How to Market Medical Devices in the U.S.
Which regulatory pathway is the best fit for a specific medical device platform? How does one get regulatory clearance for a device? Is clinical data needed to support applications?
All medical device innovation companies, particularly newer start-ups, are plagued by these questions once they have a promising technology that could benefit the human population. With each new scientific advancement, there is a requirement for higher understanding of the regulatory implications before a medical product can be developed and marketed in the United States (US). Navigating regulatory issues can become a barrier to the growth of a medical device company if the management teams do not possess a good understanding on how to address regulatory issues. This may also have an impact efforts to secure early stage funding as investors are often concerned about the ability of a company to deal with regulations. The ability to secure regulatory clearance/approval is a key milestone in bringing a medical device product to market, therefore, an early regulatory plan for product development is essential. Since regulatory strategy and marketing considerations are unique to each medical device, the information presented in this article is intended to share different options for pre-market submission pathways in the US. Contract Research Organizations (CROs) like Technical Resources International (TRI), can greatly support medical device manufacturers and start-ups in navigating the numerous business and regulatory challenges associated with the medical device industry.
In the US, medical devices are regulated by the Food & Drug Administration (FDA), and the Center for Devices & Radiological Health (CDRH) which ensures medical devices are safe for human use 1. Per section 201(h) of the Food, Drug and Cosmetics Act (FD&C), any healthcare product that does not achieve its principal intended purposes by chemical action, by metabolic action, or by being metabolized, is defined as a medical device. Medical devices can range from a simple tool such as a tongue depressor to a more complex device such as a robotic surgical instrument 2. Medical devices are products that can utilize varied combinations of mechanical, biophysical, electronic, chemical or biochemical actions to fulfill their intended purposes and hence, may pose different degrees of risk to the patient population. If one is not sure whether a medical product will be considered a device or not, the FDA website is a good place to start and review the classification database that lists all the products that FDA considers to be devices 3. Accordingly, there are multiple pathways to obtain clearance or approval to market a device in the US.
Classifying Your Device to Determine Regulatory Requirements
The FDA's medical device regulatory pathways - for premarket review, clearance, and approval - are based on three classifications, which indicate the degree of regulatory control necessary to ensure a device's safety and effectiveness (Table 1).
Table 1: General Device Classification
The classification of the device is the first step in knowing which type of regulatory clearance or approval is required from the FDA before the device can be marketed. Medical device classification primarily indicates the risk the medical device poses, based on the "intended use" of the device and its "indications for use". Class I devices are low risk and are generally exempt from premarket review, however, some may require it. Class II devices typically require FDA Premarket Notification under section 510(k) of the US- FD&C (establishing substantial equivalence to a predicate device). Class III devices are high-risk devices where no suitable predicate device is available and require FDA approval via a Premarket Approval application (PMA) 4, although some may only require a 510(k). Note that some Class II devices may not require premarket review like Class I devices, and some may require premarket approval like Class III devices.
Interestingly, all new devices (those without a predicate) are considered Class III and require approval from the FDA via a PMA. However, there is one other regulatory pathway to use if the device is brand new but also low risk. This is the De novo process, which was initiated as part of the 1997 FDA Modernization Act, and allows for risk based classification of "novel" low risk devices that are without a valid predicate (reasonable assurance of safety and effectiveness).
Knowing the classification of your device and selecting a premarket submission pathway may seem straightforward. However, selecting a regulatory pathway solely based on the above knowns may go against one's business development plans or available resources. The below sections will discuss more details about the pathways and why working with a CRO can expedite and smooth the way to market.
510(k) Premarket Notification
The most common and easiest pathway to market a new medical device in the U.S. is a 510(k)-pre-market notification. 510(k) requires the demonstration that a device is substantially equivalent, i.e., at least as safe and effective as a currently marketed predicate device, (one which has already passed FDA investigation) in terms of materials, design, technology, intended use and performance. This is used for some Class I, and most Class II devices which require "special controls" (e.g., surgical instruments) (5). For new devices subject to 510(k), premarket submission is needed to provide evidence that the device meets any required special controls and has indications and technological characteristics consistent with existing legally marketed predicate devices. Accordingly, any of the traditional, abbreviated, or special 510(k) options may be applicable for the medical device under the new 510(k) paradigm6.
The determination of the "degree of difference" between the subject device and predicate becomes a very crucial factor for successful clearance of the 510(k) application. Working with experts at a CRO during the device planning stage will help in the selection of the right 510(k) option, identification of an appropriate predicate or more than one predicate if necessary, and in generating the data required to meet the design control requirements of the 510(k).
Premarket Approval (PMA)
The most difficult pathway for medical devices in the US is the PMA. The FDA requires a PMA for high-risk Class III medical devices and innovative technology where no identifiable predicate exists. Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury, or are new and present unknown safety, effectiveness issues, or risks 4.
A PMA application is a scientific, regulatory document that is submitted to the FDA to demonstrate the safety and effectiveness of the Class III device which requires the manufacturer to present adequate scientific evidence to assure that the device is safe and effective for its intended use(s). This is typically done by conducting "adequate and well-controlled" clinical trials. Further, to initiate clinical trials an Investigational Device Exception (IDE) is required. The typical PMA application methods include: Traditional, Modular and Product Development Process 7. Due to the requirement to have clinical data in support of the PMA application, this pathway may seem burdensome and companies may be reluctant to use this as a regulatory strategy for their product development plans and may be inclined to adopt the 510(k) pathway if all applicable requirements are met. However, depending upon company's business goals a good plan would be to reconsider the PMA, not for regulatory reasons but to maintain a strong competitive edge as 510(k) cleared devices would also let competitors introduce a new device variant faster to market. So, while manufacturer may want to bring the device faster to market it may be worth considering the aspect of making it challenging for the competitors and have the longevity of their business through PMA pathway. The business team would need to have clear cut goals defined and involve regulatory experts or in case no in-house regulatory expertise is available, hire consultants from a CRO early on to make the most appropriate device development plans.
Other Pathways: De Novo and Device Exemption Pathways
Increasingly, companies may find that their medical device may fall into de novo or device exemption pathways. But how does one decide which is more appropriate? In the US, certain provisions exist so that if a device has no direct precedent but is low risk, the device is targeted only to a very small population in the US, or is being developed as a personalized device, manufacturers can consider alternative approaches to the 510(k) or PMA:
- De Novo: In the US, entirely new devices are automatically considered to be Class III regardless of the level of risk the device poses. They will receive a "not substantially equivalent" (NSE) determination in response to a premarket notification or 510(k) submissions. The de novo pathway is an option for devices that are "novel low risk" and for which there is not a legally marketed predicate device. Under the new de novo program, companies may get the benefit of the 513(g) or Pre-Submission process, which classifies a device as "novel" with no existing classification or predicate device on the market (8). The FDA has 120 days after the de novo submission to determine the device classification (Class I or II) or to issue an entirely new product code and regulation number. If the de novo option is declined, the device will remain Class III 9.
Humanitarian Device Exemption (HDE) program: The HDE has similarities to the Orphan Drug designation program for drugs. A Humanitarian Use Device (HUD) is exempted from the effectiveness requirements if it is intended to target a disease condition (treatment or diagnosis) that affects "not more than 8,000" individuals in the U.S. per year. Of note this threshold had been "fewer than 4,000" until recently when the 21 CFR part 814 was amended under 21st Century Cures Act. The HDE program can ultimately be a faster and potentially cost-effective approach to get a device to market 10.
Clinical Data Requirements
Evaluating the safety of the medical device may or may not require the conduct of clinical studies. Therefore, it is important for device manufacturers to identify early on, the unique aspects of regulatory requirements for planning the device's marketing. The determination of whether a device's clinical trial is required, is largely based upon a risk stratification of the device (Table 1). The general perception is that 510(k) applications include only non-clinical data and detailed manufacturing information for the device, however, typically in about 10-15% of 510(k) applications, the FDA requires clinical data.
It can be hard to determine what kind of clinical trials are needed and to what extent clinical data would be required to obtain 510(k) clearance. It is important to determine the degree of difference between the subject device and predicate, and the robustness of the non-clinical data pertaining to the safety and special controls. Working with a CRO can help manufacturers weigh the different pros and cons the available regulatory approaches have to offer, and develop a strong strategy to suit their business needs. Accordingly, consultation with experts can help identify the appropriate indication of use or a product label, determining clinical data requirements, planning and conduct of clinical studies, and build a strong target product profile to go along with the business plan. Further, as more and more medical companies are introducing their product around the world, to execute the right marketing strategy, companies are now finding CROs as one-stop shop to outsource the execution of bringing new devices to market.
Navigating the FDA approval process for device clearance or approval can be tricky if the business and regulatory aspects as applicable to one's unique situation are not fully taken into consideration. Working with a team of regulatory experts could help avoiding pitfalls in pre-market submissions that may lengthen the FDA review time. Hiring a full service CRO allows the manufacturer of a medical device to focus more on the research and development, distribution, sales and patents, and less on the actual implementation of the trial, collection of data, or writing the pre-market regulatory submissions and taking associated risks. Working with TRI, clients can expect high quality services including developing regulatory strategy, consulting on device classification, description and indications for use, determining appropriate pathways to market, processing pre-market applications and clinical trial management.
About the Author
Dr. Shailender S. Kanwar, holds a PhD in Biophysics and is a Regulatory Specialist at TRI with scientific expertise in molecular cancer therapeutics and diagnostics. He holds special interests in the US medical device regulatory landscape and has helped medical device startups in technology evaluation, market research and strategic planning. Continuing to advance his professional learning, Dr. Kanwar is currently pursuing a master's degree in Regulatory Science at the Johns Hopkins University.