Medical Device Approval Process PDF

PROPRIETARY. DO NOT SHARE. Transcript: The Regulatory Process for Medical Device Approval Section 1: Medical Device Overview Welcome Welcome to the Medical Device Overview & Regulation course. This course will be broken into two sections. The first section will give an overview of medical devices a...

PROPRIETARY. DO NOT SHARE. Transcript: The Regulatory Process for Medical Device Approval Section 1: Medical Device Overview Welcome Welcome to the Medical Device Overview & Regulation course. This course will be broken into two sections. The first section will give an overview of medical devices and discuss the many types of medical devices. The second section will discuss medical device regulation and the major pathways to medical device approval. Section 1: Medical Device Overview Objectives At the end of this section, you should be able to: ● Define a medical device. ● Appreciate the diversity of medical devices. ● Identify the major sectors and top companies in the medical device industry. Medical Devices: Defined The FDA defines a medical device as “An instrument, apparatus, implement, machine, contrivance, or implant, intended for use in the cure, mitigation, treatment, or prevention of disease or is intended to affect the structure or function of the body. Not a drug - no chemical action, not metabolized”. Examples of medical devices include prosthetics, which have evolved from simple wooden appendages to highly complex robotic instruments. Pumps, such as IV pumps are used to administer fluids to patients in the hospital, or the insulin pump which administers insulin to a diabetic patient at the push of a button. Pacemakers, regulate a patient’s heart rhythm via electrical impulses. Imaging systems like a CT scanner, X-ray machine, or MRI. And diagnostics such as a blood pressure monitor or pregnancy test. Many medical devices, such as an x-ray machine, create a diagnostic; the actual x-ray that the radiologist evaluates. Even eyeglasses and contacts are regulated as medical devices. In addition to correcting vision, eyeglasses are tested to ensure the corrective lens cannot shatter, thereby causing damage to the eye. Contact lenses are tested for biocompatibility to verify they won’t cause an adverse reaction to the wearer’s eye tissue such as inflammation or irritation. 1 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Medical Device Diversity There is significant diversity within the medical device category. Click each class button to learn more, when you are finished, click Next to continue. Class I Device A Band-Aid is considered a medical device as is a permanently implanted replacement hip. The risk to the patient of a band-aid not working correctly is quite different than if a replacement hip is faulty. In order to appropriately regulate the different risks posed by different medical devices, the FDA has developed a class-based system of regulation. Each medical device is assigned to a class based on the risk to the patient if the device malfunctions as well as how easily can the malfunction be detected. Class 1 medical devices require the lowest level of regulatory oversight. These include many over-the-counter products such as band-aids, slings and splints, and pregnancy tests as well as common hospital devices like stethoscopes and hand-held surgical instruments. The pregnancy test is an interesting example of a medical device that changed classification. Originally a class 2 medical device that had to be administered by a clinician, as the pregnancy test became more widespread and through use proved its robustness and accuracy, the FDA reclassified it as a class 1 device and allowed its sale directly to the public. Class II Device Class 2 medical devices carry a greater risk to the patient and have correspondingly higher regulatory oversight. Class 2 medical devices include instruments like physiological monitors such as an in-hospital heart rate monitor, blood analyzers that test for blood components such as red and white blood cells as well as molecules dissolved in the blood like salts and lipids, X-ray systems, and other imaging systems. Blood glucose monitors are used by diabetic patients to determine their blood sugar levels. IV pumps and surgical drapes help to maintain a sterile surgical environment. Surgical drapes and surgical instruments provide an interesting comparison between class 1 and class 2 designations. For both drapes as well as surgical instruments it is important that the device both work properly and be sterile to avoid infecting the patient with a microorganism. A defect in a surgical instrument is likely to be easily detected, and the sterilization of these reusable instruments is the 2 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. responsibility of the hospital which will clean and sterilize each instrument prior to use. In contrast, disposable surgical drapes are sterilized by the manufacturer and must maintain that sterility through shipping and storage. A breach in sterility can be very difficult to detect. Because of the greater risk of sterility breach and the difficulty in detecting it, a disposable drape can introduce greater risk to the patient and therefore is regulated as a class 2 medical device. Another interesting comparison is a pregnancy test and a blood glucose test. Each of these is available over the counter and is used directly by the patient. Looking from a safety perspective, the FDA essentially asks, what is the risk to the patient of an inaccurate test? An incorrect pregnancy test is not likely to result in an immediate risk to the patient's health. On the other hand, an inaccurate blood glucose measurement could result in a patient administering too much or too little insulin which could lead to hypoglycemic shock or even coma. Class III Device Class 3 medical devices have the highest level of regulatory oversight. These include permanently implanted or long-term contact devices such as heart valves, artery stents, and joint replacements as well as companion diagnostics. Similar to the pregnancy test or blood glucose monitor, a companion diagnostic typically tests for the presence of a molecule in the blood, urine, or biopsy tissue of a patient. The presence or absence of the molecule will determine whether the patient receives a certain medication. Companion diagnostics are becoming increasingly common in oncology. And the risk to the patient of receiving an incorrect diagnosis and therefore the incorrect treatment could indeed result in the patient's death. Therefore, unlike pregnancy tests or blood glucose analyses, companion diagnostics are generally regulated as class 3 medical devices. Industry Sectors In addition to designating each medical device into a regulatory class, the FDA also organizes devices into categories. There are currently 18 medical device categories comprising over 1700 distinct medical devices. The device categorization is important because the FDA has technical experts for the different categories who will review the device application. The 18 categories are: Anesthesiology, devices used both in local as well as general anesthesia. Cardiovascular devices such as EKG monitors and angioplasty balloons. Chemistry, products used in the chemical analysis of samples. Dental devices from cavity-filling amalgams to orthodontics and cosmetic implants. Devices used in the diagnosis and treatment of ailments to the ear, nose, and throat as well as the gastrointestinal and urological tract. Surgical instruments, drapes, and implants are 3 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. used in both general as well as plastic surgeries. General hospital equipment such as autoclave instruments are utilized to steam sterilize reusable implements. Hematology products such as blood collection tubes, sterile needles, and blood analyzers. Products and devices that test or regulate the immune system. Microbiology products such as those used to detect and identify microorganisms. Imaging and surgical devices are used specifically in neurology. Obstetric and gynecological devices. Ophthalmic products such as corrective lenses, Lasik correction instruments, and even eye charts. Orthopedic devices from joint braces and splints to prosthetics and implantable joint replacement. Pathology products such as microscopes and protein analyzers are used in the analysis of patient samples. Physical medicine comprises devices used in physical therapy or the physical rehabilitation of patients. Radiology or imaging devices such as x-ray machines and PET scanners, and finally toxicology which includes devices used in the detection of toxins in a patient’s system. Section 1: Medical Device Overview Summary We began this section with a definition of a medical device. ● The FDA defines a medical device as an instrument, apparatus, implement, machine, contrivance, or implant intended for use in the cure, mitigation, treatment, or prevention of disease. ● The category of medical device includes a wide range of products from bandaids and tongue depressors to companion diagnostics and artificial hearts which are manufactured by a large number of different medical device companies. 4 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Section 2: Regulation Section 2: Regulation Objectives At the end of this section, you should be able to: ● Understand the history of medical device regulation. ● Identify the major medical device approval pathways. Brief History of Device Regulation Today, medical device regulation is tightly controlled and well-managed but that has not always been the case. Let’s look at a brief history of medical product regulation in the United States. Federal regulation first began in 1906 with the Pure Food & Drug Act, a sister law to the Federal Meat Inspection Act that was signed on the same day by President Theodore Roosevelt. The law, which governed interstate commerce of food and drugs, was essentially a truth-in-labeling law intended to raise standards and protect the US public from adulterated and misbranded products. Enforcement of the law was assigned to the US Department of Agriculture which established a team of food and drug inspectors. While an improvement over no federal regulation, the act had several deficiencies and was replaced in 1938 by the Federal Food, Drug, and Cosmetics Act which remains the statutory basis for federal regulation of these products today. This set of laws gave authority to the US Food & Drug Administration or FDA to oversee the safety of food, drug, and cosmetic products. The congressional impetus to pass the law was influenced in large part by the deaths of over 100 patients using adulterated sulfanilamide medication. The Food Drug & Cosmetic Act or FD&C has been amended numerous times during the following 80 years to stay current with evolving technologies. The specific, class-based regulation system for medical devices was not implemented until 1976 as part of the medical device amendments of that year. This amendment to the FD&C Act introduced the regulation of medical devices as class 1, 2, or 3 devices. The classification of each device is determined by experts on a classification panel who evaluate the risk of the device to the patient. In 1990 the Safe Medical Devices Act or Amendment introduced more conservative clinical trial requirements as well as ongoing surveillance of medical devices to be able to detect and respond to adverse events caused by the use of medical devices. The FD&C Act continues to be amended to respond to evolving technology and there have been a total of 6 amendments to the act since 1990. For example, the 1997 modernization act 5 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. introduced a number of changes including a refocus of the FDA’s post-market surveillance on higher-risk devices. FDA Device Organizational Structure The Food and Drug Administration or FDA is organized within the Department of Health and Human Services. Within the FDA, medical devices are specifically regulated by the Center for Devices and Radiological Health or CDRH. The head of each of these departments is a political appointment. The FD&C act specifically charges the FDA with promoting and protecting public health. With regard to medical devices, the legislation entrusts the FDA to regulate the safety and efficacy of medical devices and to ensure that new devices are available to the public in a timely manner. Device Classification As we’ve mentioned, medical devices are regulated in a class-based system. Click on each of the classes to learn more about the characteristics of each. Class 1 devices have low risk to the patient and are the most prevalent, making up roughly 55% of all medical devices. Class 1 Class 1 medical devices are subject to general controls, requiring, for example, registration of the device with the FDA. Class 2 Class 2 medical devices are considered of medium risk to the patient and makeup roughly 40% of medical devices. Class 2 devices are subject to the same general controls of class 1 devices as well as special controls. These devices require premarket notification to the FDA prior to product launch. Class 3 The highest-risk devices are classified as class 3 medical devices. These are much less common, making up only 5% of all medical devices. Class 3 medical devices are subject to the same general and special controls as class 1 and 2 medical devices but must also go through premarket 6 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. notification or premarket approval. Essentially, clinical trials are designed to prove the safety as well as the efficacy of the device. FDA Controls: Class-Based Regulations Let’s take a closer look at the regulations and controls for each class of medical device. Click on the class boxes to learn about the regulations for that class. Once you have clicked each class you can click the next button to continue with the course. Class I: General Controls Class 1 medical devices, such as tongue depressors and ear swabs, are subject to general controls. This includes registration of the facility in which the device will be manufactured. Today, facility registration can be completed online. The company must also notify the FDA of its intent to manufacture and sell the device, this is accomplished by listing the device with the FDA. Class 1 devices must also follow FDA labeling regulations regarding the content and use of the device. Most class 1 devices are exempt from specific approval by the FDA. This means that in order to begin selling a class 1 medical device in the United States, a company simply needs to register the manufacturing facility, list the device, and follow the published labeling requirements. Class II: General & Special Controls, Pre-Market Notification Class 2 medical devices must follow not only general controls but also special controls and premarket notifications. Special controls, for example, could include a comparison to a gold standard. As an example, a new blood glucose monitoring device would be tested prior to product launch to prove that it measures blood glucose as well if not better than a previously qualified glucose detector. Development, manufacture, and sale of class 2 and 3 devices must be accomplished under quality system regulations and an internationally recognized set of guidance. Pre-market notification of class 2 devices is generally accomplished through the 510(k) procedure. This is a regulatory guidance that uses a predicate-based system in which new medical devices are cleared by the FDA for the market if they can be shown to be substantially equivalent to a previously approved or marketed device. 7 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Class III: General & Special Controls, Pre-Market Approval Class 3 medical devices are subject to all the general and special controls of class 1 and 2 devices and must also go through premarket approval. Premarket approval, commonly referred to as PMA, requires extensive clinical trials of the device to prove both the safety as well as the efficacy of the device. In addition to clinical trials and special controls, an FDA inspection of the manufacturing facility is required prior to the device being marketed and if the manufacturer wishes to change any of the manufacturing process, the FDA must approve the change. Let’s explore some of the regulation differences between the different medical device classes. For example, facility inspection. Facility inspection is not required for class 1 medical devices, and it is unlikely these facilities will be inspected unless an adverse event is reported. Class 2 device facilities are subject to inspection, but inspection is not required prior to device marketing. It is likely that a facility will be inspected within a few years of the product launch. In contrast, facility inspection prior to product launch is required for class 3 medical devices. Another example is the regulation of the implementation of manufacturing changes. If the change to manufacturing of a class 2 medical device does not affect safety or efficacy, the change can be implemented with a simple notification to the FDA. In contrast, any change to the manufacturing process of a class 3 device, whether minor or significant, requires approval by the FDA prior to implementation of the change. FDA Approval Pathways: 510(k) The 510(k)-approval process for class 2 medical devices is described in the CFR or code of federal regulations. Class 2 devices require premarket notification or PMN, this is approval of the product by the FDA prior to sale of the product. A company seeking to sell a medical device must file the premarket notification with the FDA at least 90 days prior to launch. The premarket notification specifies the predicate device to which the new product is compared. The FDA then has 90 days to respond to the company either agreeing that the predicate device is substantially equivalent, and the company can begin marketing the product, or the FDA can disagree or respond with questions that the company has to answer. The FDA has 90 days to respond to each round of review which can lead to long approval timelines for devices that do not have equivalent predicate devices. 8 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. The length of time for ultimate approval can vary significantly. For example, a new IV tubing set has substantial equivalence to many previously marketed tubing sets and FDA response is likely to be quick. On the other hand, a smartphone app that monitors heart rate has significant technological differences in comparison to existing heart rate monitors and may encounter several rounds of questions from FDA examiners. The cost to the company for 510(k) approval is relatively small, costing thousands of dollars in government fees. Predicate Device A new draft guidance was released in 2011 by CDRH and CBER, the Center for Biologic Evaluation and Regulation. This draft guidance includes more specific requirements for predicate devices. Importantly, 510(k) premarket notification requires that the company seeking to sell a device must prove that their new device is substantially equivalent to a predicate device. A predicate device is a medical device that is currently marketed in the United States. The basic idea is that if a company’s new device is substantially equivalent to a legally marketed device, the safety and efficacy have already been established and the new device can be released to the market without further evaluation. Substantial equivalence means that the new device has the same intended use as the predicate device and uses the same technology. If new technology is introduced, the agency is likely to raise questions about the equivalence of the devices. This is a challenging hurdle because the industry has seen so many technical advances in the past several decades, such as the introduction of microprocessors, and therefore most new devices are much more technologically advanced than existing products. The draft guidance also introduces the concept of a reference device. Similar to a predicate device, a reference device can be used as a comparison to evaluate performance characteristics. For example, using a lab-scale blood analyzer as a reference device for an in-home, handheld diagnostic device. The blood analyzer isn't a predicate device because the intended use is different, being used in a clinical lab rather than in-home setting, but its accuracy and precision have been established, making it a gold standard for the measurement of blood samples and therefore an appropriate reference for the new device to be tested against. FDA Approval Pathways: De Novo 510(k) If a substantially equivalent device cannot be found, another route to approval that avoids the lengthy PMA requirements of full-scale clinical trials is the de novo 510(k) pathway. This approval 9 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. pathway was introduced in 1997 as part of the modernization act. Until just recently, the de novo route required the rejection of a traditional 510(k) submission prior to petitioning for the de novo pathway. This increased the review time appreciably as the initial rejection can take up to 60 days, followed by a 30-day petition and subsequent 60-day review. Fortunately, companies can now submit to the de novo 510(k) pathway directly, and it is the preferred pathway if the device does not have a substantially equivalent predicate device. In order to be considered for the de novo pathway, the device must be novel and considered to be low risk to the patient. Following submission of the de novo petition, the agency has 60 days to respond to the company’s petition. This process does incur additional regulatory fees in comparison to the traditional 510(k) route but is less expensive than a PMA. Another advantage of the de novo pathway is that it avoids full-scale clinical trials required of class 3 devices that undergo PMA. In the de novo 510(k) process, clinical trials are still required, but in contrast to PMA, only safety must be proven rather than safety and efficacy. Typically, the clinical trial will show equivalency to an existing device or reference standard but does not require the company to track actual patient outcomes in terms of efficacy. Avoiding the class 3 PMA route also means less stringent manufacturing requirements for the device. Class III Approval Pathway Is Pre-Market Approval (PMA) The approval pathway for class 3 medical devices is PMA or premarket approval. Class 3 devices carry the highest risk to patient health and typically are novel, meaning they have no substantially equivalent predicate device. The PMA pathway involves extensive clinical trials which require the applicant to prove both that the device is safe and that it is efficacious. Actual patient outcomes must be tracked to prove efficacy. The clinical trial process for a PMA may take anywhere from six months to several years. Unlike pharmaceutical drugs or biologics which require multiple phases of clinical trials, showing first safety and then efficacy, medical devices can run a single clinical trial to show both safety and efficacy, concurrently. The regulatory fees for a PMA submission are higher than for 510(k) or de novo 510(k), costing tens to hundreds of thousands of dollars. Regulatory Compliance Medical device manufacture and testing are subject to strict regulation. In the United States, regulatory statutes for pharmaceuticals, biologics as well as medical devices are described in the 10 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. CFR or Code of Federal Regulations. These are often described as the GXPs which include good laboratory practices, good clinical practices, and good manufacturing practices. The FDA enforces the GXPs through inspections and audits. Non-compliance with regulatory requirements can result in warning letters, recalls, fines, facility shutdowns, and even criminal prosecution of individuals. An important part of the GXPs is documentation. A common saying in a GXP setting is “If you didn’t write it down… you didn’t do it”. Over the next few screens, we will discuss some specific GXPs. Good Laboratory Practices Good laboratory practices, or GLP, were first mandated in the United States in 1978. GLP is an internationally recognized system, having first been introduced in New Zealand and Denmark in 1972, prior to adoption by the US FDA. GLPs apply to all nonclinical studies, meaning animal studies, which will be used to support a regulatory application such as a 510(k) or PMA. These practices were instituted to ensure that supporting animal studies were appropriately performed and documented to ensure high-quality data. The GLPs ensure strict control of the laboratory management, requiring SOPs, or standard operating procedures, for laboratory maintenance, operations, and training. The laboratory environment is also tightly controlled requiring SOPs for cleaning as well as testing of the facility to verify cleanliness and sterility. And, of course, the actual animal studies are planned, executed, and documented following GLP requirements. The primary purpose of the GLPs is to assure regulatory authorities that preclinical data provided in regulatory submissions are not fraudulent. The practices, for example, witness signatures and quality personnel oversight of testing and documentation, provide this assurance and thereby allow regulatory authorities to rely on the data for risk and safety assessments. Good Clinical Practices Good clinical practices, or GCPs, are international quality standards describing the planning, execution, and documentation of human clinical trials. The GCPs are written by the ICH or International Conference on Harmonization, an international body that defines standards of medical testing. The two main objectives of good clinical practices are to ensure the rights, wellbeing, and confidentiality of clinical trial volunteers and to ensure that the data generated by human clinical trials are credible and can be relied on for the evaluation of novel medicines and medical devices. As part of the code of federal regulations or CFR, the FDA is finalizing guidance similar to the ICH GLPs. 21 CFR part 50 describes regulations assuring the protection of human 11 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. subjects. For example, all human subjects must provide informed consent - understanding the purpose, procedures, and risks of the clinical trial and participating in the trial voluntarily. All volunteers have the right to discontinue the trial at any time. 21 CFR part 54 mandates financial disclosures by clinical investigators, making public any potential financial conflict of interest the investigator may have such as stock in the company conducting the trial. 21 CFR part 56 describes the role of institutional review boards or IRBs. The IRB is an independent panel of experts who must approve, monitor, and review research conducted on human subjects. The primary objective of the IRB is to protect human subjects from physical or psychological harm. Current Good Manufacturing Practices The manufacture and testing of pharmaceuticals, biologics, and medical devices are governed by the GMPs, or good manufacturing practices. The GMPs are often written as cGMP, the c standing for current, a reminder that regulations may change at any time. Similar to GLP and GCP, cGMP is an internationally recognized regulatory system. Current good manufacturing practice guidelines are designed to ensure the final product meets the high-quality standards required of medical products. cGMP practices govern product formulation, manufacture, packaging, labeling, testing, and even distribution and sale of products. For example, all parts are procured from a validated vendor and their procurement can be traced to the PO used to order them. All testing procedures have been independently validated to prove that the test detects product failures. Every step in the manufacturing process must be tested to verify product conformity. Manufacturing processes are described in standard operating procedures, are performed as described in the SOP, and are documented in real-time exactly as they are performed. Remember, if you didn’t write it down… you didn’t do it. Intermediates as well as the final products are inspected and tested to confirm quality. For example, a surgical instrument will undergo manual visual and performance testing to verify it was assembled correctly. If a process step cannot be verified by testing or inspection, the process must be validated. Sterility is a common requirement of medical devices but testing of each product would negate the sterility. Therefore, the process by which the product is sterilized, such as steam autoclaving, is validated to prove that the process sterilizes the product. This validation must be performed prior to product marketing as well as periodically throughout the lifetime of the product. Another example is the tightness of screws holding a medical device together. Testing of the screw tightness would change the parameter, therefore a torque limiting tool would be used that 12 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. can only tighten the screw to specification. That torque limiting tool would also be tested periodically to prove that it is working correctly. Controls: Quality System Regulations In addition to following the GXPs, medical device manufacturers are expected to control the design, manufacture, testing, and sale of their products under the QSRs or quality system regulations. Similar to the GXPs, QSR is an internationally recognized system. It is an overreaching system that governs all aspects of the device from conception to use and even disposal. Implementation of the quality system regulations is the responsibility of the company’s management team. This involves the creation of procedures and controls that ensure the company is complying with quality system regulations. Click each control to learn more. When you are finished, click Next to continue. Design Controls Product quality begins with good design and specific SOPs must be in place to govern the product design process, including gate controls to ensure the review of each step in the design process. Production & Process Controls Once the product is designed, the manufacturing process is developed to include production and process controls that ensure and verify manufacturing quality. Materials Controls An important aspect of product quality is the control of materials used in the manufacturing process. All incoming materials will be purchased from qualified vendors and will undergo inspection upon receipt to verify raw material quality, and the receipt and testing of the product will be documented. Incoming materials will be inventoried, and their storage and use will be controlled and documented, using for example a first-in-first-out system of material rotation. Facility & Equipment Controls The QSRs also dictate control of the facilities and equipment used in the design, manufacture, and packaging of the product. For example, if the manufacturer includes the use of a cleanroom, the maintenance of the cleanroom will be described in cleaning SOPs. The cleaning will then be 13 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. performed following those SOPs and the cleaning will be documented, filed in the facility's records, and kept for at least seven years. Additionally, quarterly bioburden testing will be performed to verify that the clean room environment has an acceptable level of airborne particles. The performance of all equipment used in manufacture will be qualified. For example, the temperature of refrigerators and freezers used to store materials or products will be continuously monitored and the devices used to monitor the temperature will be tested to verify their performance. Most facilities require backup power, and the performance of the backup power system will be periodically tested. Records & Documents Change Control Specific practices will also be in place dictating the storage and handling of all records and documents. At times it is necessary to make additions or changes to documents and records. For example, if an operator forgot to include a raw material lot number in the manufacturing batch record. Change control procedures will be in place to allow for the addition of the lot number in a controlled fashion so that the document change is completed and the change itself is documented. A reviewer could then see that the lot number had been added to the document by whom and on what date. Change control is mandatory not only for written and paper records but also for electronic records such as instrument data. Corrective & Preventive Action In the event of product failure or manufacturing non-compliance, a system of corrective and preventative actions or CAPA must be in place. This system describes how problems or potential problems are reported, documented, and mitigated. One aspect of this system is medical device reporting. A device user such as a patient or clinician must be able to reach a company representative in order to report a problem or complaint with the product. This reporting can be done by phone, mail, or electronically through the company's website or even a smartphone app. A federal requirement is that these complaints be reported to the FDA within a specified period. The company's response to a complaint or an internal report of noncompliance or even potential noncompliance must follow a specified procedure and the response must be documented. Finally, the company may be required to track each of its products in the event of a recall. For example, joint replacements are usually serialized, and the serial number of the device is documented along with the patient who received that implant. 14 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Controls: Quality System Regulations To summarize: ● The internationally recognized quality system regulations are an overreaching system that dictates primary regulatory controls. ● A QSR system ensures the company has appropriate resources, organizational structure, design and operation methods, and facilities to implement quality processes and create a quality product. Every phase of product design, manufacture, packaging, labeling, marketing, sale, storage, installation, and service is planned, executed to plan, and documented. ● Following product launch, a reporting and surveillance system ensures that any problems the end-user has with the product can be easily reported, documented, and mitigated. ● Quality system regulations supersede good manufacturing practices, being a more all-encompassing system than the GMPs. Documentation is a key component of quality system regulations. Each business and manufacturing practice, with the exception of financial practices, must be described by a standard operating procedure, and conformance with the SOP must be established by documentation. Proof of conformance will be tested both by internal as well as external audits. The basic idea behind QSRs is to document in an SOP how a process will be performed. Follow the SOP while performing that process. Document how the process was performed and then audit the documentation. Say what you’re going to do, do what you said, and then write down what you did. QSR Examples Let’s look at some specific examples of how companies follow quality system regulations. Processes as simple as employee hiring and onboarding must follow QSRs. The company will have an SOP in place to describe the hiring process. Each employee requisition will be accompanied by an approved job description and the candidates’ experience must qualify him or her for that position. When the employee is onboarded, the company will carefully document that the new hire understands their job description. The employee will undergo training in all the job functions he or she will perform. This training must be completed prior to the employee beginning actual work and annual re-training is also required. If the employee’s job function changes, he or 15 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. she must be trained in the new procedures and responsibilities. And, of course, the company will document each step in the process so that an auditor can verify each employee’s hire, onboarding, and training. A second example is the process of product development. A device manufacturer or design firm will have a very detailed SOP describing the process of product development from initial conception to the final product. Parallel SOPs will be in place for software development, coding processes, and testing requirements. These SOPs will require gate reviews at specific points in the design process which will ensure that key personnel and managers review the product development throughout the process, not just at the end. The design process often begins with a set of product requirements and every aspect of the product will be tested to verify that the requirements have been met. Requirement testing will be performed throughout the development process and at the very end to confirm that the final product performs as needed, meeting all of the customer requirements. Risk Management Plan Risk management is utilized in all modern industries today. In the medical device industry, it is a regulatory requirement of the development process. At its essence, risk management evaluates the potential failure modes of the device itself as well as hazards inherent to the use of the device. The design, manufacture, and use of the device are carefully analyzed to anticipate potential hazards. For example, the physical, mental, emotional, educational, and even cultural background of the end user is considered. Might a typical user have impaired vision from cataracts or lowerthan-average hand dexterity due to arthritis? Both the typical device use, as well as potential atypical uses, are considered and analyzed. Could this device potentially be used for a function other than that for which it’s designed? If so, what are the risks to the user, and might there be a way to prevent incorrect use? A common incorrect use is improper cleaning of the device. The label for example may describe proper cleaning by wiping the device with a damp cloth. In anticipation of potential inappropriate cleaning by submersion, the manufacturer may make the device water-resistant and test the product following splashing, rinsing, and submersion in water. The characteristics of the device itself are evaluated. Does the device have sharp edges that could impose a hazard? Are electrical components grounded to avoid electric shock? Are there 16 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. special considerations of the environment in which the device will be used that could impose a risk? Will the device be used in a hospital or clinic or is this an over-the-counter device that will be used by the customer at home? Will the device be used inside or outside? In what temperature range? Subject to rain or snow? And finally, what are risks specific to interaction between the user, device, and use environment? What if a user with impaired vision uses a device with a smallprint readout in a low-light environment? The risk management plan will include an analysis of chemical, mechanical, thermal, electrical, radiation, and biological risk. A complete risk evaluation for a product may be 30 pages long or longer ( 2:18/43:36 ). Risk Management: Human Factors Considerations A special aspect of medical device risk management is the consideration of human factors. What are the risks specific to the customer’s use of the product? Human factors risk management regulatory requirements were issued in November 2011. Human factors considerations are divided into a use environment, user, and device. The manufacturer must evaluate how these various risks may intersect to affect the outcome. Resulting in either safe and effective use of the device or unsafe and ineffective use. Let’s look at a defibrillator as an example of human factors risk analysis for a medical device. What are the characteristics of the potential use environment? Will the defibrillator only be sold to hospitals, or will the device be installed in public places like airports, shopping malls, and casinos? Will the device potentially be used in a low light environment, making it more challenging to read instructions, or in a noisy environment making it difficult to hear audible cues the device emits? Is the user likely to be distracted by the environment? By things like bells ringing, lights flashing, or crowds of other people? Will the device be fixed in place, or will it be subject to motion and vibration? How often will the device be used? Is a heavy workload anticipated? Does the device have to be tested or replaced periodically and/or after each use? What kind of knowledge and ability might a potential user have? Will the defibrillator be installed in ambulances and therefore only be used by trained medical personnel or is the defibrillator intended for use by the general public? What are the expectations of the user? Is the user likely to have seen fictitious depictions of the device’s use on television or in films and therefore have preconceived ideas about how the device functions? What are the potential limitations of the user? Can the manufacturer presume that the user reads English or is 17 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. it important for the instructions to be pictorial? An advantage of pictorial instructions is that it negates the need to print instructions in multiple languages for the international marketplace. What are the operational requirements and procedures for the device? Is the device ready for use at notice, or does it need to build a charge prior to use and how will the user know when charging is complete? Is the device simple enough for the intended user to use effectively? Does it require a 15-step process that has to be conducted in a specific order or do the leads simply have to be attached to the patient and a button pressed to operate the defibrillator? Are the leads interchangeable so it doesn’t matter which is attached where or must each lead be placed correctly on the patient? If so, can the leads be easily distinguished? Can the manufacturer anticipate specific user interface characteristics? For example, can the user be presumed to see color, or should visual indicators be apparent even to color-blind individuals? So, as you can see, the factors that must be considered are extremely wide-reaching, and all of these considerations must be made when determining how to manage the risks involved in the use of a medical device. On the next screen, we will describe how this risk analysis is performed. Risk Analysis Plan Process The risk analysis process follows a defined pathway. First, all potential risks are identified. Each identified risk is then evaluated and quantified, how severe is the potential hazard? Would misuse of the defibrillator result in mild shock or potential death? Methods to assess each risk are then developed and evaluated. For example, the voltage and current of the defibrillator are directly measured. Each risk is then assessed to determine if it is an acceptable risk or if the risk needs to be mitigated. If the risk is not acceptable, a mitigation solution is implemented. This change, of course, is documented as part of change control management and then the entire process is repeated to reanalyze the device risks given the implemented solution. Rest Of World Thus far, this course has focused on US regulatory requirements for medical devices. In order to market a medical device internationally, the company must obtain clearance from each country’s regulatory authority. While each country will have specific regulations and requirements the company must follow, there are fortunately several international organizations that are working to 18 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. harmonize regulatory requirements. Click each organization’s logo to learn more. When you are finished, click Next to continue. ICH The ICH or International Conference on Harmonization brings together the regulatory authorities from Europe, Japan, and the United States as well as experts from the medical industry to discuss scientific and technical aspects of product registration. This includes the publication of good manufacturing practice guidelines and quality system regulations. OECD The OECD or Organization for Economic Co-operation and Development is an international organization of 34 countries founded in 1961 to promote economic progress and world trade. The OECD publication, “Test Guideline and Principles of GLP”, describes good laboratory practice standards and dictates that data generated in one country following these GLP guidelines will be accepted in all other OECD member countries. ISO ISO or the International Standards Organization has over 25 member countries and 2,700 technical committees which establish technical standards for products and product testing. ASTM The American Society for Testing and Materials, or ASTM, is another international standards organization that develops voluntary technical standards for a wide range of materials, products, systems, and services. AAMI Specific to the medical device industry is AAMI, or the Association for the Advancement of Medical Instrumentation. It is an organization dedicated to advancing the development as well as safe and effective use of medical technology which sets safety standards for the design and use of medical devices. While each country still has specific regulatory requirements, the efforts of these various organizations have significantly harmonized medical product regulation. 19 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. European Union Approval Process A significant market for medical devices is the European Union. Previously, the sale of a medicinal product to Europe required approval from each country’s regulatory body. Today, clearance by the declaration of conformity and issuance of the CE mark enables a company to sell its product to customers in all countries within the European economic area. This process was established in 1993. The CE mark is proof that the product conforms to all applicable European directives appropriate to that product. For medical devices, the development and regulatory processes are similar to US FDA requirements. The actual approval is obtained not from a government representative but rather from a notified body. The notified body is a private individual or company that has obtained authorization from European Union authorities to review and approve products requiring the CE mark, including medical devices. The product manufacturer selects and pays the notified body to review the product’s technical file, also called a design dossier, and to review the company’s quality management system. If the product file and quality system meet the audit requirements, the notified body issues a declaration of conformity and the CE mark can be added to the product label, effectively clearing it for sale in the EU. If the company seeking approval does not have a physical presence in Europe, it will hire an authorized representative. An important role of the authorized representative is to field customer inquiries and complaints. Section 2: Regulation Summary This section described: ● How the FDA utilizes a risk-based regulatory system in which low-risk, class 1 devices require minimal regulatory oversight while higher-risk class 2 and class 3 devices require stricter testing and regulation, up to and including human clinical trials. ● The entire product development process from design to testing and manufacture must follow regulatory guidance including good laboratory practices, good clinical practices, current good manufacturing practices as well as quality system regulations. 20 Copyright 2024 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. ● An important part of product development is risk management which for medical devices is required to include evaluation of human factors which can affect the product’s risk. 21 Copyright 2024 Biotech Primer, Inc.