Standards and Regulatory Considerations

Acknowledgments

The authors acknowledge Gregory Welyczko of GE Healthcare (retired), Stanley Weitzner, MD, and Mark Graber of GE Healthcare (retired) for their contributions to the anesthesia equipment standards in Table 27.8 .

Overview

It was once possible to practice “safe” and “modern” anesthesia without any awareness of the regulatory and voluntary standards governing anesthesia equipment and practice. This has changed, however, and individual practitioners are now subject to federal and state regulations regarding the use of these devices, and are strongly influenced by international standards and agreements. The arena of medical device standards and regulations is complex and arcane, and there is much overlap of authority. This chapter reviews the history, current status, interested parties, relevant standards, standards processes, and pending developments that will affect the clinician in the future. The reader should be left with a good understanding of both the processes and the interested parties in the constantly evolving international setting of standards and regulations.

What is a Standard?

A standard is a document, established by consensus and approved by a recognized body, that provides for common and repeated use, rules, guidelines, or characteristics for activities or their results, aimed at the achievement of the optimum degree of order in a given context. Standards should be based on the consolidated results of science, technology, and experience, and they should be aimed at the promotion of optimum community benefits. In reality, a standard is an agreed restriction for a common good and a shared benefit.

Regulation of Medical Devices

The rules governing medical devices differ throughout the world. Many different models exist, such as the U.S. Food and Drug Administration (FDA), European Union (EU) CE-marking system, and various registrations, listings, licenses, and approvals in other countries. Efforts have been under way since the early 1990s via organizations such as the Global Harmonization Task Force (GHTF), now reorganized as the International Medical Device Regulators Forum (IMDRF), to achieve better uniformity among national medical device regulatory systems around the world. This is being done with two aims in mind: enhancing patient safety and increasing access to safe, effective, and clinically beneficial medical technologies.

International Medical Device Regulators Forum

The IMDRF was conceived in February 2011 as a forum to discuss future directions in medical device regulatory harmonization. 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, which it replaced. The goal of both groups is to accelerate international medical device regulatory harmonization and convergence. The GHTF, consisting of five founding members: the EU, United States, Canada, Australia, and Japan, was a partnership between regulatory authorities and regulated industry whereas the IMDRF is a regulators-only forum.

The IMDRF intends to provide guidance on strategies, policies, directions, and activities to accelerate international medical device regulatory harmonization. Unlike the GHTF, various stakeholder groups, such as industry, academia, health care professionals, and consumer and patient groups, are no longer invited to participate in the steering committee or management committee, although they can be invited to participate in ad hoc working groups. Since its founding, the IMDRF has added the regulatory authorities of Russia, Singapore, and South Korea as full members. ^a

Building on the work of the GHTF, the IMDRF has developed the Medical Device Single Audit Program (MDSAP), which is a program that allows the conduct of a single regulatory audit of a medical device manufacturer’s quality management system that satisfies the requirements of multiple regulatory jurisdictions. Currently a single audit can fulfill the regulatory requirements for Australia, Brazil, Canada, Japan, and the United States. This is efficient for both the regulators and the manufacturers as quality system (QS) audits are quite labor-intensive and expensive. Following upon this success, the IMDRF has begun the process of developing the infrastructure to support a unified medical device premarket program. This is a significantly more difficult challenge that may take more than a decade to complete. ^b

Medical Device Regulation in the United States

Manufacturers of medical devices distributed in the United States must comply with certain basic regulatory requirements:

Establishment registration
Quality systems
Labeling requirements
Premarket notification (PMN) 510(k), unless exempt, or Premarket approval (PMA)
Medical device listing
Medical device reporting (MDR)

Definition of Terms

Establishment Registration

A manufacturer must file its name and all places of business with the U.S. FDA. Any additional place of business must be registered immediately. Registration is now performed electronically online.

Quality System Requirements

The QS regulation requires the manufacturer to have a written QS that is subject to periodic audit by the FDA. The FDA has announced their intent to replace the current QS regulation (21 CFR 820) with the internationally utilized medical device QS standard, ISO 13485:2016. This is a positive step toward international regulatory harmonization and recognizes the FDA commitment to the IMDRF MDSAP program.

ISO 13485 requires every medical device to be designed, manufactured, packed, stored, and installed in conformity with controlled practices. ISO 13485 requires use of design validation, investigation of complaints, and a corrective and preventive action plan to identify root causes of product nonconformance with standards and specifications and to implement effective actions to prevent recurrence.

Labeling Requirements

Medical devices must be labeled either on the medical device or on its immediate container. The label must identify the company name, trade name, or trade symbol of the manufacturer, as well as the name and place of business of the manufacturer, packager, or distributor and the identity of and quantity of the contents of the package. In addition, the labeling of a medical device must provide adequate directions for use and adequate warnings against unsafe use for a layperson, unless the medical device is a prescription medical device, in which case the labeling may be written for health care professionals. The labeling of a prescription medical device may be made available electronically. Additionally, the FDA now requires manufacturers to identify their medical devices and accessories in label form with the Unique Device Identification (UDI). Not only must a medical device and its accessories be labeled in a human- and machine-readable form, but certain information about each device must be entered into the FDA’s Global Unique Device Identification Database (GUDID). Elements of this database are available to the public. ^c

Premarket Notification 510(k)

The 510(k) process, named for the Code of Federal Regulations (CFR) section empowering it, is designed to ensure, through a quality review process, that marketed medical devices, subject to general and applicable special controls, provide a reasonable assurance of safety and effectiveness. It is also designed to foster innovation. This is achieved by comparing the (new) device to an existing (predicate) moderate-risk medical device and demonstrating that the new medical device is substantially equivalent to the predicate. The 510(k) process applies to moderate-risk medical devices (typically class II; Table 27.1 ).

Table 27.1

Comparison of FDA 510(k) Premarket Notification and Premarket Approval

Factor	510(k) Premarket Notification	Premarket Approval
Classes of devices	Class I and II devices	Class III devices
Number annually	3892 ^a	48 ^a
Documentation (length)	Depends on type of submission (special, traditional) Typically 50–250 pages	Typically thousands of pages
Regulatory requirement	Reasonable assurance of safety and effectiveness	Reasonable assurance of safety and effectiveness
Evidence	“Substantial equivalence”: comparison to an existing predicate medical device	Scientific review process of safety and effectiveness data
Clinical studies provided?	Varies depending on device type, overall about 10% with clinical studies	Required for both safety and effectiveness
Review period (goal/typical)	90/120 days ^b (traditionally 74% of submissions ^b )Average time for anesthesiology branch: 140 days ^b	180/410 days ^c
Source of required information	21 CFR 807.87	Section 515(c)(1) of the Federal Food, Drug, and Cosmetic Act
Outside review?	No	FDA Advisory Panel meeting
User fees	$10,953 ^d	$322,147 ^d
		Additional changes made via PMA supplements: - real-time—$22,550 ^d - 180 day—$48,322 ^d - panel track—$241,610 ^d

CFR, Code of Federal Regulations; FDA, Food and Drug Administration; PMA, premarket approval.

a 3-year average, FY2015 to FY2017, actual.

b An analysis of FDA 510(k) data from 2006 to 2010, Emergo Group (January 9, 2012).

c 3-year average, fiscal years 2006 to 2008.

d FY2019 actual.

Premarket Approval

The PMA process is designed to ensure that a specific marketed medical device provides a reasonable assurance of safety and effectiveness through a scientific review process of safety and effectiveness data (clinical trials). The PMA process applies to novel medical devices or new high-risk medical devices (typically class III; see Table 27.1 ).

Medical Device Listings

A manufacturer must file a list identifying each medical device made or processed for commercial distribution in the United States and its labels and labeling. Additionally, the manufacturer must provide a notice of discontinuance once a medical device is no longer made. Listing is performed electronically.

Medical Device Reporting

Manufacturers of medical devices must report to the FDA when they learn of information that reasonably suggests that a medical device has or may have caused or contributed to the death or serious illness of, or serious injury to, a patient, or when they learn of an event that might contribute to the death or serious illness of, or serious injury to, a patient should it reoccur.

Medical Device Regulation in the European Union

In the EU, medical devices are regulated by one of three directives: the Medical Devices Directive (MDD), the Active Implantable Medical Devices Directive (AIMDD), or the In Vitro Diagnostic Directive (IVDD). Directives are an instrument from the European Parliament directing each member state to enact a law that embodies the content of the directive. The directives establish the regulatory scheme based on a risk-based classification system and, for higher risk devices, a certified QS. In an effort to improve safety and uniformity, these three directives are being replaced by two regulations: the Medical Device Regulation (MDR), which also covers active implantables; and the In Vitro Diagnostic Regulation (IVDR).The regulations establish broad safety and performance criteria called the General Safety and Performance Requirements (GSPRs). All medical devices are required to demonstrate compliance with all the relevant GSPRs.

Medical Device Regulation in Japan

The Pharmaceutical Affairs Law (PAL) applies to all medical devices in Japan. The PAL is controlled by the Ministry of Health, Labor, and Welfare (MHLW). All medical devices are classified with a Japanese classification rule that was basically an adopted GHTF rule. Based on the classification, a medical device can require notification , certification , or approval (respectively, from lower to higher risk and from lower to higher effort). Additionally, certain measuring devices require a separate metrological (pattern) approval.

Medical Device Regulation in China

The National Medical Products Administration (NMPA), has been reorganized and renamed from the China Food and Drug Administration (formerly the State Food and Drug Administration or SFDA), is the central government agency in charge of drug and medical device administration with functions similar to those of the FDA in the United States. All medical devices must be registered with the NMPA before they are exported to, or sold in, China. The NMPA process requires in-country testing of medical devices for the Chinese market. Additionally, certain measuring devices require a separate metrological approval.

The General Administration of Quality Supervision, Inspection, and Quarantine (AQSIQ) is tasked with oversight, inspection, and quarantine as well as with establishing the technical standards for imported and exported goods. AQSIQ maintains responsibility for certifying electrical safety for a wide variety of products with the so-called China Compulsory Certificate (CCC). The CCC safety license process requires manufacturers to obtain the CCC mark before exporting or selling products listed in the CCC catalog into the Chinese market. The CCC mark is administered by the Certification and Accreditation Administration (CNCA). The China Quality Certification Centre (CQC) is designated by the CNCA to process CCC mark applications. Electrical medical devices require CCC certification prior to SFDA registration.

Role of Standards in Medical Device Regulation

In almost all jurisdictions, standards are used for the detailed requirements used to regulate medical devices, and regulations are used to set the high-level principles. The exception is China, where the standards are written into the law and become part of the regulation.

The U.S. FDA reviews standards and, when found appropriate, recognizes them as suitable by publishing them in the Federal Register (FR). Manufacturers may then use those standards to simplify regulatory submissions. The EU harmonizes standards that they find acceptable by publishing them in the Official Journal (OJ). A Harmonized Standard has a special status. Medical devices that comply with the relevant Harmonized Standards are presumed to demonstrate compliance with the relevant essential or GSPRs, and this presumption cannot be easily challenged.

Early Efforts in the United States

The passage of the Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938 was hastened by a tragedy the previous year in which nearly a hundred people died after ingesting “Elixir Sulfanilamide.” This act included new provisions to:

Extend control to cosmetics and therapeutic medical devices.
Start a new system of drug regulation that requires new drugs to be shown to be safe.
Loosen misbranding requirements by eliminating the need to prove intent to defraud.
Ensure that safe limits be created for unavoidable poisonous substances.
Authorize food standards created for identity, quality, and container filling.
Authorize medical device factory inspections.
Add the remedy of court injunctions against violative manufacturers.

Increasing public concern over the safety and effectiveness of medical devices in the late 1960s and early 1970s led to the formation of a study group within the Department of Health, Education, and Welfare, the predecessor of the present Department of Health and Human Services (DHHS). This study group, chaired by Dr. Theodore Cooper of the National Heart, Lung, and Blood Institute, estimated, as did other studies at the time, that over the previous decade more than 10,000 injuries and hundreds of deaths were linked to medical devices that were still on the market.

Recommendations from this study group formed the basis of the Medical Device Amendments of 1976. The members of the group felt that performance standards would be more effective than a PMA in ensuring the safety and effectiveness of most new medical devices. Since 1976, the FDA and medical device regulation have evolved. A timeline showing significant events since 1976 is displayed in Fig. 27.1 .

Fig. 27.1, Timeline of Food and Drug Administration–related medical device legislation since 1976.

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