The views and conclusions expressed in this work are those of the author and do not necessarily represent those of or imply endorsement from the Food and Drug Administration.
This discussion focuses on the legal and regulatory framework that governs medical device development together with the quality system framework designed to ensure their optimal performance.
Introduction
The demand for safer and more effective medical products – pharmaceuticals and medical devices – has resulted in the development of a legal framework designed to protect public health through the enforcement of several laws. In the United States (US) this role is performed by the Food and Drug Administration (FDA), a federal agency which is part of the United States Department of Health and Human Services (HHS). The role of the FDA is to enforce its legal obligations with a number of rules set forth in the Code of Federal Regulations (CFR). In addition, the FDA has adopted a number of international standards that govern the manufacturing and testing of medical products within the US to ensure maximum quality of products entering the market.
It is important to make a distinction between the terms law, regulation, and standards.
Law: A system of from rules adopted by a legislative body that are enforced through social institutions (the executive and courts) to govern behavior (Robertson, 2006)
Regulation: Regulatory rules (regulations) are adopted by a government agency based on a specific law or set of laws giving that agency authority to regulate certain behaviors. These rules and regulations are usually published in preliminary form for public comment prior to final adoption. They permit and implement intervention (regulation) in the private domain and govern much of the day-to-day regulation for medical products (Orbach, 2012).
Standards: A documented set of guidelines established through expert consensus by a nationally or internationally recognized organization. These guidelines suggest actions for a given operation or activity in order to achieve the optimum results in a given context (NATO).
The FDA, therefore, writes and enforces regulations based on specific laws adopted by Congress and develops standards to ensure manufacturers of medical products are legally bound to offer products that are safe and effective. The adoption of international standards by the FDA ensures the regulation of medical products is aligned with manufacturing practices of the industry worldwide.
Laws Enforced by the FDA
The Food and Drug Administration (FDA), is “responsible for protecting the public health by ensuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices … food supply, cosmetics and products that emit radiation” (FDA).
The origins of the FDA can be traced back to the Food and Drug Cosmetic Act of 1906, launched to control any possible contamination in foods, and to control the labelling and composition of medicines. In 1938, more than 100 patients died due to the presence of ethylene glycol in a sulfonamide product. The sulfonamide elixir tragedy led to the creation of the Federal Food, Drug and Cosmetic Act to improve safety of foods, drugs, and cosmetics. With the tragedy of thalidomide in Europe, the Kefauver–Harris Amendment Act of 1962 was introduced to strengthen the power of the FDA to monitor drug safety in the United States (Annas & Elias, 1999).
In 1976, the Medical Device Amendment Act was created, becoming the first medical device regulation in the United States. In 1990, the Safe Medical Device Act amended the Federal Food, Drug and Cosmetic Act by requiring safety studies and reporting from public institutions of any adverse event that could be related to a particular medical device. In addition, device manufacturers were required to perform safety monitoring of implantable medical devices in the form of post-marketing studies, including reports and tracking of the patients using their products.
In 1997, the Food and Drug Administration Act was approved with the purpose of protecting public health by ensuring the safety of foods and the effectiveness and safety of drugs and medical devices, including radiation-emitting products.
In 2002, the Medical Device User Fee and Modernization Act was created, giving the FDA the authority to collect user fees from medical device sponsors to finance review activities previously agreed to by industry and the agency. In the same year, the Office of Combination Products was created to oversee the regulation of products containing more than one regulated component such as drug/device, biologic/device, or biologic/drug.
The Food and Drug Administration Amendments Act of 2007 reauthorized and expanded the Prescription Drug User Fee Act (PDUFA) and the Medical Device User Fee and Modernization Act (MDUFMA). This was a significant addition to FDA authority and gave the FDA additional resources to conduct complex and comprehensive reviews of new drugs and devices.
The Code of Federal Regulations
The FDA is empowered to enforce compliance with regulations set forth in the Code of Federal Regulations (CFR). The CFR is the “codification of the general and permanent rules and regulations published in the federal register by the executive departments and agencies of the federal government of the United States.” The CFR Title 21 contains several sections reserved to the functions performed by the FDA. For example, section 820 refers to quality assurance regulation, section 814 refers to premarket approval of medical devices, section 860 refers to medical device classification procedures, and section 892 refers to radiology devices.
Regulation of Medical Devices in the US
Food and Drug Administration Organization
The Food and Drug Administration (FDA) is divided in six product centers, one research center, and two offices:
Center for Biologics and Evaluation Research (CBER). The CBER regulates of a wide variety of products – gene therapy, blood and blood components, vaccines, tissues, and tissue-engineering materials. Some of the FDA regulatory actions involve manufacturing establishment inspections, licensing and safety evaluations of blood supplies (blood and blood components), and post-marketing activities, including the post-marketing surveillance of biological products where many adverse events related to the products are first detected.
Center for Drug and Evaluation Research (CDER). The CDER evaluates every drug intended to be marketed.
Center for Food Safety and Applied Nutrition (CFSAN). The CFSAN regulates the labeling and safety of food and cosmetics.
Center for Tobacco Products (CTP). The CTP evaluates tobacco products and inspects manufacturers of tobacco products.
Center for Veterinary Medicine (CVM). The CVM is responsible for assessing the safety and effectiveness of animal food, drugs, and devices.
Center for Devices and Radiological Health (CDRH). The CDRH is the center responsible for regulating manufacturing and performance standards for medical devices and radiation emitting products. It performs medical device premarket evaluation and approval and tracks reports of medical device and radiation-emitting products malfunctioning and any serious adverse reactions from these products.
Radiation-emitting products are defined by the FDA as those products that emit energy (radiation) through one of several mechanisms: ionizing radiation, acoustic radiation, radiofrequency/microwave/magnetic radiation, and optical (visible, ultraviolet [UV], infrared [IR]) radiation.
Examples of radiation-emitting products regulated by the CDRH include:
(a) Ionizing radiation – general radiography, dental radiography, computed tomography (CT), mammography, medical accelerator.
(b) Optical radiation – slit lamp, Psoralen Ultraviolet A therapy (PUVA), fluorescence spectroscopy.
(c) Magnetic microwave/radiofrequencies (RF)/ultraviolet light radiation – magnetic resonance imaging (MRI), electrocautery, prostate therapy, blood warmers.
National Center for Toxicological Research (NCTR). The NCTR plays a critical role in assessing the safety of new technologies, such as materials developed using nanotechnology. These materials include titanium oxide and zinc oxide nanoparticles, compounds commonly used in sunscreens and other products.
Office of Regulatory Affairs (ORA). ORA is the FDA Office responsible for FDA inspections of health and veterinary manufacturer facilities, inspections of health and veterinary manufactured products, and regulatory control of health and veterinary imported products.
Office of the Commissioner: This office takes responsibility for effectively conducting the FDA’s mission. Within this office, the Office of Combination Products (OCP), created in 2002, addresses the regulatory gap of the increasing number of products made by more than one technology, such as drug-eluting stents, drug-delivery polymer scaffolds, and antibiotic bone cements. The OCP has a jurisdictional and classification authority that allows it to determine which center will be responsible for performing a premarket review of a combination product. This is accomplished by defining the primary mode of action of the product that will contribute to the desired therapeutic effect. For instance, in a drug-delivery device, where the drug is the main determinant in the mode of action, the CDER will have primary jurisdiction over the product review, whereas if the device itself determines the primary mode of action, the CDRH will be the final reviewer.
Regulatory Pathways for Medical Devices
According to the FDA, a medical device can be defined as “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”
The FDA regulates medical devices according to the risk they represent to the patient. Class I devices are considered the lowest risk. Examples of class I devices include medical gloves and some stethoscopes. Class III devices are considered the highest risk and are subjected to very stringent regulations (Rome et al., 2014). Examples of Class III devices include pacemakers and defibrillators. Class II devices are of intermediate risk. Examples of class II devices include urological catheters (Jarow & Baxley, 2015; Schuh, 2008; van Eck et al., 2009).
In order to enter the market, a medical device has to go through a very stringent process of evaluation by the CDRH. These regulatory pathways vary in complexity according to device category. For example, class I medical devices are usually exempted from preclinical and clinical testing, although most devices have to comply with good manufacturing practices (GMP) to obtain clearance for commercialization. Class III devices, on the other hand, require clinical data in order to obtain FDA approval for commercialization (Kaplan et al., 2004; Sweet et al., 2011).
FDA regulation of in vitro medical devices involves the Clinical Laboratory Improvement Amendments (CLIA). Before a laboratory can accept a human sample for analysis, it has to be CLIA-certified. This involves the regulation of laboratory devices under three different agencies, namely the Centers for Disease Control and Prevention (CDC), FDA, and Centers for Medicare & Medicaid Services (CMS). The FDA performs the following activities related to CLIA:
Categorizes device complexity and develops guidance on device complexity and categorization.
Reviews request for waivers (Burd, 2010).
Premarket Submission
Medical devices that have gone through clinical trials or medical devices that do not require clinical trials because they can demonstrate equivalence with existing products in the market can submit a premarket submission to FDA to request approval for commercialization.
There are two main routes for medical premarket submission:
510k: 510k premarket submission refers to the demonstration of substantial equivalence (SE) between a new device and a legally marketed device (also known as predicate device), defined in Title 21 of the CFR 807.92 in terms of efficacy and safety. SE is based on similar intended use and technological features between the new device and the predicate device.
Alternatively, a new device could differ from the predicate device if it demonstrates that it is as effective and safe as the later. The 501k route usually does not require clinical trials (Schuh, 2008; Wizemann, 2011).
Premarket notification (PMA): Premarket notification refers to the medical device pathway for commercialization of innovative but high-risk devices, such as pacemakers. This pathway requires, in addition to non-clinical data (microbiological, toxicological, engineering, and animal studies), clinical data to establish that the device is safe and effective (Schuh, 2008).
Investigational device exemption (IDE) refers to medical devices that will be tested for the first time in human subjects. These devices are not intended for commercial purposes; instead, they are used for collecting safety and effectiveness information that will serve to support a premarket approval to obtain FDA clearance for commercialization.
IDE is usually required for class III devices (high-risk) (Holbein & Berglund, 2012; Saviola, 2005; Schuh, 2008). For an IDE, the sponsor must present an IDE plan that requires much of the information usually required for clinical trials, including informed consent from the patient, an investigation plan, study monitoring, records, and reports.
De-novo Devices
New devices that do not possess equivalence with existing marketed devices tend to be automatically classified as class III devices and subjected to premarket approval. A de-novo request by the sponsor provides an alternative pathway for manufacturers of devices that are novel (which do not have a substantial equivalence with a predicate device) to be classified into class I or class II, if appropriate, thus avoiding the stringent premarket submission process for a class III device (Felten et al., 2005; Schuh, 2008).
Post-marketing Regulation
While the FDA has developed a very stringent process for the evaluation and approval of medical devices prior to their entering the market, their long-term safety and effectiveness is often unknown. Most medical devices have been tested in clinical trials for a limited number of patients or have not been tested at all.
This limitation is based on the economical and logistical impossibility of testing every medical device on the entire population. It is also based on the real need for medical devices to be available to patients in a timely fashion. Unfortunately, these factors can increase the risk to patients of unexpected adverse effects originating from approved devices thought to be safe and effective.
In order to address this challenge, the FDA performs post-marketing surveillance of medical devices. Surveillance of medical devices can be either passive or active. Passive surveillance involves medical device reporting (MDR). MDR is a requirement for medical devices manufacturers, while it is voluntary for physicians and patients. On the other hand, an active surveillance system known as Medical Device Postmarket Surveillance (MDS) serves to monitor the safety and effectiveness of medical devices that are already in the market. MDS uses a number of programmed activities, including post-approval studies and post-marketing studies. An additional surveillance system comprises the Medical Product Safety Network (MedSun), which operates in collaboration with the FDA to report medical device safety issues. MedSun involves 280 hospitals and other facilities across the country and is focused on specific devices, such as cardiovascular apparatus, which tend to involve higher patient risk.
Humanitarian Use Device
Rare diseases are defined by the FDA as diseases affecting fewer than 4000 patients in the United States each year. To encourage companies to develop devices to treat rare diseases (having what is known as orphan indications), the FDA created the humanitarian device exemption pathway. To market a device as HUD/HDE two conditions must be met:
1. Designation of the device as an humanitarian use device (HUD).
2. Approval of a humanitarian device exemption (HDE).
A device can be considered as a HUD if (a) the disease for which the device is indicated is rare (4000 or less cases per year in the US), and (b) there is a complete lack of a comparable device on the market that addresses the unmet needs of the disease. HUD/HDE allows manufacturers to commercialize the device in a limited number of patients and achieve a certain profit without having to demonstrate device effectiveness (Kaplan et al., 2005; WHO, 2003).
Summary Box 1: Medical Device Classification Categories and Main Regulatory Pathways (Mehta, 2008)
CLASS I: Low-risk devices such as surgical gloves. Some class I devices are FDA-waived from review.
CLASS II: Medium-risk devices such as simple urinary catheters. Many class II devices follow the 510k pathway and do not require clinical testing.
CLASS III: High-risk devices such as pacemakers and defibrillators. Due to their inherent risk, these types of devices must follow the PMA pathway in order to obtain FDA clearance for commercialization. Most class III devices require clinical testing.
510k (premarket notification): this pathway applies for medical devices that are demonstrated to be substantially equivalent (same technological features, same intended use) to existing products in the market. The manufacturer must provide proof of equivalence to a legally marketed device in order to obtain clearance for commercialization.
PMA (premarket approval): this pathway applies to high-risk medical devices that have not been demonstrated to be equivalent to existing products on the market. Most PMAs require clinical data to support their application to obtain FDA clearance for commercialization.
IDE (investigational device exemption): novel devices that are being tested for the first time in human subjects must obtain IDE approval prior to commercialization. IDE does not provide clearance for commercialization but for investigational use only in order to obtain safety and effectiveness data to support a later PMA application.
De-novo: a de-novo request allows a medical device manufacturer to obtain reclassification of a novel device that is not equivalent to prior legally marketed devices, into class I or class II, if applicable, instead of it otherwise being automatically designated as a class III device.
CLIA: In-vitro devices used in clinical laboratories require CLIA certification prior to receiving human samples for laboratory diagnostics.
Medical Devices: Quality Assurance Considerations
Quality Systems (QMS) for Medical Devices
Medical device advances have been possible because of modern technology, but modern medical devices are also only possible with the concomitant development of standards to ensure their safety and effectiveness. These standards are being developed by well recognized international organizations, such as the International Organization for Standardization (ISO), ASTM International (formerly known as the American Standard for Testing Materials), and the Institute of Electrical and Electronic Engineering (IEEE).
Standards derived by ISO, ASTM, IEEE, and many other recognized national or international organizations can also be adopted or modified by the FDA. The CDRH Standards Program/Standard Management Staff (SMS) at the FDA was established as a result of the Food and Drug Administration Modernization Act of 1997. It has developed a Recognized Consensus Standards database with national and international standards. One of these standards, ISO 13485:2003, “specifies requirements for a quality management system where an organization needs to demonstrate its ability to provide medical devices and related services that consistently meet customer requirements and regulatory requirements applicable to medical devices and related services.” This standard establishes a number of interrelated processes related to manufacturing requirements for a specific medical device.
These requirements involve:
(a) Quality Management Systems (QMS) in general (e.g., control of documents and records).
(b) Management of QMS (quality planning).
(c) Resource management (e.g., quality policies, human resources).
(d) Product realization – including those processes associated with determining product requirements, design and development of the product, materials and services need to supply finished product to the customer, actual manufacturing of the product with monitoring and measurement equipment used in the manufacturing process.
Based on the ISO 13485 standard, the FDA created the Quality System (QS) Regulation/Medical Device Good Manufacturing Practices system (QSReg) for medical devices, which is now a requirement for medical device manufacturers in order to obtain FDA approval for product commercialization. QSReg involves a number of requirements, including:
Design controls
Document controls
Purchasing controls
Identification and traceability controls
Production and processes controls
Labeling and packaging controls
Handling, storage, distribution, and installation controls.
Design Controls
Design controls allow visibility during the device design process ensuring that translation into device production will ensure proper device performance. Design controls do not apply to feasibility studies and development of prototypes but to the final design ready for translation into production. This ensures that the FDA will not interfere with the creativity process while taking all the necessary precautions to avoid design errors which will be transferred into the production stage.
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