, accreditation, or market regulation. Regulation is basically ensuring that a law or legislation is put into effect and the details of how it is put into effect. The regulations are the responsibility of the executive branch. Laws and regulations are quite different from each other. While, laws are passed by the government, it falls up to regulations to ensure and enforce the law. It has the ability to maintain and regulate the laws that govern the people (http://www.differencebetween.info/ difference-between-law-and-regulation). Federal regulatory agencies, such as the Food and Drug Administration (FDA), often publish guidance documents to help define standards or expectations that are part of a rule or regulation. Guidance documents serve many important functions in regulatory programs. The FDA, for instance, often uses guidance documents to help interpret existing law, provide current agency thinking on an issue, or clarify how it might treat or enforce a governing legal norm (http://www.publichealthlawcenter.org/ sites/default/files/resources/tclc-fs-laws-policies-regs- commonterms-2015.pdf).
History of medical devices regulation in the United States Two major milestones in the FDA’s regulation of medical devices occurred when devices were first brought under federal regulatory control in 1938, and when they were first subjected to premarket review in 1976. On both occasions, the agency sought to balance the need to protect the public from adulteration and misbranding of medical devices against the need to foster the development of innovative new life-saving medical devices (https://www.fda.gov/aboutfda/ whatwedo/history/productregulation/medicaldeviceandradiologicalhealthregulationscomeofage/default.htm).
Clinical Engineering Handbook. https://doi.org/10.1016/B978-0-12-813467-2.00102-4 Copyright © 2020 Elsevier Inc. All rights reserved.
Regulations and laws Chapter | 101 723
Conformity assessment in accordance with requirements in the United States The relevant legislation for the medical devices in the United States is under the responsibility of FDA (US FDA). Medical devices are regulated by Medical Device Amendments of 1976 to the Federal Food Drug and Cosmetic Act. The Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic Administration established three regulatory classes for medical devices. These three classes are based on the degree of control necessary to assure that the various types of devices are safe and effective (http:// www.fda.gov/medicaldevices/productsandmedicalprocedures/deviceapprovalsandclearances/pmaapprovals/default. htm). The FDA has established classifications for approximately 1700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. The United States has demands for marking of certain medical devices before their placement in the market, which must have premarket approval (PMA) equal to the European CE mark. The most regulated devices are in Class III, as defined in the amendments as devices that support or sustain human life or are of substantial importance in preventing impairment of human health or presenting a potential, unreasonable risk of illness, or injury. Insufficient information exists within Class III devices so that performance standards (Class II) or general controls (Class I) cannot provide reasonable assurance that the device is safe and effective for its intended use. Under Section 515 of the act, all devices placed into Class III are subject to PMA requirements. PMA by FDA is the required process of scientific review to ensure the safety and effectiveness of Class III devices. The official website of the FDA gives a wide range of information related to the medical devices which are useful for the manufacturer and other interested parties (user). Placing the medical device in the market of the United States consists of five steps (http://www.fda.gov/MedicalDevices/ DeviceRegulationandGuidance/HowtoMarketYourDevice/ default.htm) as follows: ● ● ●
●
●
Classify your device. Select the correct premarket submission. Prepare the appropriate information for the premarket submission. Send your premarket submission to the FDA and interact with FDA staff during review. Complete establishment registration and device listing. Before marketing a device, each submitter must receive an order, in the form of a letter, from the FDA which finds the device to be substantially equivalent and states that the device can be marketed in the United States.
A 510(k) requires demonstration of substantial equivalence to another legally US marketed device. Substantial equivalence means that the new device is at least as safe and effective as the predicate. Substantial equivalence is established with respect to intended use, design, energy used or delivered, materials, chemical composition, manufacturing process, performance, safety, effectiveness, labeling, biocompatibility, standards, and other characteristics, as applicable. The following four categories of parties must submit a 510(k) to the FDA: ● Domestic manufacturers introducing a device to the US market. ● Specification developers introducing a device to the US market. ● Re-packers or re-labelers who make labeling changes or whose operations significantly affect the device. ● Foreign manufacturers/exporters or US representatives of foreign manufacturers/exporters introducing a device to the US market. 510(k) is required for anyone who wants to sell a device in the United States after May 28, 1976 (effective date of the Medical Device Amendments to the Act), if the purpose is different from the intended use for a device which is already in commercial distribution and if there is a change or modification of a legally marketed device and that change could significantly affect its safety or effectiveness.
Third-party review The Accredited Persons Program was created by the FDA Modernization Act of 1997 (FDAMA), based on an FDA pilot. The purpose of the program is to improve the efficiency and timeliness of FDA’s 510(k) process, the process by which most medical devices receive marketing clearance in the United States. Under the program, the FDA has accredited third parties (Accredited Persons) that are authorized to conduct the primary review of 510(k) for eligible devices. Persons who are required to submit 510(k) for these devices may elect to contract with an Accredited Person and submit a 510(k) directly to the Accredited Person. The Accredited Person conducts the primary review of the 510(k), and forwards the review, recommendation, and the 510(k) to the FDA. By law, the FDA must issue a final determination within 30 days after receiving the recommendation of an Accredited Person. The 510(k) submitters who do not wish to use an Accredited Person may submit their 510(k) directly to the FDA. Once all the described steps have been conducted, the medical device can be placed in the US market. Two major milestones in the FDA’s (USA FDA) regulation of medical devices occurred when devices were first
724 SECTION | 11 Medical device standards, regulations, and the law
brought under federal regulatory control in 1938, and when they were first subjected to premarket review in 1976. On both occasions, the agency sought to balance the need to protect the public from adulteration and misbranding of medical devices against the need to foster the development of innovative new life-saving medical devices. Today, among other activities, the CDRH (Center for Devices and Radiological Health) devotes a great deal of time to working cooperatively with other agencies or centers to resolve issues relating to combination products, such as drugs that are also considered as devices: miniature devices (nanotechnology) that will provide less-invasive surgery, which ultimately will result in quicker recovery times for patients; and FDA training on new technology as it develops. Because of the agency’s timely, science-based decisions, millions of Americans get the medical products they need and can be assured of their safety and effectiveness. The FDA’s scientific investment brings tangible public health benefits, such as the development of state-of-the-art diagnostic techniques based on genetic mapping.
EU legislation in the field of medical devices The first harmonized Directive of European Union which covers the field of medical devices came into force in early 1990s. Legislation in the field of medicine in the European Union, i.e., legislation relating to medical devices, is based on Council Directive 93/42/EEC of June 14, 1993. This directive further relies on the following directives (http:// www.ema.europa.eu/ema/): ● ●
●
●
●
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Directive 93/68/EEC (CE Marking); Directive 98/79/EC of the European Parliament and of the Council of October 27, 1998 on in vitro diagnostic medical devices; Directive 2000/70/EC of the European Parliament and of the Council of November 16, 2000 amending Council Directive 93/42/EEC as regards to medical devices incorporating stable derivates of human blood or human plasma; Directive 2001/104/EC of the European Parliament and of the Council of December 7, 2001 amending Council Directive 93/42/EEC concerning medical devices; Directive 2007/47/EC of the European Parliament and of the Council of September 5, 2007 amending Council Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable medical devices, Council Directive 93/42/EEC concerning medical devices and Directive 98/8/EC concerning the placing of biocidal products on the market. Regulation (EU) 2017/745 of the European Parliament and of the Council of April 5, 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 April 5, 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU.
In the past, one more directive was in force, but it has been repealed as of January 1, 1995. This was the Council Directive 76/764/EEC on the approximation of the laws of the member states on clinical mercury-in-glass, maximum reading thermometers. As mentioned in the introduction, beside directives, there are a great number of written standards used in the manufacturing of medical devices (Memic et al., 2018; Badnjevic et al., 2017; Bosnjakovic et al., 2018). In the field of medical devices, there are c.200 standards which have been issued under the European Committee for Standardization CEN (without revision), and close to 100 standards issued under the European Committee for Electrotechnical Standardization CENELEC (without revision) (https://ec.europa.eu/growth/single-market/european-standards/harmonised-standards/medical-devices_ en; Badnjevic et al., 2015, 2017; Gurbeta et al., 2016a, 2017a,b,c). Taking into account such a large number of standards regulating the requirements for a particular product group, it is easy to conclude that this area of manufacturing presents an area where most attention is paid in relation to the safety of the product itself and its users. In order to place medical devices into the European Market based on requirements of Medical Devices Directive 93/42/ EEC (MDD), manufacturer or his authorized representative has to follow certain procedures. Those procedures, e.g., for medical devices of Class I are as follows (http://ec.europa.eu/consumers/sectors/medical-devices/files/guide-stds-directives/ notes-for-manufacturers-class1-09_en.pdf): ● ●
● ● ● ● ● ● ● ● ●
confirm product as a medical device confirm product as a Class I medical device procedures before the placing on the market meet the essential requirements prepare technical documentation request notified body intervention prepare instructions for use and labeling draw-up the EC Declaration of Conformity affix the CE marking notify the competent authorities record, evaluate, and notify incidents review experience gained from post-market surveillance
Risk management Risk management is a systematic application of management policies, procedures, and practices to the tasks of
Regulations and laws Chapter | 101 725
analyzing, evaluating, controlling, and monitoring risk. The International Standards Organization (ISO) Technical Committee 210 (ISO/TC 210), quality management, and corresponding general aspects for medical devices, was formed in 1994, and the group published the first edition of the ISO 14971 risk management standard for medical devices in 1998. A second edition of this standard was published in October 2007 as ISO 14971:2007, Medical devices—Application of risk management to medical devices. The standard describes the requirements for risk management to determine the safety of a medical device by the manufacturer during the product life cycle (https:// www.meddeviceonline.com/doc/the-what-why-when-andhow-of-risk-management-for-medical-device-manufacturers-0001; Gurbeta and Badnjevic, 2017; Gurbeta et al., 2015, 2016b; Vukovic et al., 2018). Risk management program is required by higher level regulation and other quality standards. ISO 13485, the standard that represents the requirements for a comprehensive quality management system for the design and manufacture of medical devices, states under product realization: the organization shall establish requirements for risk management throughout product realization. Risk management is also a requirement of the FDA’s Quality System Regulation (QSR), especially under 21 CFR 820.30 Design controls (g) Design validation: design validation shall include software validation and risk analysis, where appropriate. This standard, adopted by European Committee for Standardization (CEN) as EN ISO 14971:2012, is also harmonized with respect to the current European Medical Devices Directive 93/42/EEC, and is required by ANSI/AAMI/IEC/EN 60601-1-2:2014 Medical electrical equipment—Part 1-2: General requirements for basic safety and essential performance, subclause 4.2. In addition, it is recommended by the International Medical Device Regulators Forum (IMDRF), which supplanted the Global Harmonization Task Force (GHTF/SG3/N15R8) in 2011.
European approach on implementation of ISO 14971 standard The European harmonized standard EN ISO 14971 was initially released in 2009 and recently revised in 2012. This latest 2012 revision has modifications that are intended to aid in the identification of remaining discrepancies between ISO 14971:2007 and the essential requirements for medical devices as contained in the preexisting EU directives (93/42/EEC on Medical Devices, 90/385/EEC on Active Implantable Medical Devices, and 98/79/EC on In Vitro Diagnostic Devices). With the release of EN ISO 14971:2012, the requirements laid out in ISO 14971:2007 are still current because the normative text is the same between the two standards
and these requirements provide the foundation for the subsequent regional or country-specific risk management standards. A harmonized EN ISO standard is accomplished via appendices (Informative Annex Z) that clarify any gaps or differences between the requirements of the worldwide ISO standard and those of the EEC medical device directives. It is not the primary goal of the standard to cover exactly any of the European Essential Requirements. Conformity is not entirely achieved by complying only with the requirements specified in this standard, EEC directives add a further level of compliance in key areas of risk assessment. Appendices of EN ISO 14971:2012 standards bring requirements of ISO standard and EEC directive into closer agreement. How risks can influence the design, production, and market of medical devices in EU can be briefly shown throughout the following description of risks/benefits (https://www.namsa.com/wp-content/uploads/2015/10/ Impact-of-EN-ISC-2013-11-6-2013.pdf): ● ●
● ● ●
●
All risks must be taken into account. A risk/benefit analysis must be conducted for all products and take into account all risks. All risks must be reduced as far as possible. All risks control options/measures must be taken. Risks need to be reduced by an inherently safe design and construction. Information to users is a requirement but does not reduce residual risk.
International medical device regulators forum The IMDRF was born in October 2011, when representatives from the medical device regulatory authorities of Australia, Brazil, Canada, China, European Union, Japan, and the United States, as well as the World Health Organization (WHO) met in Ottawa to address the establishment and operation of this new forum (http://www.imdrf.org/about/about.asp). It is a voluntary group of medical device regulators from around the world who have come together to build on the strong foundational work of the GHTF on medical devices and to accelerate international medical device regulatory harmonization and convergence. The GHTF was operating till 2011, which was founded in 1993 by the governments and industry representatives of Australia, Canada, Japan, the European Union, and the United States to address the corresponding issues. In accordance with its terms of reference, the mission of the IMDRF is to strategically accelerate international medical device regulatory convergence to promote an efficient and effective regulatory model for medical devices that is
726 SECTION | 11 Medical device standards, regulations, and the law
responsive to emerging challenges in the sector while protecting and maximizing public health and safety. The IMDRF is established with the goal to address the common public health regulatory challenges to convergence due to the globalization of medical device production and the emergence of new technologies. The IMDRF provides the structure where the strategic decisions and operational mandates are made by public health-missioned medical device regulators, based on appropriate, equitable, and transparent input from stakeholders. The IMDRF will facilitate the identification, design, and implementation of activities that best meet the needs of the participants with regard to convergence. The scope of activities includes: ●
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●
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Working with IMDRF participants to develop a prioritized annual work plan of activities, taking into consideration the regulatory requirements and constraints that govern each regulatory authority (with respect to the sovereignty of each regulatory authority). Undertaking initiatives, projects, and issues of common interest and concern to regulatory authorities considering, when appropriate, the input from stakeholders. Enhancing the knowledge about regulated medical devices through information sharing. Facilitating mechanisms for the sharing and use of relevant information and the exchange of scientific expertise. Complementing the goals and objectives of the GHTF by providing a structured approach to implementing, revising, and maintaining GHTF documents and, if required, develop other guidance documents to achieve convergence across global medical device regulatory activities.
IMDRF activities and initiatives (work products) that further convergence may fall into three categories: 1. governance documents (created to address procedural and decision-making matters of the IMDRF); 2. technical documents (created to address technical matters relating to the regulation of medical devices); and 3. information documents (created to provide clarification, status, and/or needed information about a particular work item where public consultation is not needed).
Document development The IMDRF undertakes initiatives and projects to address issues of common interest and concern to regulatory authorities. The key work products produced from the agreed work plan priorities consist of governance documents and technical documents. The governance documents are consensus-driven documents and are applicable to all MC
(Management Committee of IMDRF) members once approved by the MC. Technical documents relating to the regulation of medical devices will be developed to reflect the regulators’ efforts to achieve convergence of regulatory practices across a specific area. Final documents can be found on official website of IMDRF (containing also GHTF documents) http://www. imdrf.org/documents/documents.asp.
Conclusion Regulations and laws are very important in our everyday life and are important guidelines on how to deal in different situations on the the same way if the same problem is to be solved. Without regulations and laws, we would not be able to carry out adequate conformity assessment and judge if some of products fulfill requirements which could be highly influential on the lives of all citizens, important to the health, the environment, and the protection of economic transactions. Regulations and laws allow us to achieve a better quality of life. Anyhow, laws and regulations are quite different from each other. While, laws are passed by the government, it falls up to regulations to ensure and enforce the law. It has the ability to maintain and regulate the laws that govern the people.
References Badnjevic, A., Gurbeta, L., Boskovic, D., Dzemic, Z., 2015. Measurement in medicine—past, present, future. Folia Med. Fac. Med. Univ. Saraeviensis J. 50 (1), 43–46. Badnjevic, A., Gurbeta, L., Jimenez, E.R., Iadanza, E., 2017. Testing of mechanical ventilators and infant incubators in healthcare institutions. Technol. Health Care 25 (2), 237–250. Badnjevic A., Cifrek M., Magjarevic R., Dzemic Z. (eds) Inspection of Medical Devices. Series in Biomedical Engineering, 2017, Springer, Singapore. Bosnjakovic, A., Badnjevic, A., Dzemic, Z., 2018. Legal metrology system—past, present, future. In: Badnjevic, A., Cifrek, M., Magjarevic, R., Dzemic, Z. (Eds.), Inspection of Medical Devices. Series in Biomedical Engineering. Springer, Singapore. Gurbeta, L., Badnjevic, A., 2017. Inspection process of medical devices in healthcare institutions: software solution. Health Technol. 7 (1), 109–117. https://doi.org/10.1007/s12553-016-0154-2. Gurbeta, L., Badnjevic, A., Pinjo, N., Ljumic, F., 2015. Software package for tracking status of inspection dates and reports of medical devices in healthcare institutions of Bosnia and Herzegovina. In: XXV International Conference on Information, Communication and Automation Technologies (IEEE ICAT), 29–31 October 2015, Sarajevo, Bosnia and Herzegovina, pp. 1–5. Gurbeta, L., Badnjevic, A., Dzemic, Z., Jimenez, E.R., Jakupovic, A., 2016a. Testing of therapeutic ultrasound in healthcare institutions in Bosnia and Herzegovina. In: 2nd EAI International Conference on Future Access Enablers of Ubiquitous and Intelligent Infrastructures, 24–25 October 2016, Belgrade, Serbia.
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Gurbeta, L., Badnjevic, A., Sejdinovic, D., Alic, B., Abd El-Ilah, L., Zunic, E., 2016b. Software solution for tracking inspection processes of medical devices from legal metrology system. In: XIV Mediterranean Conference on Medical and Biological Engineering and Computing (MEDICON), 31 March–2 April 2016, Paphos, Cyprus. Gurbeta, L., Dzemic, Z., Bego, T., Sejdic, E., Badnjevic, A., 2017a. Testing of anesthesia machines and defibrillators in healthcare institutions. J. Med. Syst. 41, 133. Gurbeta, L., Alic, B., Dzemic, Z., Badnjevic, A., 2017b. Testing of infusion pumps in healthcare institutions in Bosnia and Herzegovina. In: Eskola, H., Väisänen, O., Viik, J., Hyttinen, J. (Eds.), EMBEC & NBC 2017. EMBEC 2017, NBC 2017. IFMBE Proceedings. vol. 65. Springer, Singapore.
Gurbeta, L., Alic, B., Dzemic, Z., Badnjevic, A., 2017c. Testing of dialysis machines in healthcare institutions in Bosnia and Herzegovina. In: Eskola, H., Väisänen, O., Viik, J., Hyttinen, J. (Eds.), EMBEC & NBC 2017. EMBEC 2017, NBC 2017. IFMBE Proceedings. vol. 65. Springer, Singapore. Memic, H., Dzemic, Z., Badnjevic, A., 2018. Regulations and directives—past, present, future. In: Badnjevic, A., Cifrek, M., Magjarevic, R., Dzemic, Z. (Eds.), Inspection of Medical Devices. Series in Biomedical Engineering. Springer, Singapore. Vukovic, D., Badnjevic, A., Omanovic-Miklicanin, E., 2018. Cost effectiveness and increasing of accuracy of medical devices in legal metrology system: case study Bosnia and Herzegovina. In: Badnjevic, A., Cifrek, M., Magjarevic, R., Dzemic, Z. (Eds.), Inspection of Medical Devices. Series in Biomedical Engineering. Springer, Singapore.
Regulations and laws Zijad Džemića, Haris Memićb, Almir Badnjevićc a
Institute of Metrology of Bosnia and Herzegovina, Sarajevo, Bosnia and Herzegovina, bDepartment for Legal Metrology, Institute of Metrology of Bosnia and Herzegovina, Sarajevo, Bosnia and Herzegovina, c Medical Devices Verification Laboratory Verlab Ltd., Sarajevo, Bosnia and Herzegovina
Introduction People usually do not make any difference between laws and regulations but there is certain difference in hierarchy between laws and regulations. In the United States, e.g., Congress, and only Congress, creates laws. Federal executive departments and administrative agencies write regulations to implement the authority of laws. Regulations (as well as Executive Orders and Proclamations) are ancillary or subordinate to laws but both laws and regulations are enforceable. The US Code is the official compilation of current, codified laws by subject; the US Statutes-at-Large is the official chronological compilation of all laws; and the Code of Federal Regulations is the official compilation of regulations (http://wemakeitsafer.com/blog/2010/06/ laws-regulations-and-standards-whats-the-difference/). Laws are actually rules and guidelines that are set up by the social institutions to govern behavior. In simple terms, laws are basically things that a person can and cannot do. These laws are made by government officials. Laws must be obeyed by all, including private citizens, groups, and companies as well as public figures, organizations, and institutions. Laws set out standards, procedures, and principles that must be followed. Many people have heard laws and regulations being used in the same sentence. It is also assumed that they are related to each other in many ways. However, definitions of both the words often cause confusion between the two words making people believe that they are the same. These words are different from each other in distinct ways. Laws are rules that are enacted by governing body, while regulation is the process of monitoring and enforcing the rules. Regulations can be used to define two things: a process of monitoring and enforcing legislations and a written instrument containing rules that have law on them. It can come in many forms including legal restrictions, c ontractual
722
obligations, self-regulation, co-regulation, third-party regulation, certification, accreditation, or market regulation. Regulation is basically ensuring that a law or legislation is put into effect and the details of how it is put into effect. The regulations are the responsibility of the executive branch. Laws and regulations are quite different from each other. While, laws are passed by the government, it falls up to regulations to ensure and enforce the law. It has the ability to maintain and regulate the laws that govern the people (http://www.differencebetween.info/ difference-between-law-and-regulation). Federal regulatory agencies, such as the Food and Drug Administration (FDA), often publish guidance documents to help define standards or expectations that are part of a rule or regulation. Guidance documents serve many important functions in regulatory programs. The FDA, for instance, often uses guidance documents to help interpret existing law, provide current agency thinking on an issue, or clarify how it might treat or enforce a governing legal norm (http://www.publichealthlawcenter.org/ sites/default/files/resources/tclc-fs-laws-policies-regs- commonterms-2015.pdf).
History of medical devices regulation in the United States Two major milestones in the FDA’s regulation of medical devices occurred when devices were first brought under federal regulatory control in 1938, and when they were first subjected to premarket review in 1976. On both occasions, the agency sought to balance the need to protect the public from adulteration and misbranding of medical devices against the need to foster the development of innovative new life-saving medical devices (https://www.fda.gov/aboutfda/ whatwedo/history/productregulation/medicaldeviceandradiologicalhealthregulationscomeofage/default.htm).
Clinical Engineering Handbook. https://doi.org/10.1016/B978-0-12-813467-2.00102-4 Copyright © 2020 Elsevier Inc. All rights reserved.
Regulations and laws Chapter | 101 723
Conformity assessment in accordance with requirements in the United States The relevant legislation for the medical devices in the United States is under the responsibility of FDA (US FDA). Medical devices are regulated by Medical Device Amendments of 1976 to the Federal Food Drug and Cosmetic Act. The Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic Administration established three regulatory classes for medical devices. These three classes are based on the degree of control necessary to assure that the various types of devices are safe and effective (http:// www.fda.gov/medicaldevices/productsandmedicalprocedures/deviceapprovalsandclearances/pmaapprovals/default. htm). The FDA has established classifications for approximately 1700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. The United States has demands for marking of certain medical devices before their placement in the market, which must have premarket approval (PMA) equal to the European CE mark. The most regulated devices are in Class III, as defined in the amendments as devices that support or sustain human life or are of substantial importance in preventing impairment of human health or presenting a potential, unreasonable risk of illness, or injury. Insufficient information exists within Class III devices so that performance standards (Class II) or general controls (Class I) cannot provide reasonable assurance that the device is safe and effective for its intended use. Under Section 515 of the act, all devices placed into Class III are subject to PMA requirements. PMA by FDA is the required process of scientific review to ensure the safety and effectiveness of Class III devices. The official website of the FDA gives a wide range of information related to the medical devices which are useful for the manufacturer and other interested parties (user). Placing the medical device in the market of the United States consists of five steps (http://www.fda.gov/MedicalDevices/ DeviceRegulationandGuidance/HowtoMarketYourDevice/ default.htm) as follows: ● ● ●
●
●
Classify your device. Select the correct premarket submission. Prepare the appropriate information for the premarket submission. Send your premarket submission to the FDA and interact with FDA staff during review. Complete establishment registration and device listing. Before marketing a device, each submitter must receive an order, in the form of a letter, from the FDA which finds the device to be substantially equivalent and states that the device can be marketed in the United States.
A 510(k) requires demonstration of substantial equivalence to another legally US marketed device. Substantial equivalence means that the new device is at least as safe and effective as the predicate. Substantial equivalence is established with respect to intended use, design, energy used or delivered, materials, chemical composition, manufacturing process, performance, safety, effectiveness, labeling, biocompatibility, standards, and other characteristics, as applicable. The following four categories of parties must submit a 510(k) to the FDA: ● Domestic manufacturers introducing a device to the US market. ● Specification developers introducing a device to the US market. ● Re-packers or re-labelers who make labeling changes or whose operations significantly affect the device. ● Foreign manufacturers/exporters or US representatives of foreign manufacturers/exporters introducing a device to the US market. 510(k) is required for anyone who wants to sell a device in the United States after May 28, 1976 (effective date of the Medical Device Amendments to the Act), if the purpose is different from the intended use for a device which is already in commercial distribution and if there is a change or modification of a legally marketed device and that change could significantly affect its safety or effectiveness.
Third-party review The Accredited Persons Program was created by the FDA Modernization Act of 1997 (FDAMA), based on an FDA pilot. The purpose of the program is to improve the efficiency and timeliness of FDA’s 510(k) process, the process by which most medical devices receive marketing clearance in the United States. Under the program, the FDA has accredited third parties (Accredited Persons) that are authorized to conduct the primary review of 510(k) for eligible devices. Persons who are required to submit 510(k) for these devices may elect to contract with an Accredited Person and submit a 510(k) directly to the Accredited Person. The Accredited Person conducts the primary review of the 510(k), and forwards the review, recommendation, and the 510(k) to the FDA. By law, the FDA must issue a final determination within 30 days after receiving the recommendation of an Accredited Person. The 510(k) submitters who do not wish to use an Accredited Person may submit their 510(k) directly to the FDA. Once all the described steps have been conducted, the medical device can be placed in the US market. Two major milestones in the FDA’s (USA FDA) regulation of medical devices occurred when devices were first
724 SECTION | 11 Medical device standards, regulations, and the law
brought under federal regulatory control in 1938, and when they were first subjected to premarket review in 1976. On both occasions, the agency sought to balance the need to protect the public from adulteration and misbranding of medical devices against the need to foster the development of innovative new life-saving medical devices. Today, among other activities, the CDRH (Center for Devices and Radiological Health) devotes a great deal of time to working cooperatively with other agencies or centers to resolve issues relating to combination products, such as drugs that are also considered as devices: miniature devices (nanotechnology) that will provide less-invasive surgery, which ultimately will result in quicker recovery times for patients; and FDA training on new technology as it develops. Because of the agency’s timely, science-based decisions, millions of Americans get the medical products they need and can be assured of their safety and effectiveness. The FDA’s scientific investment brings tangible public health benefits, such as the development of state-of-the-art diagnostic techniques based on genetic mapping.
EU legislation in the field of medical devices The first harmonized Directive of European Union which covers the field of medical devices came into force in early 1990s. Legislation in the field of medicine in the European Union, i.e., legislation relating to medical devices, is based on Council Directive 93/42/EEC of June 14, 1993. This directive further relies on the following directives (http:// www.ema.europa.eu/ema/): ● ●
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Directive 93/68/EEC (CE Marking); Directive 98/79/EC of the European Parliament and of the Council of October 27, 1998 on in vitro diagnostic medical devices; Directive 2000/70/EC of the European Parliament and of the Council of November 16, 2000 amending Council Directive 93/42/EEC as regards to medical devices incorporating stable derivates of human blood or human plasma; Directive 2001/104/EC of the European Parliament and of the Council of December 7, 2001 amending Council Directive 93/42/EEC concerning medical devices; Directive 2007/47/EC of the European Parliament and of the Council of September 5, 2007 amending Council Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable medical devices, Council Directive 93/42/EEC concerning medical devices and Directive 98/8/EC concerning the placing of biocidal products on the market. Regulation (EU) 2017/745 of the European Parliament and of the Council of April 5, 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No
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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 April 5, 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU.
In the past, one more directive was in force, but it has been repealed as of January 1, 1995. This was the Council Directive 76/764/EEC on the approximation of the laws of the member states on clinical mercury-in-glass, maximum reading thermometers. As mentioned in the introduction, beside directives, there are a great number of written standards used in the manufacturing of medical devices (Memic et al., 2018; Badnjevic et al., 2017; Bosnjakovic et al., 2018). In the field of medical devices, there are c.200 standards which have been issued under the European Committee for Standardization CEN (without revision), and close to 100 standards issued under the European Committee for Electrotechnical Standardization CENELEC (without revision) (https://ec.europa.eu/growth/single-market/european-standards/harmonised-standards/medical-devices_ en; Badnjevic et al., 2015, 2017; Gurbeta et al., 2016a, 2017a,b,c). Taking into account such a large number of standards regulating the requirements for a particular product group, it is easy to conclude that this area of manufacturing presents an area where most attention is paid in relation to the safety of the product itself and its users. In order to place medical devices into the European Market based on requirements of Medical Devices Directive 93/42/ EEC (MDD), manufacturer or his authorized representative has to follow certain procedures. Those procedures, e.g., for medical devices of Class I are as follows (http://ec.europa.eu/consumers/sectors/medical-devices/files/guide-stds-directives/ notes-for-manufacturers-class1-09_en.pdf): ● ●
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confirm product as a medical device confirm product as a Class I medical device procedures before the placing on the market meet the essential requirements prepare technical documentation request notified body intervention prepare instructions for use and labeling draw-up the EC Declaration of Conformity affix the CE marking notify the competent authorities record, evaluate, and notify incidents review experience gained from post-market surveillance
Risk management Risk management is a systematic application of management policies, procedures, and practices to the tasks of
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analyzing, evaluating, controlling, and monitoring risk. The International Standards Organization (ISO) Technical Committee 210 (ISO/TC 210), quality management, and corresponding general aspects for medical devices, was formed in 1994, and the group published the first edition of the ISO 14971 risk management standard for medical devices in 1998. A second edition of this standard was published in October 2007 as ISO 14971:2007, Medical devices—Application of risk management to medical devices. The standard describes the requirements for risk management to determine the safety of a medical device by the manufacturer during the product life cycle (https:// www.meddeviceonline.com/doc/the-what-why-when-andhow-of-risk-management-for-medical-device-manufacturers-0001; Gurbeta and Badnjevic, 2017; Gurbeta et al., 2015, 2016b; Vukovic et al., 2018). Risk management program is required by higher level regulation and other quality standards. ISO 13485, the standard that represents the requirements for a comprehensive quality management system for the design and manufacture of medical devices, states under product realization: the organization shall establish requirements for risk management throughout product realization. Risk management is also a requirement of the FDA’s Quality System Regulation (QSR), especially under 21 CFR 820.30 Design controls (g) Design validation: design validation shall include software validation and risk analysis, where appropriate. This standard, adopted by European Committee for Standardization (CEN) as EN ISO 14971:2012, is also harmonized with respect to the current European Medical Devices Directive 93/42/EEC, and is required by ANSI/AAMI/IEC/EN 60601-1-2:2014 Medical electrical equipment—Part 1-2: General requirements for basic safety and essential performance, subclause 4.2. In addition, it is recommended by the International Medical Device Regulators Forum (IMDRF), which supplanted the Global Harmonization Task Force (GHTF/SG3/N15R8) in 2011.
European approach on implementation of ISO 14971 standard The European harmonized standard EN ISO 14971 was initially released in 2009 and recently revised in 2012. This latest 2012 revision has modifications that are intended to aid in the identification of remaining discrepancies between ISO 14971:2007 and the essential requirements for medical devices as contained in the preexisting EU directives (93/42/EEC on Medical Devices, 90/385/EEC on Active Implantable Medical Devices, and 98/79/EC on In Vitro Diagnostic Devices). With the release of EN ISO 14971:2012, the requirements laid out in ISO 14971:2007 are still current because the normative text is the same between the two standards
and these requirements provide the foundation for the subsequent regional or country-specific risk management standards. A harmonized EN ISO standard is accomplished via appendices (Informative Annex Z) that clarify any gaps or differences between the requirements of the worldwide ISO standard and those of the EEC medical device directives. It is not the primary goal of the standard to cover exactly any of the European Essential Requirements. Conformity is not entirely achieved by complying only with the requirements specified in this standard, EEC directives add a further level of compliance in key areas of risk assessment. Appendices of EN ISO 14971:2012 standards bring requirements of ISO standard and EEC directive into closer agreement. How risks can influence the design, production, and market of medical devices in EU can be briefly shown throughout the following description of risks/benefits (https://www.namsa.com/wp-content/uploads/2015/10/ Impact-of-EN-ISC-2013-11-6-2013.pdf): ● ●
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All risks must be taken into account. A risk/benefit analysis must be conducted for all products and take into account all risks. All risks must be reduced as far as possible. All risks control options/measures must be taken. Risks need to be reduced by an inherently safe design and construction. Information to users is a requirement but does not reduce residual risk.
International medical device regulators forum The IMDRF was born in October 2011, when representatives from the medical device regulatory authorities of Australia, Brazil, Canada, China, European Union, Japan, and the United States, as well as the World Health Organization (WHO) met in Ottawa to address the establishment and operation of this new forum (http://www.imdrf.org/about/about.asp). It is a voluntary group of medical device regulators from around the world who have come together to build on the strong foundational work of the GHTF on medical devices and to accelerate international medical device regulatory harmonization and convergence. The GHTF was operating till 2011, which was founded in 1993 by the governments and industry representatives of Australia, Canada, Japan, the European Union, and the United States to address the corresponding issues. In accordance with its terms of reference, the mission of the IMDRF is to strategically accelerate international medical device regulatory convergence to promote an efficient and effective regulatory model for medical devices that is
726 SECTION | 11 Medical device standards, regulations, and the law
responsive to emerging challenges in the sector while protecting and maximizing public health and safety. The IMDRF is established with the goal to address the common public health regulatory challenges to convergence due to the globalization of medical device production and the emergence of new technologies. The IMDRF provides the structure where the strategic decisions and operational mandates are made by public health-missioned medical device regulators, based on appropriate, equitable, and transparent input from stakeholders. The IMDRF will facilitate the identification, design, and implementation of activities that best meet the needs of the participants with regard to convergence. The scope of activities includes: ●
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Working with IMDRF participants to develop a prioritized annual work plan of activities, taking into consideration the regulatory requirements and constraints that govern each regulatory authority (with respect to the sovereignty of each regulatory authority). Undertaking initiatives, projects, and issues of common interest and concern to regulatory authorities considering, when appropriate, the input from stakeholders. Enhancing the knowledge about regulated medical devices through information sharing. Facilitating mechanisms for the sharing and use of relevant information and the exchange of scientific expertise. Complementing the goals and objectives of the GHTF by providing a structured approach to implementing, revising, and maintaining GHTF documents and, if required, develop other guidance documents to achieve convergence across global medical device regulatory activities.
IMDRF activities and initiatives (work products) that further convergence may fall into three categories: 1. governance documents (created to address procedural and decision-making matters of the IMDRF); 2. technical documents (created to address technical matters relating to the regulation of medical devices); and 3. information documents (created to provide clarification, status, and/or needed information about a particular work item where public consultation is not needed).
Document development The IMDRF undertakes initiatives and projects to address issues of common interest and concern to regulatory authorities. The key work products produced from the agreed work plan priorities consist of governance documents and technical documents. The governance documents are consensus-driven documents and are applicable to all MC
(Management Committee of IMDRF) members once approved by the MC. Technical documents relating to the regulation of medical devices will be developed to reflect the regulators’ efforts to achieve convergence of regulatory practices across a specific area. Final documents can be found on official website of IMDRF (containing also GHTF documents) http://www. imdrf.org/documents/documents.asp.
Conclusion Regulations and laws are very important in our everyday life and are important guidelines on how to deal in different situations on the the same way if the same problem is to be solved. Without regulations and laws, we would not be able to carry out adequate conformity assessment and judge if some of products fulfill requirements which could be highly influential on the lives of all citizens, important to the health, the environment, and the protection of economic transactions. Regulations and laws allow us to achieve a better quality of life. Anyhow, laws and regulations are quite different from each other. While, laws are passed by the government, it falls up to regulations to ensure and enforce the law. It has the ability to maintain and regulate the laws that govern the people.
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Gurbeta, L., Badnjevic, A., Sejdinovic, D., Alic, B., Abd El-Ilah, L., Zunic, E., 2016b. Software solution for tracking inspection processes of medical devices from legal metrology system. In: XIV Mediterranean Conference on Medical and Biological Engineering and Computing (MEDICON), 31 March–2 April 2016, Paphos, Cyprus. Gurbeta, L., Dzemic, Z., Bego, T., Sejdic, E., Badnjevic, A., 2017a. Testing of anesthesia machines and defibrillators in healthcare institutions. J. Med. Syst. 41, 133. Gurbeta, L., Alic, B., Dzemic, Z., Badnjevic, A., 2017b. Testing of infusion pumps in healthcare institutions in Bosnia and Herzegovina. In: Eskola, H., Väisänen, O., Viik, J., Hyttinen, J. (Eds.), EMBEC & NBC 2017. EMBEC 2017, NBC 2017. IFMBE Proceedings. vol. 65. Springer, Singapore.
Gurbeta, L., Alic, B., Dzemic, Z., Badnjevic, A., 2017c. Testing of dialysis machines in healthcare institutions in Bosnia and Herzegovina. In: Eskola, H., Väisänen, O., Viik, J., Hyttinen, J. (Eds.), EMBEC & NBC 2017. EMBEC 2017, NBC 2017. IFMBE Proceedings. vol. 65. Springer, Singapore. Memic, H., Dzemic, Z., Badnjevic, A., 2018. Regulations and directives—past, present, future. In: Badnjevic, A., Cifrek, M., Magjarevic, R., Dzemic, Z. (Eds.), Inspection of Medical Devices. Series in Biomedical Engineering. Springer, Singapore. Vukovic, D., Badnjevic, A., Omanovic-Miklicanin, E., 2018. Cost effectiveness and increasing of accuracy of medical devices in legal metrology system: case study Bosnia and Herzegovina. In: Badnjevic, A., Cifrek, M., Magjarevic, R., Dzemic, Z. (Eds.), Inspection of Medical Devices. Series in Biomedical Engineering. Springer, Singapore.