While FDA has developed and overhauled the regulatory landscape as applied to food and drugs since 1906, the emphasis on regulating devices has essentially been evolving only over the last 40 years or so. The concept of providing reasonable assurances of safety and efficacy of devices is well-founded, but the need to adapt the regulatory framework developed for drugs and apply it to medical devices continues to evolve, particularly regarding the differences in the benefits and risks associated with devices versus drugs. Following is a summary overview of FDA and its laws, regulations, and oversight of drugs and devices, including recent guidance documents that provide insight into FDA’s current thinking on determinations of safety and efficacy with respect to devices.
OVERVIEW OF FDA
The Food & Drug Administration (FDA) was originally created through the Food & Drugs Act of 1906 in an effort to provide public health and consumer protections related to drug products. The federal Food, Drug & Cosmetic Act (FDCA) authorized FDA to take a more active role in public health, including additional requirements that any companies selling new drugs provide evidence to FDA that the drugs be safe for consumers and that drugs and devices not be adulterated or misbranded. In 1962, the FDCA added more stringent drug safety requirements, including that companies prove drugs are effective through controlled clinical studies, post-market surveillance, and adverse event reporting. The Medical Device Amendments of 1976 and the Safe Medical Devices Act of 1990 required that devices also be safe and effective and required post-market surveillance and adverse event reporting for devices.
More recently, the 21st Century Cures Act (Cures Act) funds grants to spur innovation, accelerate product development, and put drugs and devices in the hands of patients who need them in a more expedient and effective manner. The Cures Act addresses devices specifically and grants authority to FDA to prioritize product development for particular devices that address life-threatening and irreversibly debilitating diseases or conditions (“Breakthrough Devices”). In implementing these latest programs, FDA reiterated that while speeding up the approval process is the intent, it will not reduce or eliminate any requirements of safety and effectiveness.
FDA APPROVAL PROCESS
In reviewing a drug or a device for approval/clearance, FDA’s objective is to weigh the benefits and corresponding risks associated with each and to confirm its safety and effectiveness. The process for this determination may differ between drugs and devices. The oversight responsibility for drugs is regulated and managed by FDA through its Center for Drug Evaluation and Research (CDER) while the responsibility for devices is regulated and managed through its Center for Devices and Radiological Health (CDRH). A product is regulated as a drug if the primary intended use is achieved through a chemical action or by being metabolized by the body. A product is regulated as a device if it is an “instrument, apparatus, machine, implant, or other similar product which is (1) a device recognized in an established formulary or supplement, (2) intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or other conditions, or (3) intended to affect a structure or function of the body, and does not achieve its primary intended purpose through chemical action and is not dependent upon being metabolized to achieve its intended purpose.”
DRUG APPROVAL PROCESS
Prior to seeking approval to market and sell its drug product, the sponsor conducts preclinical animal testing to assess the potential product’s safety and the biological activity triggered by such product. If satisfactory, the sponsor will submit an Investigational New Drug (IND) application to FDA. FDA reviews the IND and determines whether a Phase I study is appropriate in order to obtain information about the pharmacologic actions caused by the drug (typically testing 20-80 healthy participants). If successful, the sponsor seeks FDA confirmation to conduct a Phase II study within the targeted disease state to confirm appropriate dosage and preliminary efficacy along with the associated risks and side effects (30-300 patients). If the Phase II study confirms the expected results, FDA may authorize a Phase III clinical study with larger samples of patients to verify prior results and provide additional significant data on safety and efficacy (200-3,000 patients). Upon completion of the Phase III study, the sponsor submits a New Drug Application (NDA) with relevant preclinical and clinical data, including data on manufacturing and quality systems, to FDA for review and approval determination. All new drugs must go through this process to be marketed and sold.
The FDA review process for the NDA generally takes 10-15 months, although expedited reviews are potentially available to reduce that timeline for certain drugs that meet the expedited review requirements. This does not consider the time between initiating product development through submission of the NDA, which on average extends this time-line to 8-10 years. According to a 2012 Tufts study, the estimated cost of a new prescription drug approval was $2,558,000,000 (inclusive of all clinical, research and preclinical development costs, success and phase attrition rates, development times, and cost of capital).
DEVICE APPROVAL PROCESS
For devices, FDA’s review process depends on the applicable classification for the device. Devices are separated into Class I, II, and III based on the perceived risk level from those products, subject to conditions and controls increasing as the risk level increases. Class I devices are generally subject to establishment registration, labeling requirements, and compliance with manufacturing requirements. Class II devices are either subject to premarket notification (i.e., 510(k) devices) or exempted from such premarket notification requirements. To qualify as a 510(k) device, the sponsor must demonstrate that the device is “substantially equivalent” to a predicate device marketed prior to May 28, 1976. Class II devices are subject to conditions and controls, such as performance standards, post-market surveillance, patient registries, special labeling, premarket data requirements, and other guidelines. Class III devices, which present potential unreasonable risk of illness or injury where existing information or regulatory controls are insufficient, typically require the sponsor to demonstrate safety and effectiveness by providing nonclinical data on toxicology, biocompatibility, stress, wear, shelf life, and laboratory or animal test results along with clinical trial data as set out in the trial protocol. Initially, the sponsor selects and prepares the necessary information (such as design controls, nonclinical testing, clinical evidence, and labeling) for the premarket submission required for the proposed classification and submits the packet for administrative review and interaction with the company. A large majority of devices fall within Class I and II categories.
As for the time-lines applicable to devices, they also increase in accordance with the applicable classification. Given that devices can differ from each other in almost every respect, including how they work, how they are applied to the patient, and how their effectiveness is measured, this forces FDA to adopt ad hoc rules for testing of new devices in order to properly gauge safety and effectiveness, resulting in a fair amount of differentiation in the approval processes and timelines. However, approvals for Class I and exempt Class II devices, as applicable, are likely to take less than one month. Non-exempt Class II devices took an average of just under six months, but the average time-frame went from a low of 112 days for radiology devices to 250 days for immunology devices.
From a cost standpoint, the average cost-to-market for high-risk devices under Class III was $94,000,000. Class III devices can take 18-30 months for the approval process, unless under an expedited program, and a total of 3-7 years for the typical product development cycle.
RECENT FDA GUIDANCE DOCUMENTS
FDA has issued various draft and final guidance documents since December 1, 2017 related to medical devices. These cover FDA’s current position on medical device accessories and classification, additive manufacturing of medical devices, review of premarket approval applications, the Breakthrough Devices program, and making the approval/clearance decisions based on means less burdensome to the sponsors.
FINAL GUIDANCE DOCUMENTS
Medical Device Accessories – Describing Accessories and Classification Pathways
This guidance issued December 20, 2017 modifies the historical rationale for classification of accessories that require FDA to classify accessories based on the risks of that accessory when used as intended and the level of regulatory controls necessary to provide reasonable assurance that such use is safe and effective. This determination is made independently of the parent device and may result in a classification that is different from the parent device. FDA first determines whether the article meets the definition of an accessory, and then it determines the risk of the accessory and necessary regulatory controls to provide reasonable assurance of safety and effectiveness when used with the intended parent device.
Technical Considerations for Additive Manufactured Medical Devices
FDA issued recent guidance on its view of technical considerations applicable to various types of additive manufacturing (i.e., manufacturing that builds devices using newly available technologies, such as stereo-lithography or 3D printing). FDA recognizes the value of using these new technologies to create devices that match a patient’s anatomy or create devices with complex internal, geometric, or porous structures more easily. FDA reiterated that regulatory requirements and expectations associated with devices made with additive manufacturing will be the same as those used to assess devices made with traditional manufacturing methods for the same type of device. The sponsor must maintain their manufacturing quality system as required under 21 CFR 820.30 and must still establish, monitor, and validate the manufacturing process requirements, including those related to any necessary software applications, raw materials, and post-processing testing and specifications. Any changes to the above must be analyzed to determine if revalidation is necessary.
KEY DRAFT GUIDANCE DOCUMENTS
Breakthrough Devices Program
FDA published guidance on implementation of the Breakthrough Devices Program (Breakthrough Program) that identifies the criteria FDA proposes to use to accelerate the approval time-line of certain Breakthrough Devices. As draft guidance, it provides FDA’s current thinking on a topic, but is not a legally enforceable requirement. The Breakthrough Program guidance outlines principles proposed by FDA to approve Breakthrough Devices, including: (1) a structured communication process with a collaborative, interactive approach to address the regulatory approval pathway; (2) a risk-benefit analysis balancing possible risk of harm to patients with the benefits of earlier patient access; (3) developing steps to provide scientifically appropriate, but efficient and flexible clinical trial design, if applicable; (4) required training for FDA’s review team on the requirements of the Breakthrough Program in their respective area of expertise; and (5) expedited review of manufacturing and quality systems, taking into consideration the manufacturing and quality history of the sponsor and its manufacturing sites and possible post-approval inspection. If the Breakthrough Device qualifies, the Breakthrough Program permits different approaches for FDA review, including either a “Sprint Discussion” (which is limited to a single topic with defined schedule and documentation requirements); a “Data Development Plan” (which outlines data collection expectations for the entire product lifecycle, including premarket and post-market data, clinical and nonclinical data, and reviews following the same general schedule and documentation requirements as the Sprint Discussion); or “Clinical Protocol Agreement” (which defines agreed endpoints to meet for safety and effectiveness of the device). In each case, FDA and the sponsor may agree to have regular status updates on the progress of the review and projected next steps and time-lines.
The Least Burdensome Provisions: Concept and Principles
Although the “least burdensome” concept has been in place, the original concept focused on a device’s premarket evaluation only. The Cures Act modified those least burdensome principles to apply them throughout the entire life-cycle of a medical device, both premarket and post-market, to assure the safety and effectiveness of new and existing medical devices at any point that they are available to consumers, which FDA has clarified in this guidance issued on December 15, 2017. The least burdensome concept requires the FDA to require the minimum amount of information necessary to adequately address a current regulatory question or issue. While reasonable assurance of safety and effectiveness is still required, that evidence may be provided from alternative sources of existing data, such as nonclinical data, peer-reviewed literature, non-US data, and real-world evidence, to analyze patient usage data, registries and claims data, and/or well-documented case histories. The guidance suggests that FDA and sponsors should consider the most efficient ways to obtain necessary evidence. Efforts to improve efficiency may potentially include: reducing requirements of traditional clinical studies by using historical or non-comparative control groups or study results; use of alternative study designs; streamlining of processes and administrative burdens to reduce redundancies; use of more efficient tools or methods to collect data; and in some cases, allowing sponsors to utilize post-market data to confirm safety and effectiveness.
The enactment of the Cures
Act and subsequent final and draft guidance may not reduce the requirements
that FDA assure drugs and devices are safe and effective, but they do show that
FDA is working toward finding different alternatives to bring those products to
the consumer where the benefits of the products outweigh the risks. It is encouraging
to have FDA consider how to permit sponsors of new products to use existing
real world data to support the approval or clearance of their new products and
not look at each product in a vacuum, thereby reducing each sponsor’s time and
costs to bring new and innovative products to the patients that need them. FDA
has also shown interest in bringing products to the patients more quickly where
no or only extremely limited alternatives exist. While not replacing the
existing systems, they can potentially enhance the lives of patients in a more
efficient and timely manner.
 P.L. 114-255.
 21 USC 515B(b).
 Journal of Managed Care Pharmacy, Jan/Feb. 2011 (Vol 17, No. 1), at 43.
 21 USC 814.82.
 21 U.S.C. 360c(f).
 Technical Considerations for Additive Manufactured Medical Devices – Guidance for Industry and Food and Drug Administration Staff (12/5/2017).
 Breakthrough Devices Program – Draft Guidance for Industry and Food and Drug Administration Staff (10/25/2017).
 The Least Burdensome Provisions: Concept and Principles – Draft Guidance for Industry and Food and Drug Administration Staff (12/15/2017).