Many of us are accustomed to the 65MPH speed limit of much of the U.S. interstate highway system. But one might recall that prior to 1987, when Congress passed the Surface Transportation and Uniform Relocation Assistance Act, all interstate speed limits were 55MPH. It was not until 1995 that all 50 states had adopted these increased limits across all of their rural interstates (and some urban, and some non-interstate). However, when these higher speed limits were adopted, was evidence used that demonstrated or credibly projected public safety at these higher speeds? Equally important, was there real world evidence (RWE) , that more effective (and faster) travel had been achieved without increasing harm after the speed limits had been changed?
During the coronavirus pandemic, the Food and Drug Administration (FDA) had changed its version of speed limits as well by changing the rate at which certain diagnostics and therapeutics, yet unapproved, may be brought to the market for the public good in a time of emergency. For the first time in history, an FDA Emergency Use Authorization (EUA) has included digital health tools, otherwise known as Software as a Medical Device (SaMD). What are the implications to public health and safety during this time of global emergency? Are these new “speed limits” both safe and effective?
Although not known by its current name until 1930, the regulatory functions of the FDA began in 1906. The FDA “is responsible for protecting the public health by ensuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.”  But the FDA is “also responsible for advancing public health by helping to speed innovations that make medicines more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medicines and foods to maintain and improve their health.”  There is always a balance between the need to understand the risk/benefit profile of a given product and the need to get those that are effective as soon as it is safely possible to the patients who stand to benefit.
Pumping the brakes or hitting the gas may depend on context. During the coronavirus pandemic, the calculus on the risk/benefit ratio for certain products has changed. The FDA has addressed pre- and postmarket requirements for emerging technologies by issuing EUA’s for a variety of products that are unapproved or that have not yet received approval for specific uses, including digital health applications. What does EUA mean for these products? Will experience with coronavirus EUAs change the regulatory environment in the future post-pandemic world that will move us from interstate to Autobahn speeds, or will we find a need to slow down to customary speed limits once more?
As digital health tools began hitting the market in the early 2000’s, followed by the explosion of direct-to-consumer health apps available via online app stores such as Apple’s App Store and Google Play, the lines between medical applications and consumer health applications began to blur. Unlike traditional pharmaceuticals whose processes for FDA approval followed a well-established sequence of steps, digital health tools not only could iterate and update on much more rapid cycles, but they could (and in many cases did) make claims about efficacy that had not been reviewed or substantiated. In 2016, James Madara, CEO and Executive Vice President of the American Medical Association, described the risks of “digital snake oil” to the public; digital health applications promising a variety of unsubstantiated benefits, without appropriate protections to the consumer.
In 2017, the FDA formed the Software Precertification (Pre-Cert) Pilot Program to help develop a framework for a future regulatory model for software-based medical devices. While the Pre-Cert Program is still in process, the FDA reserves “enforcement discretion” for many digital health tools. Some digital health tools, the FDA indicates, do not fall under regulatory purview. However, digital health tools which utilize the word “treatment,” diagnose a medical condition, or are designed to help individuals manage a specific medical condition are considered digital medical devices, and may be subject to FDA regulation. The FDA Pre-Cert program aims to use a framework developed by the International Medical Device Regulators Forum (IMDRF) to risk stratify SaMD into four categories based on the state of the patient or user’s healthcare condition, and the intended function of the software. The higher the risk, the more appropriate would be the regulation.
In October 2019, the FDA updated its software categories in its “Policy for Device Software Functions and Mobile Medical Applications,” outlining which categories are subject to FDA regulation or enforcement discretion, and provided examples of device functions which it did not plan to regulate. (Table 1)  In October, 2019, the FDA revised its interpretation of the 21st Century Cures Act, which modified the Federal Food, Drug, and Cosmetic Act to exclude specific types of clinical decision support software from FDA regulation, with new enforcement discretion guidance.
Shortly thereafter, the world found itself in a pandemic.
|Use of patient characteristics (e.g. age, sex, and behavior) to “provide patient-specific screening, counseling, and preventive recommendations from well-known and established authorities”|
|Use of checklists of common signs and symptoms to “provide a list of possible medical conditions and advice on when to consult a health care provider”|
|Use of a questionnaire of signs and symptoms to “provide a recommendation for the type of health care facility most appropriate” to a user’s needs.|
|Software to allow a user to place a “pre-specified nurse call or emergency call using broadband or cellular phone technology”|
|Create and send an “alert or general emergency notification to first responders.”|
In March, 2020, following the widespread outbreak of SARS-CoV-2 in the U.S., the federal government declared a Public Health Emergency. In response, the FDA authorized emergency use for a variety of unapproved medical products or unapproved uses of approved medical products “to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions.”  While many included product categories were devices, diagnostic tests, or pharmaceuticals, regulations around certain digital health products were also relaxed as part of the FDA’s risk/benefit analysis of these software technologies. In essence, the bar for demonstrating efficacy during an emergency may be lowered. The FDA stated that “Medical products that may be considered for an EUA are those that “may be effective” to prevent, diagnose, or treat serious or life-threatening diseases or conditions…The ‘may be effective’ standard for EUAs provides for a lower level of evidence than the “effectiveness” standard that FDA uses for product approvals.” 
What makes current times dramatically different are the first FDA EUAs encompassing digital health tools. For example, the H1N1 outbreak in 2010 resulted in an EUA for the unapproved off-label use of several anti-virals, the MERS outbreak in 2013, the several Ebola outbreaks following 2015, and the Zika virus outbreak in 2016, resulted in EUAs for diagnostic tests. But new to EUAs are SaMD products.
Four broad areas touching digital health have seen EUA declarations that have changed the speed limits for innovation, development, and implementation.
The digital mental health space has been a primary beneficiary of the FDA’s 2020 EUAs. In April, 2020, the FDA issued guidance on its enforcement policy for digital health devices intended to treat psychiatric disorders during the coronavirus pandemic. The important goal was to make sure that digital health therapeutic devices for psychiatric conditions could increase patient access during stay-at-home orders. Examples included computerized behavioral therapy devices used as adjuncts to clinician supervised outpatient treatment plans, and low risk general wellness and mental health or psychiatric illness digital health tools that do not create an undue risk in light of the public health emergency. Tools creating undue risk would include those involving “underlying psychiatric condition[s that] may require an urgent or immediate clinical intervention and the delay of the intervention may pose significant harm to the patient, such as treatment of suicidality.”
This deregulation coincided with unparalleled consumer demand for mental health apps and at-home therapies during social distancing and shelter in place orders. For example, January of each year is a common time for surges in mental health app downloads related to new year resolutions, but that surge is usually transient. Between January and April of 2019, there was a 30% drop in mental health app downloads. But in the same timeframe in 2020, there was actually a 29% increase, reaching as many as 4.1 million downloads, and demonstrating the public demand for mental digital health applications during the pandemic.
There are several examples of direct beneficiaries of the digital mental health EUA put in place. Akili Interactive, for example, had been in the process of seeking FDA clearance for its product EndeavorRx™, a gaming device to improve inattention or combined-type Attention Deficit Hyperactivity Disorder in children between the ages of 8 and 12.  While EndeavorRx™ was granted clearance in June, 2020 based on evidence from five clinical studies, including a prospective, randomized, controlled study,  the early approval of the application during the COVID pandemic was a signal consistent with the FDA’s efforts to streamline the process for getting mental health apps into the hands of users during the pandemic.
An earlier stage application, Pear Therapeutic’s unapproved product Pear-004, offering people with schizophrenia access to cognitive behavioral therapy and training, was planning formal trials to support FDA approval. Pear-004 was fast tracked to go to market under an EUA.  Although the EUA waived certain requirements to submit clinical trial data for those companies applying for FDA approval, the FDA nevertheless requires companies to establish appropriate security, analyze hazards, and advise users to consult their physicians.
However, the risk of easing off the brakes and relaxing regulation also comes with risk of “bad actors” aiming to take advantage, such as those apps claiming that they can treat mental illness by playing vital tones and harmonics  or worse, those apps listing non-existent or inaccurate suicide crisis hotline numbers.
In June 2020, the FDA issued guidance for remote monitoring devices that had previously been granted approval by the FDA, allowing device manufacturers to make software and hardware modifications to support COVID-19 care without filing a new premarket submission. Specifically, the FDA policy notes that “Software, including mobile apps, may be useful in connection with monitoring for patients with COVID-19 or co-existing conditions and providing clinical decision support.“ 
In June, 2020, Philips was able to deploy its IntelliVue Patient Monitors and Active Displays for remote patient monitoring and clinical decision support under the EUA. These monitors and displays were already being used in hospitals across Europe, but the EUA enabled their deployment to U.S. hospitals in an expedited manner.  Without thorough premarket review, these risks under EUA may be unknown.
Class II medical devices, which represent approximately 43% of medical devices, are those tools that often carry moderate risk to the user. Examples of these types of devices include catheters, contact lenses, blood pressure cuffs, pregnancy test kits, and surgical gloves. Because most Class I devices are exempt from premarket notification, the lowest class of medical device available for relaxation under an EUA, is Class II. Guidance provided by the FDA under the EUA pertained to Class II devices, which covers a variety of functions including non-invasive remote monitoring devices such as telephone EKG transmitting and receiving devices, and connected spirometers, peak flow meters, and apnea monitors.
Specific examples of companies that have been granted EUA include VitalConnect, for its disposable, adhesive, wearable sensor VitalPatch to be used for remote monitoring in the hospital. VitalConnect monitors a patient’s QT interval (the duration of time between the q-wave and t-wave on an EKG), which can change as a result of certain medications and be a warning indicator of cardiac arrhythmias. 
Others include blood glucose meters such as those from Livongo, which had previously only been used in the home setting, but now may be used in the hospital setting as well. Devices for remote ophthalmic monitoring have also seen EUA authorization. Items such as ophthalmic cameras and tonometers will be allowed to be modified within certain parameters such as healthcare to home use and mobile technology additions for remote monitoring, as long as they “do not create undue risk in light of the public health emergency.” 
In a rare move, the FDA issued guidance on its “enforcement discretion” with regard to location-monitoring and public health surveillance digital tools, turning their deployment and management over to state and local health departments – a move that can potentially decentralize the digital health ecosystem of the future by opening the door for more state and local stakeholder engagement in the regulatory process. The FDA stated it “does not consider most apps and software systems for public health surveillance and communication to be medical devices regulated by the FDA. These are mobile apps or solutions that are intended for use by public health officials at the CDC and at state and local health departments to improve communication between public health officials and members of the public, including by people who may have been exposed to a disease of interest to public health officials, such as COVID-19.” 
Furthermore, the FDA has issued temporary regulatory relief for digital health technologies designed to facilitate social distancing and COVID-19 monitoring, creating new flexibilities for device manufacturers looking to reposition products to aid in the pandemic control effort.
In November of 2019, Germany approved its landmark Digital Healthcare Act (DVG) which provides for the regulation, evaluation, and reimbursement for prescribing digital health tools. After an app, for example, has been “tested for safety, functionality, quality, data security and data protection by the Federal Institute for Drugs and Medical Devices (BfArM), it will provisionally be reimbursable by the statutory health insurance for the period of one year. During this period, manufacturers must prove to the Federal Institute that their app improves patients’ healthcare. Manufacturers then negotiate the amount of money they will receive for the app with the Central Federal Association of the Health Insurance Funds.”  Although the approval of this act pre-dated the pandemic, it marked a milestone in resetting German speed limits to bring such tools to market, and then to use postmarket RWE for decisions about ongoing use and reimbursement. Furthermore, well into the pandemic, on April 9, 2020, the Digital Health Applications Ordinance (DiGAV) went into force, regulating the review of reimbursement eligibility of digital health applications by payers.
What about the rest of the European Union? How have member countries responded in kind to concepts analogous to EUAs in the U.S.? As if in anticipation of the public health emergency, the World Health Organization released its updated Emergency Use Listing procedure guidelines on January 9, 2020, although it did not offer any specific guidance on digital products. Meanwhile, the existing EU Medical Device Regulation (MDR) of 2017, which had been set to transition to an updated set of regulations in May, 2020, including updates addressing a number of digital health technology capabilities requisite to meet the CE mark (a mark that in the EU demonstrates a manufacturer’s declaration of compliance with certain directives), was postponed for 1 year due to the pandemic, and an amendment document published in April, 2020.  Specifically, under the amendment, individual member states of the EU would be authorized to market medical devices without a CE mark in the event of a public health or patient safety interest, offering a speed-to-market approach similar to EUAs in the U.S.
Although we do not have history to guide us on the impact of EUAs for digital health tools, we may be able to learn from the outcomes of other speed limit changes. Following Congress’ 1987 Surface Transportation and Uniform Relocation Assistance Act that allowed for increased interstate speed limits, it took years of real world evidence to determine the safety outcomes of such changes. Some studies suggested, for example, as much as a 3.2% increase in road fatalities (12,545 additional deaths) and 36,583 additional injuries in fatal crashes between 1995-2005 that were attributable to the raised speed limits across the U.S.  Rural interstates, with an increase of 9.1% fatalities, were the hardest hit.
Such additional morbidity and mortality is alarming and tragic in its own right, but what does it mean when these sorts of results only become available years or decades after the policy changes go into effect? Does real world evidence move at a pace too slow for us to course correct if we find negative outcomes?
The current FDA “speed limit” changes associated with COVID EUAs may help get needed digital therapies into the hands of patients during the emergency, and they may pose either necessary or unnecessary risks. It is likely that only time will tell whether these new speed limits should become the norm, or the merely the norm in times of national emergency. However, speedier approaches can have pitfalls in that they make it “easier for products that are marginally effective – or outright ineffective – to slip into the system. [In the case of EUAs for medications, for example] ‘Drugs Into Bodies’ too easily devolves into bad drugs delivered into vulnerable bodies.” 
Fortunately, RWE with digital health tools moves at the speed of digital, not the speed of pharmaceutical, and hopefully, we will be informed about the effects of these new speed limits at feedback rates never before possible. In the end, as eloquently stated by Siddhartha Mukherjee, in the New Yorker “Before the next public-health crisis emerges, the F.D.A. must think hard about how to balance speed and oversight, adjusting the ratio to meet the moment but abandoning neither.” 
Please join us for NODE.Health’s live webinar on FDA speed limits during COVID-19 and beyond accompanying this article, with guest panelists Dr. Eric Topol of the Scripps Research Translational Institute and Bakul Patel of the FDA on August 19, 2020 from 3-4p Eastern time. Register at https://bit.ly/2PTJWjR
NODE.Health Foundation is a 501(c)(3) non-profit organization dedicated to education, validation and dissemination of evidence based digital medicine. As the largest professional association in digital medicine, NODE.Health empowers societies, executives and NODES from health systems, payers, life sciences, venture capital, startups and the public sector involved in healthcare digital transformation. NODE.Health does not endorse any specific products or services.
NODE.Health is pleased to offer this article on FDA developments in the digital health regulatory environment. As more developments come out on guidance and regulations governing digital health tools, NODE.Health will keep its readers updted. Interested in learning more about the Network of Digital Evidence (NODE.Health) and becoming a member? Click here
For inquiries and permissions to republish this article, please contact us at [email protected].