By: Brooke Struyk
Abstract
The Food and Drug Administration (FDA) is a United States agency responsible for regulating medical devices among other functions. The regulation process entails a lengthy pre-market process that looks at pre-clinical trials, clinical trials, the warehouse in which the device is manufactured, ethics behind the device, and more. When it comes to the device itself, usually it is one singular device on the market for everyone, but what about individualized devices adjustable to the needs of the user? This blogpost defines such devices and delves into how they are currently regulated. It also reviews issues with the current regulatory process within the United States using the European Medicines Agency (EMA) as a counter example to the FDA in regulating individualized technologies. This blogpost aims to highlight the flaws within the regulatory process and suggest ways the FDA can improve it.
Introduction
As of 2024 over 6.7 million people over the age of 20 are suffer from heart failure in the United States[1]. For the past 100 years, cardiovascular disease has been the leading cause of death in the United States and globally [2]. Patients with bradycardia, where the heart beats too slowly, tachycardia, where the heart beats too fast, and heart arrhythmia’s where the heartbeat is irregular, rely on pacemakers to regulate their heart rate. There are two types of pacemakers, those with leads (wires) and leadless ones. Leadless pacemakers come in one piece as a single device and do not have leads (wires) that go to the patient’s heart. Such pacemakers are implanted directly into the heart. Pacemakers with leads come in multiple different pieces with a separate battery implanted under the skin and used to send electrical pulses to regulate rhythm and rate of the heart [3]. Companies like Medtronic and Boston Scientific are the leading innovators for pacemakers. However, devices like this are created for the general public’s needs, the average user, not the individual with diverse needs.
A custom device has many definitions. In the eyes of the public, it may be accidentally misidentified as a customized device. For example, retainers for post orthodontic treatment, such as braces or aligners, are created to fit over or behind the unique arrangement of patient’s teeth. An insulin pump, a medical device that is designed to administer gives a specific amount of medicine (insulin) a day to a person with diabetes, allows users to adjust software parameters of the device to better meet their needs. Such devices are customized devices. In the case of FDA regulation, however, a custom device is more specific. It is not adjustable to fit a person and the needs of their body, it is specifically designed for diverse patients to accommodate their sensitivity or allergies, physical disabilities, unusual anatomies, etc. Custom devices cannot be adjusted but must be specifically created to be usable.
Why custom devices are needed
Patients might require custom pacemaker devices, which are used for a number of reasons. One instance is an allergic reaction to specific metals or components of the device. In 2012 Medtronic put out the first ever custom-made 24 carat gold-plated pacemaker called the Medtronic Adapta DR PVV [4]. These pacemakers are specifically used for patients that are allergic to the metal combination material that covers regular pacemakers. One specific metal is titanium that might cause a severe inflammatory reaction within the body, leading to an immediate removal of the pacemaker. Gold is specifically used in custom pacemakers due to its hypoallergenic nature.
The next reason a patient may use a custom device would be for a patient-centric device. This specific kind of device is used to fit the unique anatomy of the patient’s body. For example, an infant might require a custom device. [5] Due to the small body of infants, a regular pacemaker would be too large. In this case a manufacturer would have to create an individualized device to fit the infant. This same approach can also be applied to people who are larger in size. Due to their bigger size, a custom device may be needed. Similarly to an oversized hip device needed for a larger person since a standard hip replacement system would not be effective [6]. In this case the custom device falls under the FDA custom device regulation. Specific anatomy differences in a patient may dictate the need for a custom device.
Lastly, another reason for custom devices might be for patients with rare diseases [7]. Due to the low number of people able to participate in clinical testing and trials, the pre-market approval process would not be able to be used. This would call for a special exception. In this case, the FDA regulates medical technologies designed for people with rare conditions. These devices cannot be considered customized because they are designed and produced on a case-by-case basis.
Customizable vs custom devices
Since the regulation of custom devices cannot be done following traditional FDA pre-market processes, it is important to understand the regulation of custom and customized devices. In 1976 Congress passed the Medical Device Amendments of the Food, Drug, and Cosmetics Act. In this act, congress has determined that there should be a legislative difference between custom devices and customizable devices[8]. Custom devices should refer to one person getting a specific device, while customizable devices would imply mass produced devices with varying adjustments to better meet the needs of the individual. Regulatory requirements for custom and customizable devices differ as well. A custom device should be able to bypass the FDA premarket and 510K approval pathway. A new customizable device has to go through the FDA premarket approval process.
An example of a customizable device would be a pacemaker modified to increase a patient’s physical activity. In this case, the specifics aren’t changing the model of the pacemaker but changing the code inside. By making the software more customized to the person’s health, weight, body, and lifestyle, it will allow a person to have a safer and more efficient device. In 2021 the University of Leeds conducted a case study with a woman who, after getting a regular pacemaker, had her energy levels decline and was not able to walk more than 500 meters [9]. After changing her pacemaker’s programming to make the device specific to her body, she was able to go to the gym and run again. Opportunities to create customized devices can help many people in the long run. Customized devices do not usually involve extensive costs for customization but can offer great improvements and help many people stay healthy and maintain their active lifestyle. This is not the case for custom devices that can be very costly to create. However, custom devices are equally important as they satisfy important human health needs of a minority within the population.
How custom devices are regulated
The FDA defines custom devices with little to no gray area. If qualified, a custom device may not need to go through the FDA 510K pathway or the premarket approval process. A device can be classified as a custom device when it was created or modified by a physician or dentist to be used for a specific need that cannot be satisfied with a general medical device[10]. Another way a device can be labeled as a custom device is if the device comes from a foreign market in an incomplete form [10]. This means a device is on the market as a set to be put together. Another example is a device used by a physician or dentist to meet their specialized needs within their practice. This may be due to the physician having a physical disability or the device is customized to fit the needs of the patient that will be using the device. A custom device can also be assembled from components and manufactured together on a case-by-case basis [10].
Entities seeking approval for custom devices are required to follow Quality System Regulation (QSR). QSR is mandatory regulations that ensure quality and safety of medical devices. QSR specifically addresses the designing, purchasing, manufacturing, packaging, labeling, storing, installing, and servicing of medical devices[11]. To check that these regulatory requirements are met the FDA conducts facility inspections. QSR regulations are important to ensure that custom devices, even though they do not go through the PMA nor 510K approval pathways, are still up to standard.
Manufacturers are also limited to the number of custom devices they can sell a year. Currently, the number is less than five per manufacturer per year [6]. This is regulated very strictly. If more than one custom device is given to the same person within a year of the first device, these devices will count as one custom device on the annual report [6]. If there is a device made, but not used, this device will also not count as one of the five custom devices [6]. In all cases, the manufacturer must report the device to the FDA and state that these devices have been destroyed or returned and not used [6].
For a custom device to be approved, the manufacturer must submit an annual report to the FDA sharing the custom devices that have been supplied [6]. This places a restriction on manufacturing companies trying to bypass the expensive premarket approval process or the 510K pathway. The device also goes through a more restrictive post-market process [6]. Most devices approved by the FDA have a lengthy premarket approval process filled with requirements for lots of data to ensure the device’s safety before it introduced to the market. In this case, the FDA has the device bypass as much of the premarket process as it can and will monitor the device in the postmarked process, something that EMA, the medical device regulation agency in the European Union focuses on more.
In specific cases, if the custom device manufactured was a patient-centric device, the FDA requires additional information on the annual report. This includes the name of the patient, reason for custom device, procedure for creating this device, and patient’s condition [6]. It also requires the manufacturer to share the device name, brand name, model number, etc. The same is asked for physician-centric devices [6]. They additionally require physician-centric devices to state a reason why clinical investigations cannot occur and if the device was new or modified from the existing approved market devices. In the European Union, custom devices are regulated differently. For starters, regular medical devices are regulated based on a focus of the post market process[12]. This allows smaller companies to place their devices on the market without having to go through a very long and expensive premarket approval process that they would not be able to afford. This process is very different from the FDA approval processes [13]. Regarding custom devices, dental crowns or patient-specific dental guards, as well as prosthetics are all considered custom devices in the EU. Under the FDA these devices would be considered “customizable” and under the class I or class II premarket approval process[14].
Issues with regulation
There are many issues that come with regulating custom devices. One issue is the fact that manufacturers can only produce up to five devices per manufacturer per year. One can understand that the FDA has this strict restriction to prevent against abuse of regulation and to prevent manufacturers from bypassing the more expensive and lengthy medical device approval pathways. However, there are important issues to consider. For example, the restriction may create selectivity of patients within a manufacturer. Manufacturers may choose patients with conditions that are very rare and make more complicated devices appear to be more competitive on the market. Smaller companies, due to tighter budgets and fewer staff, engineers and other specialists, may not have time, funding or other resources to create custom devices. Lastly, lack of funding may be the barrier to some corporations for the creation of new specialized devices. This may lead to a shortage of manufacturers who are able to create a custom device.
The main regulation that cannot be bypassed for custom devices is the QSR. The issue with this being the main form of regulation is that the QSR is known for its flexibility. As said by the FDA, the QSR only provides the framework that manufacturers must follow. It is up to the manufacturer to make sure the device is safe, effective, and meets quality standards[15]. This flexibility may not be the best for custom devices considering it will not be going through the stricter PMA pathway or 510K pathway.
Another issue that is prevalent within the entire FDA system, not just for custom devices, is the lack of education on regulations [12]. Due to the wide number of very specific and very broad regulations, it is hard to keep up with what is being regulated and what isn’t. Although monthly and yearly meetings are held by the FDA to clear confusion about certain guidelines, the overall regulation system is very messy. This is not to say that this regulation system doesn’t work and gets safe devices on the market; however, one may say that for medical devices there can be a better process.
The final issue to be addressed would be the factor or monitoring risk. The FDA bases all its regulations based on risk [15]. With custom devices, it may be harder to classify the potential hazards the device may have. Once again, custom devices may need stricter guidelines. Due to the lack of availability for clinical trials and lack of feedback due to the device being for a singular individual. It may be hard to identify other risks that may be helped by this device.
How to improve the process
One improvement that can be made would be a focus on post-market surveillance of the custom devices. Due to the bypass of usual medical device regulation, the device itself is hard to regulate. If the FDA focused on an approach that is like the European Union EMA regulation, where there is a high emphasis on post-market surveillance, there will be a lot more control over the device. By changing the QSR or making a stricter pre-creation process, manufacturers will no longer be interested in making custom devices and this would cause an even greater issue. That is why focusing on more post-market regulations is the best way to ensure a device is working the way it should and the most effective way possible.
Another improvement that can be made, that is more of a long-term goal is to create a clearer set of guidelines for all medical devices, not just custom. By reframing the current FDA medical device system, one will be able to spot more loopholes and get rid of them. An example of this would be the lack of post-market surveillance on cybersecurity related issue. It will also allow for more devices to be made. With clearer guidelines, manufacturers will be able to understand more of what they can do, thus growing the medical device field. It will also allow patients with medical devices and physicians who use these devices to have a better understanding of the regulation process is and foster more trust in the FDA and government regulatory bodies of medical devices.
In 2016 a technical amendment was placed that would clear and create consistency with the medical device regulations [8]. It would be able to educate manufacturers on the devices that are/ are not considered “custom” by the FDA, so the correct devices are placed under premarket review. It also explained the Custom Device Exemption, which would further define the meaning of the term “custom devices” and place new rules under the new definition. With this amendment it takes on two issues. The fact that the term “custom devices” was originally used very loosely and broadly, and the fact that the regulation would go straight to educating the manufactures. This will curb any more potential confusion and misunderstanding that could potentially stop a device from getting to a patient.
Conclusion
Custom devices allow for greater accessibility to medical technologies to physicians and patients with rare physiology or anatomy. It is crucial for such devices to be regulated and regulated properly to ensure greater safety and effectiveness. It is also important that manufacturers understand the regulatory process guiding the approval of these devices, and why there is such a big difference between the regulation between custom and general medical devices. There are both long-term and short-term approaches that the FDA can undertake to improve the regulatory process of custom devices. Looking at other countries and learning from their processes and how they regulate custom devices may be beneficial for the United States. Thanks to custom device regulation, patients with rare diseases, allergies, and unique anatomy as well as physicians who need a custom device due to a disability or their way of practice, can all get the devices they need.
Works Cited:
[1] "More than half of U.S. adults don’t know heart disease is leading cause of death, despite 100-year reign," American Heart Association, 2024. [Online]. Available: https://newsroom.heart.org/news/more-than-half-of-u-s-adults-dont-know-heart-disease-is-leading-cause-of-death-despite-100-year-reign.
[2] "The top 10 causes of death," World Health Organization, 2024. [Online]. Available: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death.
[3] "Leadless Pacemaker," Cleveland Clinic, 2023. [Online]. Available: https://my.clevelandclinic.org/health/treatments/17166-pacemakers-leadless-pacemaker.
[4] A. Kypta, "Gold-coated pacemaker implantation for a patient with type IV allergy to titanium," National Library of Medicine, 2016. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC4867966/.
[5] "Tiny pacemakers aim to make infant heart surgeries less invasive, while cutting operating costs and time," Children's National, 2018. [Online]. Available: https://www.childrensnational.org/about-us/newsroom/2018/tiny-pacemakers-aim-to-make-infant-heart-surgeries-less-invasive.
[6] "CDRH Industry Basics: Custom Device Exemption," Food and Drug Administration, 2019. [Online]. Available: https://www.fda.gov/media/89641/download#:~:text=Remember%2C%20a%20custom%20device%20exemption,that%20custom%20devices%20are%20used.
[7] "Focus Area: Individualized Therapeutics and Precision Medicine," Food and Drug Administration, 2024. [Online]. Available: https://www.fda.gov/science-research/focus-areas-regulatory-science-report/focus-area-individualized-therapeutics-and-precision-medicine#:~:text=Precision%20medicine%E2%80%94sometimes%20known%20as,patient%20at%20the%20right%20time.
[8] G. A. V. Norman, "Expanded Patient Access to Investigational New Devices," National Library of Medicine, 2018. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC6115642/#:~:text=See%20text%20for%20further%20details,many%20of%20them%20(13).
[9] L. Kettle, "New research to study benefits of personalised pacemaker programming," British Heart Foundation, 2021. [Online]. Available: https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2021/may/new-research-to-study-benefits-of-personalised-pacemaker-programming.
[10] "Medical Devices; Custom Devices; Technical Amendment," The Daily Journal of the United States Government, 2016. [Online]. Available: https://www.federalregister.gov/documents/2016/10/12/2016-24438/medical-devices-custom-devices-technical-amendment#:~:text=The%20new%20provisions%20for%20the,limited%20to%20no%20more%20than.
[11] "Overview of Device Regulation," Food and Drug Administration, 2024. [Online]. Available: https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/overview-device-regulation#:~:text=Quality%20System%20Regulation%20(QS%20regulation,compliance%20with%20the%20QS%20requirements.
[12] B. Struyk, "The US vs. the EU: A look at the pre- and post-market regulation of medical devices with Medtronic's pacemaker devices as a case study," Tech4Humanity, 2023. [Online]. Available: https://tech4humanitylab.org/blog/2023/12/11/the-us-vs-the-eu-a-look-at-the-pre-and-post-market-regulation-of-medical-devices-with-medtronics-pacemaker-devices-as-a-case-study.
[13] S. Lamph, "Regulation of medical devices outside the European Union," Journal of the Royal Society of Medicine, 2012. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC3326589/.
[14] "Custom-Made Medical Devices: Are You Complying With EU Requirements?," ClinChoice, 2023. [Online]. Available: https://clinchoice.com/custom-made-medical-devices-eu-requirements/.
[15] "Quality System (QS) Regulation/Medical Device Current Good Manufacturing Practices (CGMP)," Food and Drug Administration, 2024. [Online]. Available: https://www.fda.gov/medical-devices/postmarket-requirements-devices/quality-system-qs-regulationmedical-device-current-good-manufacturing-practices-cgmp#flexibility.